bluuebunny/crossref_metadata_2025_split huggingface dataset:
NCOG-17. THE COMBAT PROJECT - CORE POST OPERATIVE MORBIDITY SET FOR PAEDIATRIC BRAIN TUMOURS
Authors: Krishna Sandhya Trichinopoly , Mallucci Conor , Pizer Barry , Gamble Carrol , Harman Nicola , Jenkinson Michael 
Published: November 2024

Abstract

BACKGROUND
Brain tumours are associated with high morbidity both from the tumour and the medical and surgical interventions used to treat them. Post operative morbidity reporting following surgery for paediatric brain tumours is poor due to the lack of a common language when reporting harms. One solution is to develop a core outcome set to stipulate the minimum post operative adverse outcomes that should be reported. The COMBAT (Core Post Operative Morbidity Set for Paediatric Brain Tumours) Project will develop a core outcome set that can be applied to post operative paediatric brain tumour patients to harmonise how adverse outcomes are measured and reported, enabling comparison between different trials, studies and clinical services. We aim to generate interest in The COMBAT Project and invite participation in the project from healthcare professionals and researchers experienced in paediatric neuro-oncology for the consensus process.

METHODS AND ANALYSIS
We will engage with national and international stakeholders including patients and their carers, healthcare professionals and researchers. A systematic review will identify harms reported in post operative paediatric brain tumour patients and how they are measured. Qualitative interviews with patients and carers will identify any harms of importance to them. A Delphi survey will be created from the harms identified. A consensus meeting will be held to finalise the core outcome set. The final core outcome set will be published and disseminated to encourage uptake.

DISCUSSION
There is a clear need for a common language to harmonise measurement and reporting of harms following surgery for paediatric brain tumour patients. This project will define post operative adverse outcomes that are of critical importance to key stakeholders. It will be used to standardise surgical morbidity outcome measurement and reporting in trials, studies and clinical practice and will inform future research in this field.
NCOG-23. CLINICIAN AND PATIENT REPORTED OUTCOMES IN YOUNG ADULTS WITH GLIOBLASTOMA: RESULTS FROM A MULTIMODAL PROSPECTIVE STUDY
Authors: Raheem Javeria , Roberto Katrina , Chan Aimee , Theriault Aimee , Machado Mikayla , Granovskaya Inga , Wong Andrea , Calabrese Eirena , Perry James , Lim-Fat Mary Jane 
Published: November 2024

Abstract
The median age for glioblastoma (GBM) is 65 years old, however, younger patients have a similarly dismal prognosis. The adolescent and young adult (AYA) population (15-39 years) is a unique and understudied population. Our study aimed to identify survivorship needs in adult patients in AYA population (&lt;40 yrs) with GBM through analysis of patient and clinician-reported outcomes (PROs and CROs). The Molecular, Imaging and Neurological assessment Database (MIND-CNS) captures Neurological Assessment in Neuro-Oncology (NANO) scores, MDASI-BT and FACIT-SP12 responses at first clinic visit and follow-ups for patients with GBM. We tested associations of the two age groups (18-39 vs. 40 years and older) with each domain of NANO, MDASI-BT and FACIT-SP12 at baseline and at follow-up visits using multivariate logistic regression models, adjusting for MGMT promoter methylation and extent of resection. There were 104 patients with GBM enrolled, including 11 young adults, (median =30 years) and 93 older adults (median =65 years). Young and older adults scored similarly in the domains of NANO, MDASI-BT, and FACIT-SP12 at baseline. MDASI domains at follow-up showed statistically significant lower scores on weakness, fatigue, distress, irritability, drowsiness, and disturbed sleep in younger vs. older adults (adjusted p&lt;0.05). Younger adults had less difficulty with memory and concentration, and their symptoms interfered less with work, walking, and overall enjoyment of life. They also reported feeling more peaceful, finding greater comfort and strength in their faith and beliefs. A comparison of NANO score at baseline and progression will be performed at data maturation. While PROs were similar at baseline, young adults reported lower severity in their physical symptoms and higher spiritual well-being compared to older adults at follow-up visits, highlighting different survivorship experiences. Data maturation will allow for deeper analysis to better inform supportive strategies.
NCOG-24. CHARACTERIZING NEUROTOXICITY ASSOCIATED WITH SYSTEMIC CHEMOTHERAPY IN PATIENTS WITH BREAST CANCER USING DOMAIN-SPECIFIC INTRA-INDIVIDUAL NEUROCOGNITIVE VARIABILITY
Authors: Sheppard David , Noll Kyle , Sullaway Catherine , Wefel Jeffrey 
Published: November 2024

Abstract

BACKGROUND
Systemic chemotherapy is associated with neurotoxicity and neurocognitive functioning (NCF) changes. Intra-individual neurocognitive variability (IIV) is an index of NCF spread/dispersion across neuropsychological tests and can be elevated in patients with breast cancer (BC) after systemic chemotherapy. This study investigated longitudinal IIV changes within NCF domains after chemotherapy to determine whether: (1) IIV for NCF domains are more sensitive to changes than traditional mean-based metrics, and (2) whether changes in domain-specific IIV are associated with changes in mood disturbance or quality of life (QOL).

METHODS
Prior to and during/shortly after chemotherapy, 37 women with BC were administered a standardized NCF battery including tests within domains of attention/speed of information processing (A/SoP), learning/memory (L/M), and executive functions (EF). Within each domain, the coefficient of variation (CoV) was computed using the standard deviation of normatively-adjusted T-scores while adjusting for intra-individual mean. Patients were assessed for QOL using Functional Assessment of Cancer Therapy-Breast and mood using the STAI and BDI.

RESULTS
Paired samples t-tests revealed that mean NCF performances declined for L/M (t[36])=-4.44,p&lt;.001,Hedge’s g=.70) and improved for A/SoP (t[36]=3.21,p=.003,g=.29), while CoV increased/worsened for L/M (t[36]=3.82,p&lt;.001,g=.76) but did not change for A/SoP (t[36]=-0.05,p=.959,g=.01). There was no change in EF mean or CoV (ps &gt;.10). No domain mean or IIV change was associated with mood changes (ps&gt;.10). Mean NCF changes were not associated with QOL (ps &gt;.10). Increased/worsened L/M CoV was associated with improved FACT-Breast scale QOL (ρ=.40,p=.020).

CONCLUSIONS
Both mean- and IIV-based NCF worsened for learning/memory. Discrepancies between mean and IIV change for attention/speed of information processing may be due to differential susceptibility to practice effects. Unexpected associations between learning/memory IIV changes and QOL require further investigation. Future studies are needed to examine NCF dispersion changes across treatment status and in other cancer populations.
NCOG-33. MTOR INHIBITORS AS ADJUVANT TARGETED THERAPY IN PEDIATRIC PATIENTS WITH PROGRESSIVE OR REFRACTORY LOW-GRADE GLIOMA: A SINGLE-CENTER RETROSPECTIVE STUDY
Authors: Fan Aaron E , Cunningham Jonathan , McGovern Susan , McAleer Mary , Sandberg David I , Friedman Gregory K , Zaky Wafik 
Published: November 2024

Abstract
Low grade gliomas (LGG) represent about one-third of all pediatric central nervous system tumors, with about half having disease progression despite upfront surgery and adjuvant therapies. Current treatments for LGG progression either produce toxic side effects (i.e., radiation therapy) or do not generate durable responses. Targeted agents are an effective way of attacking tumors with identified genetic mutations, but in some cases, a complete response can be subverted by the heterogeneity of tumors. Additionally, most tumors do not carry any targetable mutations. Temsirolimus and everolimus are mTOR inhibitors that have previously been shown to be well-tolerated in early clinical studies in pediatric solid tumors. We performed a retrospective study to look at the toxicity profile of mTOR inhibitors when given in combination therapy and treatment response in patients with progressive or refractory LGG. We examined 20 patients with a diagnosis of LGG including mixed glioma and glioneuronal tumors who received treatment at our institution from 2016-2024 with targeted therapy, of which 8 patients also received temsirolimus or everolimus. Of these 8 patients, 2 had partial response, 2 had minor response, 3 had stable disease, and 1 had progressive disease. The average number of cycles received was 13.6 (range 3-24). Most observed side effects were grade 2 or less, including nausea, transaminitis, myelosuppression, diarrhea, and hyperlipidemia while grade 3/4 toxicities that required dose modification included mucositis, hyperglycemia, and hyperlipidemia. Overall, the addition of temsirolimus to treatment regimens of pediatric patients with heavily pretreated refractory LGG prolonged progression free survival by an average of 478 days with only one patient progressing while on therapy. These results demonstrate feasibility and preliminary efficacy of adding mTOR inhibitors as adjuvant therapy in this patient population. There is dire need of large prospective collaborative studies in the future.
NCOG-34. CORRESPONDENCE BETWEEN INTRAOPERATIVE GAMMA BAND ELECTROCORTICOGRAMS AND DIRECT ELECTRICAL STIMULATION ACROSS DIVERSE NAMING TASKS IN PATIENTS WITH LANGUAGE-ELOQUENT BRAIN TUMORS
Authors: Noll Kyle , Tasnim Israt , Asman Priscella , Swamy Chandra , Connelly Katherine , Muir Matthew , Hall Matthew , Pellizzer Guiseppe , Ince Nuri , Prabhu Sujit 
Published: November 2024

Abstract

BACKGROUND
Few studies have examined concordance between intraoperative electrocorticography (ECoG) and direct electrical stimulation (DES) language mapping, especially across varied naming tasks.

METHODS
Twelve patients (Mdn age=59; 75% HGG) underwent awake craniotomy with ECoG and DES language mapping. Mapping utilized iPad stimulus presentation coupled to a 4x8 electrode array for both ECoG and DES. Time-frequency ECoG gamma band activity (Early and Late) was visualized for 3 naming paradigms (Object, Action, Auditory). Bipolar DES was also conducted for each task at each electrode pair. ECoG activations and DES hits were overlayed on preoperative MRI. DES hits represented ground truth for eloquence. ECoG accuracy was examined for each task with 3 different criteria: exact (identical electrodes for ECoG activation and DES hits), adjacent (ECoG &lt;1cm of DES hits), and adjacent within a predefined peritumoral region of interest (&lt;2 cm from boundaries).

RESULTS
32 DES hits (40% Auditory, 32% Action, 28% Obj) were observed across patients. Exact ECoG-DES accuracy ranged from 78%-90% [Object: Sens=11%, Spec=91%, PPV=6%, NPV=95%; Action: Sens=40%, Spec=93%, PPV=24%, NPV=97%; Auditory: Sens=69%, Spec=78%, PPV=19%, NPV=78%]. Adjacent ECoG-DES accuracy ranged from 82%-91% [Object: Sens=33%, Spec=92%, PPV=18%, NPV=97%; Action: Sens=44%, Spec=93%, PPV=25%, NPV=97%; Auditory: Sens=91%, Spec=81%, PPV=37%, NPV=99%]. When restricted to the peritumoral region, adjacent ECoG-DES accuracy ranged from 94%-97% [Object: Sens=14%, Spec=99%, PPV=25%, NPV=97%; Action: Sens=25%, Spec=99%, PPV=25%, NPV=99%; Auditory: Sens=100%, Spec=94%, PPV=54%, NPV=100%]. For patients with DES hits (N=10), all had at least 1 task activation &lt;1 cm of DES hits, with 7/10 having convergence of activations across at least 2 tasks.

CONCLUSIONS
Negative ECoG mapping is strongly predictive of non-eloquence confirmed by DES for all naming tasks. Additionally, gamma band activation elicited by auditory naming within the peritumoral region is strongly predictive of eloquence. Findings support task-based ECoG language mapping for prediction of eloquence and identification of targets for DES confirmation.
NCOG-39. EXPLORING THE POTENTIAL OF STEREOTACTIC RADIOSURGERY IN THE MANAGEMENT OF MENINGIOMAS
Authors: Sallese Greta , Kandhadai Anuttham , Brindley Paul 
Published: November 2024

Abstract

INTRODUCTION
Meningiomas present complex therapeutic challenges due to their potential impact on neurological function and quality of life. While the standard of care involves observation and surgical resection, stereotactic radiosurgery (SRS) is an alternative treatment modality. This study aimed to compare the relative efficacy of SRS and surgical resection in the management of meningiomas to inform evidence-based decision-making in this clinical context.

METHODS
A retrospective cohort study was conducted using the TriNetX database, comparing patients undergoing treatment for meningiomas with either stereotactic radiosurgery (SRS) or surgical resection. Cohorts were matched on comorbidities. Rates of mortality and malignant neoplasms of the brain within 5-years of treatment with either modality were compared. In addition, short-term outcomes were assessed at 3 months post-treatment.

RESULTS
After matching, there were 1,898 patients in each cohort. Patients receiving SRS exhibited a significantly lower risk of mortality (95% CI: 0.76-1.07) and a decreased risk of developing malignant neoplasms of the brain (RR: 0.68, 95% CI: 0.54-0.85) over 5 years, compared to surgical resection. At 3-months post treatment, patients treated with SRS demonstrated significantly lower relative risks for several outcomes, including cerebral infarction (RR: 0.27, 95% CI: 0.18-0.39), hydrocephalus (RR: 0.19, 95% CI: 0.11-0.32), cerebral edema (RR: 0.13, 95% CI: 0.10-0.18), seizures (RR: 0.27, 95% CI: 0.21-0.34), neurological deficits (RR: 0.19, 95% CI: 0.13-0.28), and post-procedural infection (RR: 0.14, 95% CI: 0.07-0.28).

CONCLUSION
This retrospective cohort study suggests that in the management of meningiomas, SRS may be associated with lower mortality rates, decreased risks of malignant neoplasms of the brain, and improved short-term outcomes compared to surgical resection. Further research is warranted to validate these results and explore long-term outcomes and potential adverse effects.
EXTH-12. POTENTIATING THE EFFICACY OF IMMUNE CHECK-POINT INHIBITORS IN GLIOBLASTOMA BY INHIBITION OF CXCL12
Authors: Makranz Chen Cam-El , Huguely Caitlin , Haynes Tuesday , Briceno Nicole , Zhang Meili , Davis Dionne , Song Hua , Zhang Wei , Gilbert Mark , Watanabe Masashi 
Published: November 2024

Abstract

BACKGROUND
The tumor immune microenvironment (TIME) in glioblastoma (GBM) is rich in CXCL12, a chemokine known for stimulating angiogenesis. CXCL12 also controls immune cell trafficking and promotes polarization to an immunosuppressive phenotype. We postulated that inhibiting CXCL12 will modulate the immunosuppressive TIME in GBM, thereby augmenting the efficacy of immunotherapy agents like immune checkpoint inhibitors (ICIs). We examined the immunomodulatory and therapeutic efficacy of CXCL12 inhibition, using a small molecule NOX-A12, with and without ICIs in pre-clinical murine GBM models.

METHODS
B6 immunocompetent mice bearing intracranial (i.c.) or subcutaneous (s.c.) SB28 tumors received either vehicle, NOX-A12, anti-PD1 and anti-CTLA4 (dual ICI) or NOX-A12 + dual ICI (combination). Tumor growth was measured by IVIS imaging and immune cells in brain were analyzed using high dimensional flow cytometry. Survival was analyzed using Kaplan-Meier curves and log rank test.

RESULTS
Combination treatment resulted in tumor regression and long-term survival in 40% of s.c. tumor bearing mice compared to 10% treated with dual ICI only. Three of 4 mice rechallenged with contralateral s.c. tumor remained tumor free while all naive mice reached endpoint. TIME from treated s.c. tumors revealed increase in CD4 and effector memory CD8 T cells by combination treatment compared to dual ICI. In i.c. GBM tumors, while no survival benefit or growth inhibition was seen, combination treatment induced an early increase in effector memory CD8 T cells and PD-L1+ B cells, and a later increase in MHC-II+ microglia compared to dual ICI.

CONCLUSION
Inhibition of CXCL12 enabled the increase of effector cytotoxic T cells by ICI, improving survival in the s.c. GBM model, but not in i.c. GBM model. This might be due to differences in CXCL12 effect between extra and intra-CNS tumor or due to robust immune response causing excessive brain edema and death. These will be further explored in ongoing and future studies.
EXTH-15. AN EGFRVIII RNA-LNP VACCINE PROTOTYPE ACHIEVES TUMOUR CLEARANCE IN A GBM MOUSE MODEL
Authors: Snelling Shannon , Nechanitzky Robert , Lun Xueqing , Ellestad Kristofer , Pyczek Joanna , Olsen Kirsten , Wu Yu , Karpov Yury , Liu Jun , Gold Matthew , Menon Haritha , Tan Yilin , Krishnan Rajesh , Mahoney Douglas , Martin-Orozco Natalia , Chan Jennifer A 
Published: November 2024

Abstract
Glioblastoma (GBM) is an aggressive high-grade glioma that is fatal despite standard-of-care therapy. Recurrent somatic alterations that form neoantigens represent opportunities for targeted therapeutic intervention. Using human EGFRvIII as a prototypical structural alteration and neoantigen, we tested the potential of a mRNA-LNP vaccine approach to improve the survival of mice with EGFRvIII-driven GBM. To generate the model, we used in vivo electroporation to introduce genetic alterations (EGFRvIII-OE/CDKN2A-KO/PTEN-KO) into periventricular cells of early postnatal C3H mice, then propagated cells from the subsequent tumours to create implantable cell lines. Following orthotopic implantation, the resulting syngeneic tumours faithfully recapitulate histologic features of GBM with infiltrative growth, mitoses, necrosis, and vascular proliferation. Also like human GBM, the models are sensitive to but not cured by temozolomide chemotherapy and are resistant to immune checkpoint blockade. We delivered mRNA-LNP vaccines against EGFRvIII into the thigh muscle of tumour-bearing mice on days 7, 10, 14, 21, and 36 after tumour cell implant. We observed no tumour in vaccine-treated mice compared to significant tumour burden in control vector-treated animals by MR imaging at day 30 post-tumour cell implant. By day 37, all control-treated mice had died, whereas vaccine-treated mice cleared their tumours with no tumour burden detectable by histology at day 150 (N= 5 per group, **p= 0.0023). In a follow-up experiment with vaccine or control treatment on days 10, 14, 18, and 25 post-cell implants, all control mice had died by day 39. Further, vaccine-treated surviving animals were re-challenged with tumour cell implant into the contralateral hemisphere on day 42 and remain alive as of day 90. Our ongoing proof-of-principle work demonstrates that neoantigen driver mutations in high-grade glioma models can be targeted with an mRNA lipid vaccine. We hope this pre-clinical work will lead to early-phase clinical trials.
EXTH-55. ANTI-TUMOR ACTIVITY OF A NEW ONCOLYTIC ADENOVIRUS DELTA-24-RGDOX-IL15 CO-EXPRESSING OX40L AND IL-15
Authors: Jiang Hong , He Jiasen , Duran Alejandra , Fan Xuejun , Shin Dong Ho , Parthasarathy Akhila , Gillard Andrew , Lopez-Rivas Andres , Moure Marc Garcia , Lang Frederick , Gomez-Manzano Candelaria , Fueyo Juan 
Published: November 2024

Abstract
Accumulating evidence show that the interaction between oncolytic viruses (OVs) and host immune system plays an essential role in cancer virotherapy. Compared to lytic potency of OVs, enhancement of OV-mediated anti-tumor immunity has become a more attractive strategy to improve OV efficacy. To this end, we have reported that the third-generation oncolytic adenovirus (OA), Delta-24-RGDOX, which expresses the immune co-stimulator OX40 ligand (OX40L), is more potent to elicit anti-tumor immunity than the second-generation OA Delta-24-RGD. Since IL-15 activates T and NK cells and promotes persistence of CD8+ memory T cells, we hypothesize that co-expression of OX40L and IL-15 by OAs will further potentiate their efficacy. For this purpose, we constructed the next generation OA Delta-24-RGDOX-IL15. In cultured human and murine tumor cell lines, this new virus effectively expressed the two molecules and displayed comparable potency in viral replication and oncolysis as OAs expressing either of the two (Delta-24-RGDOX, Delta-24-RGD-IL15). Then, we tested the anti-tumor activity of Delta-24-RGDOX-IL15 (two doses, intratumorally, one week interval) in two syngeneic tumor models in C57BL/6 mice: 1) intracranial (i.c.) gliomas from GL261-5 cells; 2) subcutaneous (s.c.)/i.c. melanomas from B16 cells (virus injected into s.c. tumors only). We found Delta-24-RGDOX-IL15 was more efficacious than the other two OAs to inhibit tumor growth of both treated tumor and the untreated i.c. tumors in the second model, leading to long-term survivors (p &lt; 0.05). Different from adoptive cell therapies with cells engineered to express IL-15, we haven’t observed any obvious toxicity with this new virus when it was injected intratumorally into either the i.c. or s.c. tumors. Further studies are in progress to analyze the modifications of the tumor microenvironment induced by the addition of IL-15 to Delta-24-RGDOX. We expect this virus to be a good candidate to be combined with CAR T cell therapies.
EXTH-63. FOCUSED ULTRASOUND HYPERTHERMIA MEDIATED CONTROL OF THERMAL RESPONSIVE CAR T CELL ACTIVITY IN BREAST CANCER BRAIN METASTASIS
Authors: Kim Chulyong , Zamat Ali , Zha Zizhen , Sridhar Shwetha , Kwong Gabe , Arvanitis Costas 
Published: November 2024

Abstract
HER2-targeted therapies are promising treatment options for metastatic breast cancer and have improved the median overall survival. However, breast cancer brain metastasis (BCBM), observed in up to 50% of HER2-positive breast cancer patients, remains a clinical challenge. While Chimeric Antigen Receptor (CAR) T cell therapy is promising therapeutic strategy to address the unmet need in treating BCBM, improving its effectiveness and safety is critical for clinical translation. We hypothesized that spatially and temporally controlled activity of CAR-T cells with a thermal gene switch (TS) under MRI-guided focused ultrasound (MRgFUS) would potentiate anti-tumor responses in difficult-to-treat BCBM. To test our hypothesis, we developed a closed-loop controlled MR-thermometry (MRTI) based FUS system (MRgFUS) and αHER2 CAR-T cells engineered with TS expressing the reporter gene firefly luciferase (TS.Fluc) or bi-specific engager on NKG2D ligands (TS.BTE) upon MRgFUS-hyperthermia (41.5°C). In vivo quantification of TS activity from intratumorally delivered TS.Fluc αHER2 CAR-T cells in HER2+ BCBM mice model (HER2+ MDA-MB-468 in NSG mice with primary human CAR-T cells) followed by pulsed MRgFUS-hyperthermia resulted in a ~10-fold increase in luminescent activity compared to unheated mice. To assess longitudinal activation, we quantified TS activity with a second sonication 4 days post the initial FUS treatment. Prior to the second sonication, TS.Fluc expression had returned to baseline levels, while following it robust TS.Fluc expression was observed again, demonstrating that MRgFUS can activate engineered T cells with TS in brain tumors with high spatiotemporal control. Subsequently we investigated the therapeutic efficacy of intratumorally delivered TS.BTE αHER2 CAR T cells in mixed tumor model of heterogeneous HER2 MDA-MB-468 (75% HER2+) and observed significant tumor regression of HER2- tumor cells in the treated group compared to controls, demonstrating the potential of the proposed strategy to noninvasively drive the local production of key transgenes and potentiate anti-tumor responses in difficult-to-treat BCBM.