bluuebunny/crossref_metadata_2025_split huggingface dataset:
EXTH-79. TRIAL WORKING GROUPS TO EXPEDITE PRECLINICAL TRANSLATION FOR PAEDIATRIC BRAIN TUMOURS
Authors: Rahman Ruman , Walker David , Campbell Emma , Aquilina Kristian 
Published: November 2021

Abstract

INTRODUCTION
Children's brain tumours are the biggest cancer killer in children and young adults. Several recent developments have the potential to change the treatment of brain tumours in children, including intra-CSF chemotherapy, ultrasound-mediated blood-brain barrier disruption, convection enhanced delivery, polymer delivery systems and electric field therapy, as well as intra-arterial and intra-nasal chemotherapy. To date, there have been very few clinical trials to evaluate these. The science and technology underlying these developments is not traditionally embedded within the paediatric neuro-oncology network. In addition, custom-built hardware, novel surgical procedures, and the testing and licensing of implantable devices, add difficulty at the regulatory level.

METHODS
In early 2021, we launched the ‘Clinical Trials Working Group for Central Nervous System Drug Delivery’. This aims to accelerate clinical trials to assess the safety and effectiveness of drug delivery devices for treating paediatric brain tumours. On March 1st, we hosted the first virtual meeting of this group, involving 38 leading brain tumour scientists and clinicians from the UK, EU and US.

RESULTS
A pre-meeting survey identified the main challenges to acceleration of this preclinical to clinical research pathway as: (1) a lack of specific funding for prototype development and/or scale up for clinical trials; (2) difficulties in navigation of the regulatory landscape; (3) lack of accurate preclinical models; and (4) increased need for multicentric working. Discussion at the meeting echoed the survey responses, and there was agreed consensus that a ‘Roadmap’ document for preclinical to clinical translation should be created. Following the meeting, we launched a pump prime funding call for projects that will address challenges along the preclinical to clinical pathway to move trial proposals into an ‘advanced state of readiness’.

CONCLUSION
The ideas generated during the initial meeting will help form the basis of a ‘Clinical Trials’ workshop in the autumn of 2021.
EXTH-82. T CELL HITCHHIKING AS A MECHANISM OF DRUG DELIVERY TO THE BRAIN
Authors: Singh Kirit , Gedeon Patrick , Schaller Teilo , Snyder David , Khasraw Mustafa , Sampson John 
Published: November 2021

Abstract

INTRODUCTION
The blood-brain barrier (BBB) restricts access to the central nervous system (CNS). Our brain bispecific T cell engager (hEGFRvIII:CD3 BRiTE) treats subcutaneous syngeneic tumor (CT2AvIII) but not intracranial CT2AvIII. CD3 engaging molecules such as nanoparticles can be carried into the brain by binding to activated T cells. We therefore sought to determine if co-administration of larger molecules (BRiTE, approx. 55kDa) with activated T cells could cross the BBB, enhancing survival.

METHODS
We implanted 8–10-week-old transgenic hCD3 mice (n=7-8 per group) with 30,000 CT2AvIII cells. Tumors were established for 6 days. Mice were administered either (1) autologous lymphocyte transfer (ALT) alone (single intravenous (IV) injection, 1 x 107 activated T cells), (2) serial IV BRiTE doses (50ug, 10 days) (3) BRiTE and ALT or (4) no treatment. Mice were followed for survival using Kaplan-Meier curves and compared via log rank test. Targeted mass spectroscopy analysis as well as PET/CT imaging of mice administered Iodine-124 radiolabelled BRiTE was performed to assess for intracranial accumulation.

RESULTS
Mice who received BRiTE and ALT demonstrated significantly enhanced survival compared to controls (median survival 29 vs 21 days, p=0.0135). Mice who received only BRiTE or ALT exhibited median survival comparable to controls (p=0.192, p=0.944 respectively). Mass spectroscopy analysis revealed that mice had a 7-fold increased peak area ratio of BRiTE in the CNS when co-treated with activated T cells compared to BRiTE alone (0.14, 0.02 respectively) while PET/CT imaging demonstrated increased radioactive signal over background localized to coordinates within the brain where tumors were injected.

CONCLUSIONS
Giving activated T cells alongside BRiTE allows better access to the intracranial compartment and is required to achieve efficacy in mice with syngeneic orthotopic glioma. Future work will determine the optimal dose and schedule for this approach, as well as defining the precise mechanism by which this occurs.
QOLP-26. ANALYSIS OF REDDIT USERS' PERSPECTIVES OF BRAIN TUMORS
Authors: Tripathi Sanidhya , Prabhu Arpan , Thomas Kevin , Parker Pearman , Rodriguez Analiz 
Published: November 2021

Abstract

BACKGROUND
Reddit, ranking 6th in worldwide Internet site traffic, is a commonly used forum among patients and caregivers affected by brain tumors to discuss diagnoses, treatment, and self-care management. The use of the online forum may suggest patients and caregivers have unmet needs and are seeking further support outside of the clinical setting. We aimed to examine trends from Reddit discussion treads on brain tumors to identify areas of need in patient care.

METHODS
We used a qualitative, descriptive design to understand patient and caregivers unmet and met needs. We analyzed the top 100 posts and accompanying 271 comments from the ‘braincancer’ subreddit to identify common themes.

RESULTS
The qualitative content analysis revealed three major topic areas: (1) moving through the grief process; (2) processing diagnostic pathway; and (3) expressing gratitude toward other Reddit users. Most of the authors of the posts were patients with brain tumors (n = 32; 38.5%) who used Reddit as a reflective journaling tool to move through the grief process for themselves or loved ones. About 47% of theses posts discussed the diagnostic process of glioblastoma multiforme (GBM) brain tumors, where users requested an inclusive/welcoming environment in the clinic by their healthcare professionals (HPs). Users also solicited and gave support for other members in the online community.

CONCLUSIONS
This study highlights the need of implementing social media as a part of HPs’ repertoire for patient outreach/needs. Furthermore, social media outlets like Reddit can help HPs understand the level of support they can give to their patients. Plans of action for physicians seeking to meet the needs of brain tumor patients include monitoring the concerns of patients, becoming verified on the platform/openly identifying themselves online, or conducting ‘Ask Me Anything’ discussions to educate patients.
RBIO-01. DEVELOPING THE FRAMEWORK FOR TUMOR TREATING FIELDS (TTFIELDS) TREATMENT PLANNING FOR A PATIENT WITH ASTROCYTOMA IN THE SPINAL CORD
Authors: de Los Santos Jennifer , Arvatz Smadar , Zeevi Oshrit , Levi Shay , Urman Noa , Naveh Ariel , Marciano Tal 
Published: November 2021

Abstract
The use of Tumor Treating Fields (TTFields) following resection and chemoradiation has increased survival in patients with Glioblastoma. Patient-specific planning for TTFields transducer array placement has been demonstrated to maximize TTFields dose at the tumor: providing higher TTFields intensity (≥ 1.0 V/cm) and power density (≥ 1.1 mW/cm3) which are associated with improved overall survival. Treatment planning was performed for a 48 year old patient following T10-L1 laminectomy, gross total resection, and postoperative chemoradiation for an anaplastic astrocytoma of the spinal cord. An MRI at 3 weeks following chemoradiation showed tumor recurrence. Based on the post-chemoradiation MRI, a patient-specific model was created. The model was created by modifying a realistic computational phantom of a healthy female. To mimic the laminectomy, the lamina in T10-L1 was removed, and the region assigned electric conductivity similar to that of muscle. A virtual mass was introduced into the spinal cord. Virtual transducer arrays were placed on the model at multiple positions, and delivery of TTFields simulated. The dose delivered by different transducer array layouts was calculated, and the layouts that yielded maximal dose to the tumor and spine identified. Transducer array layouts, in which the arrays were placed on the back of the patient with one array above the tumor and one array below the tumor, yielded the highest doses at the tumor site. Such layouts yielded TTFields doses of over 3.4mW/cm3 which is well above the threshold dose of 1.1 mW/cm3 reported previously [Ballo et al. Red Jour 2019]. The framework developed for TTFields dosimetry and treatment planning for this spinal tumor will have the potential to increase dose delivery to the tumor bed while optimizing placement that may enhance comfort and encourage device usage.
RTID-01. PHASE III MULTICENTER RCT OF POST-SURGICAL STEREOTACTIC RADIOTHERAPY VERSUS SURGICALLY TARGETED RADIATION THERAPY FOR THE TREATMENT OF LARGE NEWLY DIAGNOSED BRAIN METASTASES – TRIAL IN PROGRESS
Authors: Weinberg Jeffrey , Beckham Thomas , McAleer Mary Frances , Johnson Jason Michael , Yuan Ying , Lin Heather , Kudchadker Rajat , Schwartz Theodore , Knisely Jonathan , Dunbar Erin , McCracken David , Wefel Jeffrey 
Published: November 2021

Abstract

BACKGROUND
Resection (R) followed by single- or multi-fraction stereotactic radiosurgery (SRT) of brain metastases (BMs) lowers resection bed recurrence compared to R alone. Nevertheless, for larger BMs, 12-month recurrence rates after R+SRT can exceed 20–30%. Aiming to improve outcomes, a permanently implanted collagen tile brachytherapy device (GammaTile, GT Medical Technologies, Tempe, AZ) utilizing Cs-131 seeds embedded within a bioresorbable collagen tile was developed and is described as Surgically Targeted Radiation Therapy (STaRT) to distinguish it from external beam radiotherapy. STaRT allows rapid, intense localized radiation dose delivery directly to the tumor bed with predictable dosimetry immediately at the time of R, which may confer reduced risk for radiation necrosis compared to other therapies. It is hypothesized that R+ STaRT will increase surgical bed recurrence-free survival (SB-RFS), while reducing impact on functional and neurocognitive status compared to R+SRT.

METHODS
Multicenter, randomized, comparison trial of patients with resectable, previously untreated “index” BMs (≥ 2.5–5cm), and 0–3 other tumors, will be preoperatively randomized 1:1 to undergo R+SRT or R+STaRT to the index lesion; unresected tumors in both groups will receive SRT. Planned sample size is 180 from 14 sites. Enrollment opened 03/31/2021. First subject was enrolled 04/07/2021. Primary endpoint is SB-RFS. Secondary endpoints include overall survival, quality of life, neurocognition, functional status, imaging findings and adverse events. Follow-up will be through 24 months. This will be the first randomized trial comparing R+SRT versus R+STaRT delivered by Cs-131 sources in permanently implanted resorbable collagen tile carriers. Primary and secondary outcome measures captured will elucidate the potential risks and benefits of these two RT delivery methods in the setting of newly diagnosed BMs. We will present trial accrual progress, available data, experience and lessons learned.
SURG-09. SUCCESSFUL SAFETY AND EFFICACY OF GAMMATILE INTRACRANIAL BRACHYTHERAPY IMPLANTED DURING AWAKE CRANIOTOMY
Authors: McClelland III Shearwood , Gardner Ulysses , Le Yi , Ng Sook Kien , Shah Mitesh , Watson Gordon 
Published: November 2021

Abstract

INTRODUCTION
GammaTile intracranial brachytherapy utilizing cesium-131 seeds has demonstrated encouraging safety and local control results in a single-arm precommercial study, and recently received Food and Drug Administration clearance. The authors report the first case of GammaTile intraoperative brachytherapy performed during an awake craniotomy.

METHODS
A 50-year-old man suffered a generalized tonic-clonic seizure while a vehicle passenger. MRI revealed a 2.8 cm left lateral frontal lesion nearing his Broca’s area. Open brain biopsy revealed IDH-wildtype MGMT unmethylated GBM. Unfortunately, despite several interventions (awake craniotomy, adjuvant chemoradiation with temozolomide, Avastin, tumor treating fields) he suffered tumor progression near the left parietal resection cavity. Due to the location of this tumor, re-resection was planned with awake craniotomy and language mapping. A preoperative planning session involving Radiation Oncology and Neurosurgery identified the area of the expected postoperative bed, and consequently five GammaTiles were ordered, each containing 4 cesium-131 3.5 U seeds.

RESULTS
During surgery, once the tumor was mapped, bipolar stimulation was performed while the patient spoke in complete sentences until going into speech arrest on the posterior edge of the gyrus, indicative of language cortex. Following this mapping, microsurgical maximal safe resection occurred, after which areas at risk for tumor residual/recurrence were determined in consultation with Radiation Oncology. Subsequently, Neurosurgery placed all five GammaTiles (20 cesium-131 seeds total) in customized forward fashion to optimally cover the dosimetric needs of these areas. Following GammaTile placement, closure was completed and radioactive surveys of the room remained within state statue. Postoperative dosimetry yielded excellent coverage, and speech function was maintained.

CONCLUSIONS
The first reported case of GammaTile intraoperative brachytherapy during awake craniotomy supports the safety and feasibility of this treatment strategy. This case indicates that for patients with tumors adjacent to eloquent cortex, awake craniotomy can allow for maximum safe resection and implantation of intraoperative brachytherapy.
TAMI-03. PROGNOSTIC SIGNIFICANCE OF NEUTROPHIL-TO-LYMPHOCYTE RATIO (NLR) IN PATIENTS WITH BRAIN METASTASES FROM DIFFERENT TUMOR ORIGINS
Authors: Deng Guanhua , Wen Lei , Zhou zhaoming , Shan Changguo , Lai Mingyao , Zhou Cheng , Cai Linbo 
Published: November 2021

Abstract

PURPOSE
Brain metastases (BMs) represent the most common adult intracranial malignancy. The prognosis of BMs is subject to many factors, i.e., the number, size and locations of the metastatic sites, tumor origins, pathologic types, gene mutation status, metastatic sites, and KPS etc. This study aimed to evaluate the prognostic value of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) in brain metastases.

METHODS
A total of 480 patients diagnosed with brain metastases from a wide range of tumor origins, i.e., NSCLC, SCLC, breast cancer, melanoma, prostate, kidney, gastrointestinal cancer, cervical carcinoma, ovarian cancer, choriocarcinoma of uterus were retrospectively analyzed. Pre-radiotherapy NLR, PLR, and LMR were calculated as total neutrophil/lymphocyte, platelet/Lymphocyte, lymphocyte/monocyte, respectively. Survival rates were estimated using the Kaplan-Meier survival analysis. Cox regression models were used to identify independent prognostic factors.

RESULTS
The median overall survival (OS) was 14.4 months [95%CI: 13.4-15.5]. The median overall survival after radiotherapy was significantly different between patients with NLR&lt; 4 and those with NLR≥4 (OS 16.3 mo. vs. 12.2 mo., P&lt; 0.0001). No signiﬁcant difference was observed between PLR vs. OS, and LMR vs. OS (PLR&lt; 180: HR=1.221, P=0.240; LMR&lt; 4: HR=0.753, P=0.141). The Cox regression model for the continuous metric values revealed that the NLR increased every 1.0 was associated with additional 5.9% of fatal risk (HR: 1.059; 95%CI = 1.033–1.087, P&lt; 0.0001). NLR was validated as an independent prognostic factor for risk of death after adjusting for sex, age, and KPS.

CONCLUSIONS
We revealed pre-treatment NLR is an independent prognostic factor in patients with brain metastases for poor OS, independent of different tumor origins. The NLR warrants further studies using sub-group analysis and validation in external cohorts. Future studies in this parameter have a potential to facilitate more precise risk-stratifications to guide personalized treatment for BM.
TAMI-20. GLIOMA CELLS REPROGRAM SERINE-DEPENDENT ONE-CARBON METABOLISM TO SURVIVE GLUTAMINE STARVATION
Authors: Tanaka Kazuhiro , Nagashima Hiroaki , Fujita Yuichi , Hashiguchi Mitsuru , Sasayama Takashi 
Published: November 2021

Abstract
Cancer cells optimize nutrient utilization to supply energetic and biosynthetic pathways. This metabolic process also includes redox maintenance and epigenetic regulation through nucleic acid and protein methylation, which enhance tumorigenicity and clinical resistance. However, less is known about how cancer cells exhibit metabolic flexibility to sustain cell growth and survival from nutrient starvation. Here, we find that serine and glycine levels were higher in low-nutrient regions of tumors in glioblastoma multiforme (GBM) patients than they were in other regions. Metabolic and functional studies in GBM cells demonstrated that serine availability and one-carbon metabolism support glioma cell survival following glutamine deprivation. Serine synthesis was mediated through autophagy rather than glycolysis. Gene expression analysis identified upregulation of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to regulate one-carbon metabolism in GBM patient-derived sphere cells as well as in GBM cells. In clinical samples, MTHFD2 expression was highest in the nutrient-poor areas around “pseudopalisading necrosis.” Genetic suppression of MTHFD2 and autophagy inhibition caused tumor cell death and growth inhibition of glioma cells upon glutamine deprivation. These results may have important implications for serine-dependent one-carbon metabolism for glioma cells to survive glutamine starvation and suggest a new therapeutic strategy for patients with malignant glioma.
TAMI-30. THERAPY INDUCED REPROGRAMMING DRIVES GLIOMA VASCULAR TRANSDIFFERENTIATION AND TUMOR RECURRENCE
Authors: Muthukrishnan Sree Deepthi , Kawaguchi Riki , Nair Pooja , Prasad Rachna , Alvarado Alvaro , Qin Yue , Condro Michael , Kornblum Harley 
Published: November 2021

Abstract
Therapy-resistant glioma cells elicit phenotypic plasticity leading to aggressive tumor recurrence. Here, we employed single-cell and whole transcriptomic analyses to uncover that a standard glioma treatment, radiation induces a dynamic shift in functional states of glioma cells allowing for acquisition of mesenchymal-like and vascular-like phenotypes. The predominant phenotype switch induced by radiation in surviving tumor cells is transdifferentiation to endothelial-like and pericyte-like cells. The transdifferentiated cells in turn promote proliferation of radiated tumor cells, and their selective depletion results in reduced tumor growth and recurrence post-treatment. The acquisition of vascular-like phenotype is driven by increased chromatin accessibility in vascular genes, and blocking P300-mediated histone acetyltransferase activity prior to radiation treatment inhibits vascular transdifferentiation and tumor growth. Our findings indicate that radiation therapy reprograms tumor cells driving vascular transdifferentiation, and highlights HAT inhibitors as potential therapeutic target for preventing GBM relapse
TAMI-40. PEDIATRIC H3K27M MUTANT GLIOMAS UNDERGO METABOLIC REPROGRAMMING THAT CAN BE LEVERAGED FOR NON-INVASIVE METABOLIC IMAGING
Authors: Tran Meryssa , Batsios Georgios , Taglang Céline , Gillespie Anne Marie , Nazarian Javad , Mueller Sabine , Viswanath Pavithra 
Published: November 2021

Abstract
Diffuse midline gliomas (DMGs) are a universally lethal form of childhood cancer. The infiltrative nature of DMGs makes them difficult to visualize by conventional magnetic resonance imaging. Genomics studies indicate that DMGs are driven by unique histone H3K27M mutations that result in broad epigenetic dysregulation. Many of the resulting changes in gene expression have the potential to induce metabolic reprogramming, which has been identified as a hallmark of cancer. The goal of this study was to dissect metabolic reprogramming in preclinical DMG models in order to identify novel magnetic resonance spectroscopy (MRS)-detectable metabolic biomarkers that can be exploited for non-invasive imaging. First, we used 1H-MRS, which reports on steady-state metabolism, to examine H3K27M mutant SF7761 cells and H3 wild-type normal human astrocytes (NHA). Lactate, glutathione and phosphocholine, which are involved in glycolysis, redox and phospholipid metabolism respectively, were elevated in SF7761 cells relative to NHAs. Mechanistically, these metabolic alterations were associated with upregulation of key enzymes including hexokinase 2, glutamate cysteine ligase and choline kinase a. Importantly, in vivo 1H-MRS showed elevated lactate, glutathione and total choline (combined signal from choline, phosphocholine and glycerophosphocholine) in mice bearing orthotopic SF7761 tumors relative to tumor-free controls. We then examined alterations in dynamic metabolic pathways in our models. Using thermally-polarized 13C-MRS, we identified elevated production of [2-13C]-lactate from [2-13C]-glucose in SF7761 cells relative to NHAs. Hyperpolarized 13C-MRS is a method of enhancing the 13C-MR signal such that metabolic fluxes can be interrogated with high sensitivity. Hyperpolarized [1-13C]-pyruvate flux to [1-13C]-lactate non-invasively monitors glycolysis and is in clinical trials in adult glioma patients. Importantly, hyperpolarized [1-13C]-pyruvate metabolism to lactate was elevated in SF7761 cells relative to NHAs. Collectively, our studies suggest that H3K27M mutant DMGs undergo reprogramming of glucose, redox and phospholipid metabolism that can be leveraged for non-invasive 1H- and hyperpolarized 13C-MRS-based imaging.