tbuckley/cabot-search huggingface dataset:
P18.24.A GLIOBLASTOMA INVASION OF NEURAL STEM CELL REGIONS; MOLECULAR PATTERNS AND SURVIVAL RATES
Authors: A Chaudhary, S Lammy, A Grivas
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma is a very aggressive form of brain cancer and poses a challenge in treatment due to its profound heterogeneity and capacity for extensive infiltration into the brain parenchyma. Research has shown glioblastomas in close proximity to the ependyma have poorer survival rates. Therefore, our aim was to identify distinct molecular features of grade 4 glioma invading ependyma of lateral ventricles and neural stem cell region and the survival prognosis of these patients. MATERIAL AND METHODS Retrospective review of 180 patients with a new histologically confirmed diagnosis of grade 4 glioma between 2018 and 2019. Patients excluded if less than 18-years-old, did not have a histological diagnosis, or had missing data. Analysis of anonymised patient data were conducted with ethical consent from NHS GGC Caldicott Guardian. SPSS version-28 used for statistical analysis. RESULTS Average age of all patients was 59 +/-12.3 years with 54% male and 46% female. 170 tumours were identified as IDH-wildtype (IDHw), while 10 were IDH-mutant (IDHm). Of the total 180 patients, 77 tumours contacted the ependyma, with 10.4% being IDHm and 89.6% IDHw. 103 tumours were identified as ependymal non-contacting with 2% being IDHm and 98% IDHw. Statistically significance association found between IDH mutations and ependymal contact (p-value 0.02). For both groups, majority of the tumours were unmethylated, with 57% for contacting and 65% for non-contacting tumours. However, no statistically significant associations were observed between MGMT methylation status and ependymal-contact (p-value 0.35). For IDHw glioblastomas, over half of the tumours for ependymal contact and ependymal non-contact were unmethylated (61% and 65% respectively). Mean overall survival (OS) for all patients was 16.6 (CI 19.0, 14.1) months. OS was lower in ependymal-contact tumours compared to non-ependymal contacting tumours (14.9 months compared to 17.5 months respectively, however this was not significant (p-value 0.11). Sub-analysis of IDHw glioblastomas showed reduced survival by ependymal contact with mean OS of 11.9 months compared to 17.4 months for non-contacting IDHw tumours (p-value 0.004). Mean epicentre distance for ependymal contacting MGMT methylated tumours was 17.7mm compared to 15.6mm for MGMT unmethylated contacting tumours. Statistically significant association found between epicentre distance and methylation status of ependymal-contacting tumours (p-value 0.008). No statistically significant associations found between epicentre distance and IDH status of ependymal-contacting tumours (p-value 0.23). CONCLUSION We have found that ependymal contacting tumours are more likely to be IDHw and MGMT unmethylated. Adjusted analysis showed ependymal-contact to lower survival rates and IDHw contacting tumours to also have poorer survival outcomes.
P13.06.A EVALUATION OF BBB PERMEABLE WEE1 AND CHK1 INHIBITORS IN COMBINATION WITH STANDARD OF CARE FOR THE TREATMENT OF GLIOBLASTOMA
Authors: E L Scholefield, N Gomez-Roman
Journal: Neuro-Oncology (2024)

Abstract 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.
P22.04.B BALANCING COMMUNICATION CHALLENGES IN NEURO-ONCOLOGY: A CROSS-SECTIONAL INTERVIEW STUDY WITH NEURO-ONCOLOGY HEALTHCARE PROFESSIONALS
Authors: D M Legge, M Jeon, H Banks, J Shaw, S He, T Carlick, L J Breen, R Laidsaar-Powell, G K B Halkett, H Dhillon
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Primary brain tumours are associated with a significant symptom burden and high supportive care needs, presenting in varied and unique ways along the disease trajectory. Timely and comprehensive patient navigation is vital to ensuring both people with brain tumours (PwBT) and their caregivers have the resources and support needed to negotiate the multidisciplinary team, treatment pathways and survivorship care. We explored HCPs’ experiences and perceptions of the particular challenges in communicating with PwBT and their families. Material and Methods:This study formed part of a qualitative exploratory study investigating the roles, training and support needs of healthcare professionals involved in neuro-oncology care coordination (NOCC) for PwBT and their families. Semi-structured interviews were conducted with HCPs via videoconferencing and were audio-recorded and transcribed. Questions focused on communication experiences and challenges in the NOCC role. Themes were developed in the data using interpretive description with three coders using NVivo v14 software. RESULTS Interviews were conducted with 12 HCPs between June and November 2023, lasting a median of 58 (range: 43-82) minutes. Participants were from Australia and Aotearoa New Zealand with a median of 13 years of neuro-oncology clinical experience across medical, nursing, and allied health disciplines. An overarching meta-theme of ‘communication is key’ was identified and supported by three themes describing the elements of communication in neuro-oncology: 1) In safe hands; describing the way care is navigated for patients and families, and the importance of providing a safety net during diagnosis and early treatment; 2) Delicate balance; recognising elements of communication needing to be balanced during each interaction. Balancing hope with reality, family with patient needs, process with time. 3) Creative communication; describing the importance of creative and adaptable communication styles required for NOCC. CONCLUSION Our results highlight the unique challenges and complex nature of communicating with PwBT and their families and the pivotal nature of communication in NOCC. The findings will support the development of training and support for health professionals already working within neuro-oncology and assist in defining the core skill set and training needs of health professionals seeking to move into this area of practice.
P18.01.A ADAPTER FITC CAR T-CELLS PLUS OCTOFLUO FOR THE TREATMENT OF GLIOMAS VIA SSTR2
Authors: J Chen, C Pellegrino, P Roth, D Neri, M G Manz, M Weller, H Wirsching
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Somatostatin receptor (SSTR) 2 has been proposed as a target to deliver therapeutic agents to gliomas. The SSTR2 antagonist peptide octofluo was developed to redirect fluorescein-5-isothiocyanate (FITC)-specific adapter chimeric antigen receptor (AdCAR)-T cells towards SSTR2-expressing tumor cells. MATERIAL AND METHODS A tissue microarray of glioblastoma patient samples (N=161) was stained for SSTR2. Octofluo was used as an adapter to direct FITC-specific human CAR-T cells against glioma cells. The SSTR2- glioma cell line LN229 was lentivirally transduced to express SSTR2 and Luciferase. Flow cytometry-based killing assays were conducted in vitro. Tumor growth assessed by bioluminescence imaging and symptom-free survival were assessed in the orthotopic LN229 xenograft model. Mice harboring SSTR2+ or SSTR2- LN229 tumors were treated with two intratumor (i.t.) injections of CAR-T cells and every other day intravenous (i.v.) octofluo. RESULTS SSTR2 was highly expressed in a subset of glioblastomas (13%). In vitro, 10 nM was determined as the optimal concentration of octofluo, yielding tumor cell killing of SSTR2+ LN229 cells within 72 hours at effector-to-target cell (E:T) ratios as low as 1:10 in (CAR vs untransduced T cells 22 % vs 4 %, p &amp;lt; 0.001) and almost complete killing of tumor cells at an E:T ratio of 1:1 (CAR vs untransduced T cells 88 % vs 4 %, p &amp;lt; 0.001). In vivo, tumor growth inhibition by this AdCAR-T cell system was likewise confined to SSTR2+ LN229 tumors and was paralleled by prolonged survival compared with SSTR2+ LN229 tumors treated with untransduced T cells i.t. plus metronomic octofluo i.v. (hazard ratio [95% confidence interval], 0.24 [0.07 - 0.84], p=0.0002). CONCLUSION Targeting SSTR2+ gliomas with FITC-specific AdCAR-T cells plus octofluo is feasible. More in vivo and ex vivo translational experiments will be required prior to proceeding to early phase clinical trials in glioma patients, including careful evaluation of the octofluo tumor residence time and optimal injection frequency.
P13.15.A SULFASALAZINE AS RADIOSENSITIZER IN COMBINATION WITH STEREOTACTIC RADIOSURGERY FOR RECURRENT GLIOBLASTOMA - A PHASE 1 DOSE-ESCALATION
Authors: B Skeie, S M Bragstad, S Sarowar, D K P Goplen, J I Heggdal, P Enger
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) is an aggressive, radioresistant type of cancer with a dismal prognosis. Preclinically, Sulfasalazine (SAS) has shown radiosensitizing properties by blocking intratumoral production of glutathione (GSH). We conducted a phase 1 clinical trial to investigate safety and therapeutic potential of SAS in combination with Gamma Knife Radiosurgery (GKRS) for recurrent GBM (rGBM). MATERIAL AND METHODS Patients were pretreated with SAS 3 days prior to GKRS to deplete the tumor of GSH utilizing a 3 + 3 dose escalation design (1.5, 3.0, 4.5 or 6.0 g SAS/day. Endpoints were safety, quality of life (FACT-Br), changes in GSH-levels (GSH-MR spectroscopy), metabolism (11-C-MET-PET) and best radiographic response (RANO criteria). Freedom from local tumor progression (FFTP), progression-free survival (PFS) and overall survival (OS) were compared to contemporary controls. RESULTS Twelve patients were included. No dose limiting toxicity was observed. FACT-Br remained stable for 6 months (p= 0.056). SAS led to significant but variable reduction in intratumoral GSH levels. Six (67%) of 9 patients with PET at follow-up had reduced signal indicative of effect. Complete control was achieved for 3 (27.2%), partial response for 6 (54.5 %), stable disease for 1 (9.1 %) and immediate tumor progression in 1 (9.1 %) of the treated lesions. Median FFTP and PFS were 12.1 (95% CI 1.2 - 7.1) and 4.1 months (95% CI 1.2 - 7.1) compared to 1.6 (95% CI 1.4 - 1.8) and 1.6 (0.9 - 2.3) for controls, p &amp;lt; 0.001 and p = 0.006, respectively. OS was longer for patients responding with compete vs. partial/stable response or progressing disease, 26.0 vs. 10.0 and 7.0 months, respectively, p = 0.017. CONCLUSION SAS combined with GKRS was well tolerated with preliminary evidence of anti-tumor response.
Accuracy of continuous glucose monitoring systems in intensive care unit patients: a scoping review
Authors: Christian G. Nielsen, Milda Grigonyte-Daraskeviciene, Mikkel T. Olsen, Morten H. Møller, Kirsten Nørgaard, Anders Perner, Johan Mårtensson, Ulrik Pedersen-Bjergaard, Peter L. Kristensen, Morten H. Bestle
Journal: Intensive Care Medicine (2024)
Fluid balance neutralization secured by hemodynamic monitoring versus protocolized standard of care in patients with acute circulatory failure requiring continuous renal replacement therapy: results of the GO NEUTRAL randomized controlled trial
Authors: Laurent Bitker, Claire Dupuis, Pierre Pradat, Guillaume Deniel, Kada Klouche, Mehdi Mezidi, Louis Chauvelot, Hodane Yonis, Loredana Baboi, Julien Illinger, Bertrand Souweine, Jean-Christophe Richard
Journal: Intensive Care Medicine (2024)

Net ultrafiltration (UF
P13.13.B RADIONECROSIS VERSUS SECOND MALIGNANCY: BRAINSTEM LESION 19 YEARS AFTER PAEDIATRIC MEDULLOBLASTOMA TREATMENT
Authors: A Turcas, E Mihut, B Homorozeanu, G Avram, A Roman, Z Fekete
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain radionecrosis is a rare, but severe complication of radiotherapy. In children, the incidence ranges around 2-4% of patients and peaks around 5-7 years after conventional radiotherapy, wherease in adults treated with stereotactic radiotherapy it can occur more often and sooner, usually between 6 monts up to 2 years. Other important late side effects of radiotherapy in paediatric patients are second malignancies, which usually occur in the irradiated region, around 15-20 years after treatment. CASE REPORT We present the case of a 36-year old patient treated at the age of 16 (in 2005) with surgery, followed by standard chemotherapy and cranio-spinal irradiation (36Gy) with a boost up to 54 Gy to the entire posterior fossa for a non-metastatic medulloblastoma. Complete remission was obtained and maintained until October 2023, when the patient developed new symptoms in terms of headache, balance issues and accentuated motor deficits in the lower limbs. The MRI showed a new infiltrative, enhancing lesion in the pontine region, with diffusion restriction and heterogenous hyper-intense T2. We raised the suspicion of a second, radiation-induced malignancy or a late radionecrosis. MRI spectroscopy showed high Lactate, low NAA, Choline and Creatinine, being suggestive of radionecrosis, thus the patient was offered corticosteroids (16mg Dexamethasone for 1 week with progressive reduction of doses and cessation after 4 weeks). Monthly follow-up MRI’s showed a progressive volume and enhancement reduction of the lesion, with significant improvement of the symptoms. The last MRI (April 2024) shows a major reduction of the lesion, from 3/2cm at diagnosis to 0.6/1cm at 6 months, with good clinical status. CONCLUSION The presented case is impressive in terms of the timing of radionecrosis, given that with standard-fractionated radiotherapy this toxicity occurs very rare and usually much sooner. Also, the radiologic and clinical response to steroids was impressive. This report aims to raise awareness on the importance of long-term follow-up in paediatric brain tumour patients and underlies the importance of advanced imaging techniques for differentiating between tumour relapse, radio-necrosis and second malignancies.
P20.17.B PRIMARY CEREBRAL T-CELL LYMPHOMAS DISPLAY AN ATYPICAL PRESENTATION: A LOC STUDY
Authors: M B NDIAYE, W Jabeur, K Mokhtari, P Gaulard, S Choquet, L Nichelli, B Mathon, M Le Garff Tavernier, C Soussain, C Moluçon-Chabrot, R Gressin, H Ghesquières, R Houot, S Tricot, D Waultier, G Ahle, A Schmitt, A Emin, A Bonnet, K H Xuan, C Houillier
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Primary cerebral T-cell lymphomas are very rare and remain poorly known as opposed to diffuse large B-cell lymphomas (DLBCL) that account for more than 90% of all primary central nervous system lymphomas (PCNSL). The aim of the present study was to describe the characteristics of primary T-cell lymphomas, as well as their treatment and outcomes. MATERIAL AND METHODS We retrospectively selected from the French LOC (“Lymphomes oculo-cérébraux”) database the cases of primary T-cell lymphomas diagnosed between January 2011 to December 2023. RESULTS Of the 2966 patients diagnosed with PCNSL between January 2011 and February 2024, 16 patients (0.54%), including 9 men, were diagnosed with primary T-cell lymphoma. Their median age was 60 years [25-80], their median KPS was 70 [20-90]. The mean delay between first symptoms and diagnosis was 78 days [13-365]. Four patients had a history of auto-immune disease and 2 patients were under immunosuppressive therapy. Six patients harboured a classical aspect of brain lymphoma on MRI (tumor with intense and homogeneous contrast enhancement). In ten patients, the MRI presentation was atypical and other diagnoses were suspected before brain biopsy: high-grade gliomas in six immunocompetent patients with necrotic/hemorrhagic lesions, cerebral vasculitis in 2 patients, gliomatosis cerebri in one patient and cerebral metastasis in one patient. The histological diagnosis was NOS peripheral T-cell lymphoma in 8 patients, anaplastic large-cell lymphoma in 4 patients (2 ALK negative, 1 ALK positive, 1 undetermined), EBV-negative NK-T-cell in 1 patient, T-cell lymphomatosis cerebri in 1 patient (2 missing data). Clonality assessment by PCR found a TCR clonal rearrangement in 5/7 cases.Fifteen of 16 patients were treated with high dose methotrexate-based chemotherapy as induction therapy in first-line treatment. Six patients received intensive chemotherapy with autologous stem cell transplantation during their follow-up Nine patients relapsed, either during first-line treatment (N=3) or during the follow-up after treatment (N=6). The median follow-up was 32 months. The 2-year PFS rate was 46% (95% CI: 26-81) The 2-year OS rate was 67% (46-96) Conclusion: T-cell lymphoma represents a rare and severe form of PCNSL. It often occurs in patients with a different background than in DLBCL: younger patients, history of autoimmune disease or immunosuppression. The diagnosis can be challenging as the radiological presentation is most often atypical, often mimicking high grade gliomas or vasculitis, leading to a delayed diagnosis.
P19.12.A QUANTIFICATION OF DIVERSE IMMUNE CELL SUBSETS IN PRIMARY MENINGIOMAS
Authors: N Giuliani Canizales, C Lotsch, R Warta, L Jassowicz, A von Deimling, F Sahm, A Unterberg, C Herold-Mende
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Meningiomas (MGM) often exhibit clinically aggressive progression, although being primarily benign. Immunotherapy could be an alternative treatment, but knowledge regarding meningioma immunobiology remains limited. This study delved into less explored subtypes, such as B cells, NK cells, and granulocytes, to analyze their associations with disease progression and cell-cell relations. MATERIAL AND METHODS A cohort comprising 100 primary MGM cases was used, including all WHO grades (°1, °2, and °3), and DNA methylation classes (MCs; benign, intermediate, and malignant). To quantify infiltration of T cells, B cells, NK cells, neutrophils, and eosinophils, tumor tissue cryo-sections were obtained from the institutional biobank. Immunofluorescence stainings were performed on tumor cryo-sections and digitized as high-resolution multiple image alignments for semi-automated cell counting. The infiltration rates were then correlated with clinical data, including clinical grading, age, sex, progression-free survival (PFS) and overall survival. RESULTS Each subtype´s median cell infiltration varied, with T cells (0.64%) having the highest, followed by neutrophils (0.079%), B cells (0.003%), NK cells (0.006%), and eosinophils (0.0018%). B cell infiltration correlated with increasing T cells, as did eosinophils with neutrophils. WHO°1 cases exhibited higher NK cell and eosinophil infiltration compared to other WHO grades. High NK cell infiltration was characteristic of the benign MC. Neutrophils and NK cells infiltrated more in the younger sub-population (&amp;lt;61yo). Overall, patients with higher PFS tended to have higher infiltration of T cells, NK cells, and eosinophils, but lower B cells and neutrophils. Aggregates of T cells and B cells were found in 10% of cases, which also showed high infiltration rates of all cell types and higher PFS. CONCLUSION This study provides infiltration rates of rarer immune cell subtypes and their variation with clinical grading, age, and sex, as well as their relevance for MGM progression.
P19.11.B PRELIMINARY DATA FROM THE REGION ÖREBRO COUNTY MENINGIOMA PROJECT
Authors: D Löfgren, M Olivecrona
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Meningioma is typically benign and is occasionally detected during examinations due to other reasons (e.g. suspected stroke, trauma). Reported incidence figures usually come from various registers, and most reported prevalence figures are estimations derived from incidence figures and survival data. The Region Örebro County meningioma project aims to gain a better understanding of the incidence and prevalence of meningioma in the population. With these preliminary data, we seek to ascertain the practical feasibility of our proposed search method. MATERIAL AND METHODS In the Swedish county of Örebro with 302,252 inhabitants (2019), all radiology departments are within the public healthcare system. The electronic radiology archive (ERA) includes all patients who have undergone any type of radiological examination in the region since its introduction in 1996. To determine the number of individuals with meningioma in the region and when they were diagnosed, we conducted free-text searches for the word “meningioma” with various spelling variations in ERA and included all patients where the word appears in ERA referrals or responses. Subsequently, using data from the region’s electronic medical records (EMR), we excluded all patients not residing within the region. We then manually reviewed these patients’ referrals, written reports and radiology examinations, to determine whether they have meningioma, the date of diagnosis, whether it was an incidental finding, and presence of multiple meningioma. RESULTS We identified 3,428 patients, of which 3,064 have been included in this study (being residents of the region). In a preliminary review, we have been able to identify 1,663 (55 %) patients with likely meningioma. Of the 1,663 patients, 5 % had a diagnosis date before the introduction of ERA. The median age was 73 (IQR 61-82) years. There were 24 % males and 76 % females. Multiple meningioma were found in 9 % of the patients. In the preliminary review 64 % were incidental findings, while 21 % and 15 % were classified as non-incidental and indeterminate, respectively. CONCLUSION Performing free-text ERA/EMR searches is a potential avenue to achieve better coverage when investigating incidence and prevalence of a disease such as meningioma in a public healthcare setting. In our initial review, it is evident that the method identifies and can retrieve meningioma patients from the ERA. Gender distribution, median age and multiple meningioma numbers are comparable to other reported meningioma populations. Based on our experience with this dataset, it is not advisable to rely solely on simple automated searches. Projects akin to this would likely be well suited for future automated image analysis (volumetric measurement, meningioma identification, etc.).