tbuckley/cabot-search huggingface dataset:
P16.03.A GEMOX ADD-ON AFTER THE ITALIAN INDUCTION CHEMOTHERAPY SCHEME IN MALIGNANT BRAIN TUMORS UNDER 3 YEARS
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, C Caporalini, F Giordano, V Tintori, L D’Incerti, M Scagnet, L Genitori, I Sardi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Gemcitabine plus oxaliplatin chemotherapy (GemOx) represents a possible option in advanced hepatocholangiocarcinoma and pancreatic cancer of adulthood. Considering the pediatric population, it was evaluated in recurrent solid tumors and in children with non-Hodgkin lymphoma unable to tolerate intensive therapy. We report our single-center experience on the applicability of GemOx in infant type brain tumors. MATERIAL AND METHODS At the Meyer Children’s Hospital IRCCS in Florence (Italy), from May 2017 to April 2024, seven children received GemOx after induction chemotherapy delivered according to Italian program for malignant brain tumors under 3 years (AIEOP SNC INFANT). The median age at diagnosis was 14 months, the female/male ratio was 1.3, histology was: three high-grade gliomas, a metastatic medulloblastoma MM, a pineoblastoma, a choroid plexus carcinoma CPC, a pilomyxoid astrocytoma progressed during first line chemotherapy. GemOx was administered to ascertain a more stable disease control and to allow a better recovery from the induction chemotherapy, especially in prevision of high-dose chemotherapy, but also to consider the possibility of a second look neurosurgery. Response was evaluated maximum every four cycles and assessed according to RECIST criteria. RESULTS Gemcitabine 1000 mg/m2 and Oxaliplatin 100 mg/m2 were administered every 14-28 days for 1-11 cycles. Five patients presented stable diseases and two partial responses. GemOx treatment allowed further neurosurgery in one patient (MM). The treatment was overall well tolerated. The most common toxicities were hematological (reaching neutropenia and thrombocytopenia Common Terminology Criteria for Adverse Events grade 4). Six patients were safely exposed to HDC (1-2 courses), another patient is on GemOx treatment. Two patients (MM and CPC) progressed respectively 4 ad 19 months after the end of GemOx: considering the achievement of permissive age also through the bridge therapy, it was possible to expose both to radiotherapy (the latter after a second look neurosurgery). To date all patients are alive and in good clinical condition. CONCLUSION Infant brain tumors represent an extremely challenging subgroup, due to the vulnerable age, with subsequently major risk of therapy-related sequelae and limitation of therapeutic instruments. In the event that a bridge strategy is temporarily warranted, GemOx add on should be considered as a safe option. In our limited and heterogenous cohort, it permitted disease control during the awaiting period, and it was crucial for the patients’ course, especially when a palliative perspective emerged to the lack of other feasible strategies expecting induction therapy recovery.
P01.04.B DISSECT THE ROLE OF DRIVER GENE MUTATIONS IN THE INITIATION AND PROGRESSION OF GLIOMA
Authors: A Tian
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Cancer initiation and progression are always associated with the acquisition and accumulation of genetic mutations which drive the malignant transformation of the cancer cells of origin. It has been shown that different driver mutations can generate tumors with distinct pathological features. How driver mutations interact with tumor cells of origin and how such interactions dictate the fate of the cell of origin and the tumor pathological features are the fundamental questions in cancer biology. MATERIAL AND METHODS We developed a set of novel “all-in-one” glioma lineage-tracing model system based the intra-brain ventricle electroporation and transposon-mediated conditional gene editing techniques. By using this system in genetically engineered mouse models, we generated glioma models with the top driver mutation combinations found in IDH-WT GBM patients and trace their initiation and progression with single-cell resolution, therefore we combined lineage tracing with multi-omics analysis almost recapitulating the full driver-mutation spectrum found in glioblastoma patients. RESULTS We found that driver gene mutations combinatorially dictate the early cell fate of tumor development. Driver gene mutations and cell fate combinatorially determine the prognosis and malignancy of glioma. Driver gene mutations combinatorially affect the molecular phenotypes and the treatment of end-stage tumor via deterministic CNVs. Synergistic or exclusive patterns of driver gene mutation combinations regulate the initiation and progression of gliomagenesis. CONCLUSION The results will help to address those fundamental questions pertinent to the relationships between driver mutations, tumor evolution pathways and the final tumor phenotypes. The results will also help to understand the nature of gliomagenesis and to develop novel approaches for glioma intervention and treatment.
OS07.6.A CONNEXIN-MEDIATED NETWORKS IN GLIOBLASTOMA COMMUNICATION
Authors: H Strobel, M Mulaw, G Karpel-Massler, A Peraud, K Debatin, A Westhoff
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Recent data suggest that Glioblastoma (GB), a highly aggressive malignant brain tumor, mimics cellular interactions found in healthy brain structures. GB cells exhibit, among other types of interaction, extensive membrane protrusions linked through gap junctions (GJs), tightly regulated intercellular channels predominantly comprised of connexins (Cxs). These channels facilitate the exchange of small molecules and also provide platforms for signaling hubs. Consequently, GJs/Cxs interconnect GB cells into expansive communicative networks that substantiate tumor growth, migration, and influence the response to injury. In this investigation, we delineated the precise composition of Cxs in brain tumors, with a specific emphasis on GB, unraveling their nuanced functional roles. MATERIAL AND METHODS Using our exclusive repository of primary brain tumor specimens, we screened for the expression of all 21 known Cxs. By comparing our findings with publicly available RNA sequencing data sets and performing various in silico analyses, we identified Connexin 26 (Cx26) as an interesting candidate. The role of Cx26 in a defined signaling network was further elucidated by pharmacological modulation as well as genetic knock-out models. RESULTS We found a multitude of Cxs expressed in brain tumors, many of them dysregulated when compared to their expression in healthy brain cells. Additionally, by utilizing in silico analyses of publicly accessible RNA sequencing datasets, the expression of Cx26 emerges as a potential biomarker, correlating significantly with the overall survival of GB patients. Notably, subsequent analysis affirms that Cx26 expression is highest in grade IV brain tumors and in GBs, it exhibits a pronounced association with the mesenchymal subtype. Within the tumor, its expression is most notably concentrated in the tumor core and aligns with the recently described Connectivity Signature. The genetic manipulation of Cx26 exerted a profound impact on cellular behavior. Notably, the knock-out of Cx26 significantly impeded the cells’ ability to establish morphological networks when cultured in the presence of an extracellular matrix substrate. Furthermore, pharmacological modulation of these cells suggests Cx26 as a prospective mediator in facilitating TGF-β1-associated cell-cell communication. CONCLUSION Cx26 is a novel mediator of connectivity that facilitates cell-cell interaction in the recently described network that characterizes a particular aggressive GB subpopulation. This effect seems to be associated with the tight regulation of the TGF-β1 signaling cascade.
P01.02.B CLONAL ARCHITECTURE, 3D TUMOR GROWTH, TRANSCRIPTIONAL STATES AND IN-VITRO DRUG RESPONSE IN GLIOBLASTOMA
Authors: Y Song, Y Miller-Michlits, L Greutter, K Nenning, B Kiesel, D Loetsch-Gojo, V Redl, J Gesperger, J Jana Breu, D Nam, G Widhalm, J K Sa, A Woehrer
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) is one of the deadliest types of cancer with median overall survival of little more than a year. It is the prototypic example of a molecularly diverse tumor associated with multiple subclones and high transcriptional plasticity. We here set out to map the clonal architecture and link it with growth patterns, transcriptional states and drug response in-vitro. MATERIAL AND METHODS Seventy-eight multiregional samples from 24 GBM patients (F/M ratio = 0.60, median age= 65.5ys) were profiled using deep whole-exome sequencing with a nominal coverage of &amp;gt;300x. Clonal complexity was assessed by the Euclidean distance based on somatic mutations between regions. Molecular distance was integrated with 3D neuronavigation-based physical distances and patient survival. Fresh tumor slices of 8 patients were cultured in minimal essential media and treated with 4.2Gy plus 200µM temozolomide for 48h. Spatial Transcriptomics was performed on matched tumor slices with /without treatment. RESULTS Integrative characterization revealed two evolutionary trajectories termed expansive and stochastic diversification based on the correlation between physical and molecular distance (RE=0.6, RS=-0.2). High molecular distance was associated with reduced PFS (R=-0.5538, p=0.026). Tumors with expansive evolution demonstrated volume-based growth that directly correlated with increased molecular diversification, while stochastic models showed irregular and discordant patterns. Patients with stochastic evolution were characterized by unfavorable prognosis (p= 0.35) and tumors appeared more frequently in the frontal lobe. In-vitro drug response varied considerably between patients based on cell proliferation (minus 0.5-13.8%), apoptosis (30.1-44.4%), and viability (minus 7.8-34.1%). Under treatment an increase of mesenchymal states with peculiar redistribution of transcriptional patterns and increased clonal complexity was observed. CONCLUSION In sum, we report on an ongoing study in glioblastoma that seeks to link the clonal architecture with tumor growth, transcriptional patterns and in-vitro drug response. Our study will provide new insights into the clinical relevance of the clonal composition of this deadly cancer.
P18.41.A SINGLE CENTRE EXPERIENCE OF BENEFIT OF CHEMOTHERAPY WITH 40GY/15# RADIOTHERAPY IN PATIENTS WITH GLIOBLASTOMA MULTIFORME (GBM)
Authors: K Streatfield, A Davies, J Glendenning, S L Forner
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND GBM patients are associated with a poor prognosis. Hypofractionated radiotherapy (RT) - 40Gy/15# - is standard in the older population (&amp;gt;70), lower performance status and in extensive disease. This regimen provides a median overall survival (mOS) of 8 months and progression free survival (PFS) of 3.9 months (1). The addition of Temozolomide increases outcomes (mOS 9.3 months, PFS 5.3 months). Methylated MGMT status further improves mOS to 13.5 months (2). This review analyses outcomes of patients treated with this regimen at the Kent Oncology Centre (KOC). MATERIAL AND METHODS A retrospective review of GBM patients at the regional KOC treated with the 40Gy/15# regimen between 2018 and 2022. Demographics, histology, treatment and survival data were gathered through electronic records. Statistical information was gathered using Python and the Lifelines survival analysis library. RESULTS Data was collected for 82 GBM patients with a 33-80 age range. Of the cohort, 39 patients (48%) were female and 43 were male (52%). Type of surgery was divided into biopsy (46%) and debulking (50%), with the remaining not applicable. Within the cohort, 27 patients received temozolomide with RT, with an average of 5 adjuvant cycles received; the remaining receiving RT alone (55). 28 patients were MGMT methylated, 48 unmethylated, with the remaining unknown. mOS for the total population was 8 months. In MGMT methylated patients, OS increased to 13 months. In the sub group of unmethylated patients OS increased to 10 months with the addition of temozolomide, compared to 7 months for radiotherapy alone. PFS was measured as the time between the date of action sheet and date of first progression. For the whole cohort this was 4 months, however this increased to 5 months for the methylated cohort. The addition of temozolomide for unmethylated patients showed no improvement for PFS. CONCLUSION Local results support previously published trial data, validating the use of chemotherapy for GBM patients, regardless of MGMT status, with additional overall survival benefit. However, unmethylated patients saw no additional PFS benefit from temozolomide.
P16.06.B PROTEOMIC ANALYSIS OF PEDIATRIC-TYPE DIFFUSE HIGH-GRADE GLIOMAS
Authors: S Ferreyra Vega, H Carén
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric-type diffuse high-grade gliomas (pHGGs) are among the most lethal primary brain tumors in children, which lacks effective treatment. Glioma stem cells are thought to play a key role in tumor initiation, regrowth, and treatment resistance. We therefore profiled the proteomic landscape of pHGG stem cells to identify novel molecular drivers and therapeutic targets in this disease. MATERIAL AND METHODS Large-scale proteomic data was acquired from patient-derived pHGGs stem cell lines and neural stem cell lines (NSCs) using Tandem mass tag mass spectrometry. Differentially expressed proteins between pHGGs and NSCs were examined. Selected relevant proteins were validated by western blot and immunocytochemistry. RESULTS A total of 8499 proteins were identified and quantified by mass spectrometry, of which 557 were significant differentially expressed proteins between pHGGs and NSCs. We found 240 proteins to be upregulated in pHGGs compared to NSCs, while 317 proteins were downregulated in the tumor group. Enrichment analysis of differentially expressed proteins revealed significant alterations in biological processes related to RNA processing, ribosome biogenesis and cell division. CONCLUSION The study provides insights into important pathological mechanisms implicated in pHGGs and highlights novel therapeutic targets of potential clinical significance.
KS04.5.A DIFFERENCES IN COGNITIVE FUNCTIONING BETWEEN PATIENTS WITH IDH1-MUTANT OLIGODENDROGLIOMA AND ASTROCYTOMA BEFORE AND AFTER SURGERY
Authors: M Landers-Wouters, E Butterbrod, B Brouwers, G Rutten
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Alongside differences in growth rate, IDH1-mutant oligodendroglioma and astrocytoma exhibit differences in growth pattern. Whereas oligodendroglioma seem to infiltrate subcortical tracts, astrocytoma tend to displace them. Tracts traversing a tumor are more likely to be damaged during surgical resection than displaced tracts, possibly resulting in a (temporary) worse cognitive outcome. This study explored differences in cognitive functioning before and after surgery between patients with IDH1-mutant astrocytoma and oligodendroglioma. MATERIAL AND METHODS Patients who underwent surgery for confirmed IDH1-mutant, WHO grade 2 or 3 oligodendroglioma (1p19-codeleted) or astrocytoma were included. Cognition was assessed with computerized and paper-and-pencil tests before surgery, and 3 and 12 months after. Test scores were standardized. Diagnostic groups were compared on sociodemographics, tumor location, awake vs. asleep surgery, type of mapping, extent of resection (EOR), adjuvant treatment and baseline cognition. We performed longitudinal mixed models (LMM) to investigate differences in performances over time in the total sample and stratified according to surgical modality (awake or asleep), α=.05. We first examined the effect of diagnosis only, and subsequently with correction for group differences. RESULTS Compared to astrocytoma patients (n=95), those with oligodendroglioma (n=67) were significantly older, more often harbored a tumor located in the frontal lobe, and less often in the temporal lobe. Gross total resection (vs. subtotal) was more frequently achieved in oligodendroglioma surgery. Diagnosis was not related to any baseline test performance, but WHO grade (3 vs 2) was. In univariable LMM, oligodendroglioma patients performed worse than astrocytoma patients on cognitive flexibility over time. This effect was most apparent in the first time interval (astrocytoma: B= -0.45, oligodendroglioma: B=-0.84), after which both groups improved (B=0.23, B=0.24). Stratification showed no effect of diagnosis on longitudinal performances in the awake surgery group, but there was a difference between diagnoses on cognitive flexibility in the asleep surgery group, where astrocytoma patients remained stable (B=-0.01) while oligodendroglioma declined significantly (B=-0.55). Differences were not significant after correcting for baseline differences and EOR. Age and EOR were associated with multiple performances. CONCLUSION Differences in cognitive trajectories between patients with IDH1-mutant oligodendroglioma and astrocytoma seem explained by other patient and tumor characteristics or surgical factors rather than tumor type. Studies directly linking pre- and postoperative tract integrity to test performances can enhance understanding of the interplay between tumor growth pattern, surgical resection and cognitive outcome.
P18.44.B THE IMMUNE CELL INﬁLTRATION IN PERIVASCULAR AND INTRATUMORAL OF EPITHELIOID GLIOBLASTOMA
Authors: s jiang, q yan, y wu, j zeng, s xi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Epithelioid glioblastoma (eGBM) is a rare subtype of adult glioblastoma(GBM)and was proven to portend an extremely poor prognosis. Perivascular lymphocyte proliferation was commonly observed in eGBM. To disclose the relationship between the tumor’s microenvironment and survival and clinical implications in eGBM, we collected the eGBM cases and conducted a study on the tumor microenvironment of eGBM. MATERIAL AND METHODS We collected 38 cases of eGBM, 36 cases of typical adult glioblastoma with IDH and H3 wildtype (typical GBM), and 7 cases of inflammatory tumor-like demyelinating diseases (ITDD) from the Sun Yat-sen University Cancer Center, as well as 4 cases of ITDD from Guangzhou Sanjiu brain Hospital. Tumor-infiltrating immune cells including CD4, CD8, Foxp3, and CD20 positive cells, and tumor-associated macrophages (TAMs), including CD68, CD80, and CD163 positive cells, were performed by immunohistochemical staining (IHC). Under the high-power microscope, two hot spots were selected to quantify the positive immune cells of the tumor center and perivascular lymphocytes, respectively. PD-L1 was also detected by IHC and analyzed by combined positive score (CPS) in eGBM. Nonparametric and chi-square tests were used for intra-group and inter-group comparisons. Overall survival was calculated via Kaplan-Meier estimation using the log-rank test. RESULTS Compared with typical adult GBM, perivascular lymphocyte proliferation was more common in eGBM (23/38 vs 4/36, p &amp;lt; 0.001). The counts of CD68+ and CD163+ macrophages in the intratumoral zone were significantly higher than in the perivascular zone in eGBM (Median(cells /HPF):29 vs 7.25, p=0.002, 184.75 vs 78, p&amp;lt;0.001, respectively), while CD20+ lymphocytes were lower (Median(cells /HPF): 3.75 vs 27, P=0.03). Overall, the most common type of immune cells is CD163+ macrophages in both the perivascular zone and intratumoral zone of eGBM (Median=184.75 cells/HPF, P &amp;lt; 0.001), and the higher intratumoral CD163 count is an unfavorable prognostic factor for eGBM (OS:11.1 months vs 15.09 months, p=0.023). We also found that the high CD4/CD8 ratio of perivascular lymphocytes predicted a worse prognosis of eGBM (OS:8.77 months vs 15.66 months, p=0.02). The incidence of PD-L1 expression in eGBM patients is frequent, with 16/38 cases showing a CPS score ≥1. Compared with typical GBM and IDD, the count of intratumoral CD163+ macrophages in eGBM was significantly higher than that in typical GBM (Median(cells /HPF):184.75 vs 141, p =0.048), and the number of perivascular Foxp3+ lymphocytes of eGBM was less than that of tumor-like IDD (Median(cells /HPF):0 vs 2, p =0.044). CONCLUSION The immune microenvironment of eGBM consisted of the immune cell inﬁltration in the perivascular and intratumoral zones, and significantly differed from that of typical GBM and tumor-like IDD, which may contribute to the poor prognosis of eGBM.
P22.16.A THE EXPERIENCE OF LIVING WITH MALIGNANT MENINGIOMA
Authors: A D Maier, S Nordentoft, T Mathiesen, R Guldager
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Meningiomas are the most common, primary intracranial tumor and most are benign. Little is known of the rare patient group living with a malignant meningioma, comprising 1-3% of all meningiomas. Our aim was to explore how patients perceived quality of daily life after a malignant meningioma diagnosis. MATERIAL AND METHODS This qualitative explorative study was composed of individual semi-structured interviews. Eligible patients (n = 12) were selected based on ability to participate in an interview, from a background population of 23 patients diagnosed with malignant meningioma at Rigshospitalet from 2000 to 2021. We performed an inductive thematic analysis following Braun and Clarke’s guidelines. RESULTS Eight patients were interviewed. The analysis revealed 4 overarching themes: (1) perceived illness and cause of symptoms, (2) identity, roles, and interaction, (3) threat and uncertainty of the future, and (4) belief in authority. The perceived quality of daily life is negatively impacted by the disease. Patients experience a shift in self-concept and close interactions, and some struggle with accepting a new everyday life. Patients have a high risk of discordant prognostic awareness in relation to health-care professionals. CONCLUSION We provide a much-needed patient-centered perspective of living with malignant meningioma: quality of life was affected by perception of threat and an uncertainty of the future. Perception of illness and the interpretation of the cause of symptoms varied between subjects, but a common trait was that patients’ identity, roles, and interactions were affected. Shared decision-making and a strengthened continuity during follow-up could aid this rare patient group.