bluuebunny/crossref_metadata_2025_split huggingface dataset:
RADT-39. 68Ga- DOTATATE CT/PET FOR GAMMA KNIFE RADIOSURGERY PLANNING AND TARGET DELINEATION IN PATIENTS WITH MENINGIOMA
Authors: Ma Daniel , Rana Zaker , Viswanatha Sirisha , Potters Louis , Chang Jenghwa , Schulder Michael , Goenka Anuj 
Published: December 2020

Abstract

BACKGROUND
Stereotactic radiosurgery (SRS) planning for patients with meningiomas can be confounded by difficulty in identifying the tumor boundary, especially in those who have had prior surgery. Recent data have suggested the benefit of 68Ga-DOTATATE CT/PET scans in delineation of meningioma compared to MRI alone. We propose that incorporating 68Ga-DOTATATE PET scans in addition to MRI in SRS planning will provide better target identification and tumor coverage compared to MRI alone.

METHODS
We reviewed patients with meningioma who had MRI and 68Ga-DOTATATE PET imaging over 12 months. Images were imported into Velocity treatment planning software and separated into two different sessions, one in which only the MRI was accessible, and a second which had the PET scan fused to the MRI. Three different users were asked to contour the residual meningioma as gross tumor volume (GTV) first with MRI alone, and then with the PET/MRI fusion. The volume of each GTV pre-and post-PET fusion was compared and a Dice index was generated.

RESULTS
Four patients with 6 GTV targets were identified. PET fusion identified new lesions close to the initial GTV targets in 2 patients. The first was a discontinuous dural lesion in the post-op bed. The second was a nodular dural lesion along the left high parietal convexity adjacent to a prior craniectomy and mesh duraplasty site. In the third patient, PET scan identified a greater extent of disease in the skull base. Across all observers, GTV volumes were significantly increased when PET fusion was used. The average volume (cc) increase was 111.6%±66.2%. The average Dice index was 0.58±0.17.

CONCLUSION
68Ga-DOTATATE PET scan fused with MRI improved the visualization of meningiomas in patients undergoing SRS. A larger experience is needed to confirm this trend. We have begun to use DOTATATE-PET imaging regularly when imaging patients with meningiomas for SRS.
RADT-44. STEREOTATIC RADIOSURGERY FOR RESIDUAL LESIONS OF PINEAL NON-GERMINOMATOUS GERM CELL TUMORS AFTER CONVENTIONAL RADIOTHERAPY: A RETROSPECTIVE STUDY
Authors: Lai Mingyao , Li Juan , Hu Qingjun , Zhou Jiangfen , Zhen Junjie , Wen Lei , Cai Linbo 
Published: December 2020

Abstract

OBJECTIVE
To evaluate the safety and efficacy of stereotatic radiosurgery (SRS) in treating residual lesions of pineal non-germinomatous germ cell tumors (NGGCTs) after conventional radiotherapy.

METHODS
The patients admitted to Guangdong Sanjiu Brain Hospital from 1 January 2008 to 31 December 2018 who diagnosed with pineal NGGCTs pathologically or clinically were retrospectively analyzed. Among those, the patients received conventional radiotherapy with or without SRS were included. The residual lesions after radiotherapy were defined with a maximum diameter &gt; 10mm. Prognosis related parameters such as local control rate, progress-free survival, overall survival and treatment-related toxicity were determined.

RESULTS
The median follow-up time was 34 months (range 8-142 months). The objective response rate and disease control rate were 71.4% and 95.2%, respectively. Three-year progression-free survival rate was 85.2% and 3-year total survival rate was 88.0%. The univariate analysis revealed that both age and concurrent chemotherapy were not correlated with the prognosis (P=0.286, 0.824). Partial tumor resection before radiotherapy and chemotherapy, AFP＞500ng/ml, and no more than 4 cycles of adjuvant chemotherapy were poor prognostic factors (P=0.037, 0.010, 0.006). Moreover, no acute radiation response was observed after treatment with SRS. Only 1 out of 27 patients (3.7%) had brain neurotoxicity related to a prolonged course of radiochemotherapy.

CONCLUSION
SRS for residual lesions of NGGCTs following conventional radiotherapy appears to be well tolerant and improved local control. However, the combination of conventional radiotherapy and SRS warrants further investigations in a large-scale randomized controlled clinical trials.
RBIO-01. PROSPECTIVE OBSERVATIONAL STUDY TO DETERMINE THE IMMUNE SYSTEM RESPONSE TO GAMMA KNIFE RADIOSURGERY FOR VESTIBULAR SCHWANNOMAS
Authors: Silverman Joshua S , Gurewitz Jason , Gunter Courtney , Cooper Benjamin , Palermo Amy , Boulio Lynda , Schafrick Jessica , Lim Whei Ying , Karhan Ece , Renzullo Stephanie , Kozhaya Lina , Golfinos John , Sulman Erik , Unutmaz Derya , Kondziolka Douglas 
Published: December 2020

Abstract

INTRODUCTION
The effects of radiosurgery for primary intracranial tumors on systemic immune response are unknown. Vestibular schwannomas (VS) treated with Gamma Knife (GK) have high control rates and low risk of adverse effects. This study examines if radiosurgery for VS is associated with an immune response detectable by peripheral blood sampling, and if that response can be correlated with tumoral expansion and/or toxicity.

METHODS
50 patients treated with GK for VS were enrolled on an IRB-approved, prospective study at initial consultation. Blood samples were drawn preceding GK and 6 months and 1 year follow-up. Neurological and hearing outcomes were assessed. Tumor volume was measured at treatment, 6 months, and 1 year follow-up. Tumoral expansion (TE) was defined by volumetric increase &gt;20%. Immunophenotyping via multicolor flow cytometry panels evaluated lymphoid and myeloid differentiation, phenotypic characterization, activation, tissue homing, and immune exhaustion.

RESULTS
Median volume at radiosurgery was 0.55cc (range 0.04-11.94) and median margin dose was 12.5Gy (11.5-13) prescribed to the 50% isodose line (50-60). 22 tumors exhibited TE, 20 at six months and 2 at one year. No VS with TE grew at median follow-up of 30.8 months (9.8-52.8). 1 tumor, non-expanding (NE) post-GK, showed progression at 24 months. Presence of cranial neuropathy and hearing decline was similar in both groups. Immunophenotyping showed numerous significant (p&lt; .05) changes in the TE group, not seen in NE, at 6 months and 1 year follow-up compared to baseline. Major changes were observed in cytokine secretion (e.g. IFNg, TNF or IL-17) of CD4+ and CD8+ memory T cells, frequencies of regulatory T cells, increased death of CD8+ effector cells in culture, suggesting chronic activated state.

CONCLUSION
Vestibular schwannomas that expand after GK are associated with a peripherally measurable change in systemic immune response that is absent from non-expanding tumors. The biologic underpinnings of these findings require further study.
RBIO-03. HETEROGENEITY OF HUMAN PATIENT-DERIVED XENOGRAFTS GROWTH RATES RESPONSES TO THE RADIATED MICROENVIRONMENT
Authors: zhang Jibo , Olson Ian E , Carlstrom Lucas P , Rahman Masum , Rajani Karishma , Gupta Kshama , Liu Libo , Tang Zhi , Sananikone Eliot F , Dong Anqin Dong , Warrington Arthur E , Rodriguez Moses , Chen Jincao , Schroeder Mark A , Ikram Samar , Sarkaria Jann , Burma Sandeep , Burns Terry C 
Published: December 2020

Abstract

BACKGROUND
Radiotherapy, combined with surgical resection and chemotherapy, remains a first-line treatment for infiltrative gliomas. However, these tumors are not surgically curable, and often recur, even within the prior radiation field, and may demonstrate a more aggressive phenotype. Importantly, high grade gliomas display diverse molecular phenotypes, and whether this genetic variability leads to divergent behaviour in the radiated tumor microenvironment is unknown. Herein, we characterize the effects of the irradiated brain microenvinroment on nine additional unique GBM cell lines to better understand the nuances of how tumor molecular phenotypes influence cellular dynamics.

METHODS
Female athymic nude mice were randomly divided into cranial radiation (15 Gy) and non-radiated groups. Mice then underwent intracranial implantation with one of the selected patient-derived xenograft (PDX) GBM cell lines (GBM 6, 10, 12, 39, 46, 76, 123, 164, 196; total n=8-15, per group, per line). Kaplan-Meyer (K-M) and log-rank tests were performed to compare the survival between irradiated and non-irradiated groups.

RESULT
Of nine previously untested human GBM lines, we found that five demonstrated shorter survival in the pre-radiated brain (GBM 6, 46, 76, 164, 196). However, two lines yielded prolonged survival in the pre-radiated brain (GBM 10, 12); GBM 39, 123 whose rate of growth was not impacted by the radiated brain.

CONCLUSION
These results highlight the likely critical impact of the irradiated microenvironment on tumor behaviour, yet illustrate that different tumors may exhibit opposing responses. Although further evaluation will be needed to understand mechanisms of divergent behavior, our data suggest the increased rate of growth in the radiated microenvironment may not apply to the fastest-growing tumor lines, which could instead demonstrate a paradoxical response.
RBIO-05. MITOTIC ENRICHMENT AS AN EFFICIENT STRATEGY TO RADIOSENSITIZE GLIOBLASTOMA
Authors: de Gooijer Mark C , Slangen Paul L G , Çitirikkaya Ceren H , Çolakoğlu Hilal , El Ouazani Amal , Shah Ronak , Borst Gerben R , van Tellingen Olaf 
Published: December 2020

Abstract
Their location and highly aggressive nature renders glioblastoma (GBM) among the most deadly and devastating of human malignancies. Despite extensive treatment involving surgery and adjuvant chemo-radiotherapy, the prognosis is still dismal and novel treatment strategies are urgently needed. Of all existing adjuvant therapies, radiotherapy contributes the most to extending the median overall survival. Increasing the efficacy of existing radiotherapeutic regimens is therefore a logical avenue to improve the survival of GBM patients. We have developed a novel radiosensitization strategy called ‘induction of mitotic enrichment’. It has long been known that the radiosensitivity of a cell depends on the phase of the cell cycle and that especially mitotic cells are especially vulnerable. Enriching the tumor for mitotic cells by arresting them during division prior to each radiotherapy fraction should therefore render the tumor population more sensitive to irradiation. Ideally, induction of mitotic enrichment should be reversible and non-cytotoxic to prevent healthy tissue toxicity and be compatible with clinically applied hyperfractionated radiotherapy regimens. We have now identified an orally available targeted tubulin polymerization inhibitor that can achieve repeated and reversible mitotic enrichment for up to 10 hours prior to radiotherapy, without causing cytotoxicity in vitro or healthy tissue toxicity in vivo. Most importantly, this tubulin inhibitor efficiently radiosensitizes a range of preclinical GBM models in vitro and in vivo, including GSC models, and significantly improves survival, but only in a mitotic enrichment setup when given 6-8 hours prior to radiotherapy to allow accumulation in mitosis. We are currently expanding our preclinical development of mitotic enrichment as a radiosensitization strategy to other mitotic targets and different intra- and extracranial cancer models representing several diseases for which radiotherapy is a mainstay treatment. In parallel, we are preparing a phase 0 trial to demonstrate induction of mitotic enrichment in human GBM.
RTID-03. A PHASE I CLINICAL TRIAL TO EVALUATE MTD OF PERAMPANEL AND MEMANTINE IN COMBINATION WITH STANDARD CHEMORADIOTHERAPY FOR THE TREATMENT OF PATIENTS WITH NEWLY DIAGNOSED GBM –A STUDY DESIGN
Authors: Kong Xiao-Tang , Albala Bruce , Du Senxi , Hrachova Maya , Bota Daniela 
Published: December 2020

Abstract

BACKGROUND
Glioblastoma (GBM) is the most aggressive malignant brain tumor in adults with poor prognosis. Effective treatment is urgently needed. Recent studies demonstrated cross-talk between neuron and glioma through neuro-transmitter glutamate receptors (AMPA and NMDA receptors) promotes glioma invasion and progression in vitro and in vivo. Therefore, dual blocking AMPA and NMDA receptor therapy is a potential strategy to prevent and treat GBM progression, particularly given the fact that the two blockers act through different anti-glioma mechanism. OBJECTIVE/

HYPOTHESIS
We hypothesize that adding Perampanel (an AMPA receptor blocker) and Memantine (a NMDA receptor antagonist) to standard temozolomide plus radiation therapy for the treatment of newly diagnosed GBM patients may be well tolerated and have a safe profile to prevent tumor progression, seizure recurrence or cognition impairment from radiation.

STUDY DESIGN
3 + 3 DESIGN: Maximum Tolerated Dose (MTD) is dose level at which 0/3 or 1/6 patients experience DLT with the next higher dose having at least 2/3 or 2/6 patients encountering DLT. MTD will not be more than FDA approved maximized doses for Perampanel (12 mg daily) and Memantine (20 mg bid) for the treatment of neurological diseases. Once the MTD is found, the patient will continue at MTD for the completion of concurrent chemoradiation therapy plus completion of 6 cycles of adjuvant temozolomide therapy.

SUMMARY
A Phase I trial to study the safety and toxicity of combined Perampanel and Memantine with standard chemo-radiation therapy to treat patients with newly diagnosed glioblastoma (GBM). To find Maximum Tolerated Dose (MTD) Levels of Perampanel and Memantine at concurrent chemoradiation therapy phase and adjuvant chemotherapy phase to prepare for future phase II or III trial.
RTID-11. GBM AGILE: A GLOBAL, PHASE 2/3 ADAPTIVE PLATFORM TRIAL TO EVALUATE MULTIPLE REGIMENS IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA
Authors: Buxton Meredith , Alexander Brian , Berry Donald , Cavenee Webster , Colman Howard , de Groot John , Ellingson Benjamin , Gordon Gary , Khasraw Mustafa , Lassman Andrew , Lee Wenbin , Lim Michael , Mellinghoff Ingo , Perry James , Sulman Erik , Tanner Kirk , Weller Michael , Wen Patrick , Yung W K Alfred , Cloughesy Timothy , Investigators G B M Agile 
Published: December 2020

Abstract
Developing new therapies for patients with glioblastoma (GBM) requires focused interaction between industry, academia, nonprofits, patient advocacy, and health authorities, and novel approaches to clinical trials. GBM Adaptive Global Innovative Learning Environment (GBM AGILE) Trial was designed by over 130 global key opinion leaders in consultation with health authorities to provide an optimal mechanism for phase 2/3 development in GBM. The Sponsor of GBM AGILE is the Global Coalition for Adaptive Research, whose mission is to accelerate the development of treatments rare and deadly diseases by serving as sponsor of innovative trials. GBM AGILE is an international platform trial designed to evaluate multiple therapies in newly diagnosed and recurrent GBM. Its goals are to identify effective therapies for GBM and match effective therapies with patient subtypes, with data generated to support regulatory filing for new drug applications. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. The primary endpoint is overall survival. The trial is being conducted under a master Investigational New Drug Application/Clinical Trial Agreement and Master Protocol, allowing multiple drugs from different companies to be evaluated simultaneously and/or over time. The plan is to add experimental therapies as new information is identified and remove therapies as they complete their individual evaluation against a common control. GBM AGILE received IND approval from the FDA in April 2019, screening its first patient in June 2019. As of June 2020 over 200 patients have been screened. Expansion to Canada, Europe, China, and Australia is also underway. There is currently one investigational arm under evaluation in the trial, with two additional arms to be added in Q4 2020/ Q1 2021. Clinical trial information: NCT03970447.
STEM-02. IN VIVO PHAGE DISPLAY IDENTIFIES PEPTIDE TARGETING N-CADHERIN ON GLIOMA STEM CELLS
Authors: Potez Marine , Kim Jongmyung , She Chunhua , Chaudhary Neelkamal , Liu James 
Published: December 2020

Abstract
Glioblastoma (GBM) is the most aggressive primary brain tumor with high mortality rates and resistance to conventional therapy. Glioma stem cells (GSCs) comprise a sub-population of glioma tumor cells with the ability of self-renewal and tumor recapitulation, and may be responsible for GBM’s treatment resistant properties. Identification of surface receptors that are novel and specific to GSCs may be the key to the development of effective therapeutic strategies. We have selected a GSC specific targeting peptide isolated through in vitro and in vivo phage display biopanning. This screening technique allowed us to determine a peptide (GBM-IC2) which binds specifically to GSCs in vitro, and to GBM tissue in vivo. Although this screening process allows for isolation of cell specific targeting peptides, it does so without identification of the cellular binding partner. Given the specificity of the peptide, identification of the cellular receptor may allow for discovery of novel markers to identify GSCs. To identify the peptide binding partner of GBM-IC2, the biotinylated peptide was incubated with GSC protein lysate. The peptide, along with its binding partner, was isolated using streptavidin agarose resin. The binding partner protein was then identified using mass spectroscopy. This revealed N-cadherin (CDH2) as a potential binding partner for the GBM-IC2 peptide. GBM-IC2 demonstrated specificity for targeting CDH2 compared to control peptide using ELISA. Lentiviral induced overexpression of CDH2 in HEK293 cells allowed for GBM-IC2 peptide binding. Competition assay was performed by applying anti-CDH2 antibody to GBM-IC2 peptide and GSCs in culture. Application of anti-CDH2 antibody decreased peptide binding to GSCs, confirming CDH2 as the binding partner for GBM-IC2. These results demonstrate that cell specific targeting peptides isolated through phage display may lead to the isolation of novel cell specific proteins through immunoprecipitation isolation and mass spectroscopy analysis.
STEM-04. PLATELETS DRIVE GLIOBLASTOMA ONCOGENESIS BY ENHANCING THE GLIOMA STEM CELL PHENOTYPE
Authors: Sloan Anthony , Lee-Poturalski Christine , Elder Theresa , Harris Peggy , Cioffi Gino , Raghavan Alankrita , Willis John , Rich Jeremy , Kerstetter-Fogle Amber , Barnholtz-Sloan Jill S , Jankowsky Eckhard , Sloan Andrew E 
Published: December 2020

Abstract
Glioblastoma (GBM) is recognized as one of the deadliest forms of cancer, despite aggressive therapy consisting of maximal surgical resection followed by concurrent radiation and chemotherapy, the median survival remains ~12 months. Glioma stem cells (GSCs) possess potent tumor-initiating properties and comprise a cellular hierarchy that is responsible for treatment resistance and progression. Specifically targeting GSCs has been considered a promising therapeutic approach, however no clear method has been identified. Histologically, it is known that GSCs are found in perivascular and pseudsopalisading regions of GBM. Similarly, platelet aggregates are often found in pseudsopalisading necrotic regions, suggesting a potential interaction between platelets and GSCs due to their spatial locations. High platelet counts have been associated with poor clinical outcome in many cancers including ovarian and endometrial cancer. While platelets are known to affect progression of other tumors, mechanisms by which platelets influence GBM oncogenesis are unknown. Our work aimed to understand the crosstalk between GSCs and platelets within GBM solid tumors that work to enhance disease progression and treatment resistance. Our clinical studies suggest elevated platelet counts positively correlate with tumor growth and negatively correlate to overall patient survival. We found platelets and GSC co-localization in GBM solid tissue; platelet exposure to GSCs results in increased proliferation of GSCs specifically, by increasing the self-renewing capacity of GSCs in a dose dependent manner, and resulted in an increased “Stem-like” transcriptional pattern. Inhibiting the GSC-platelet interaction results in a decrease in GSC renewal and stemness. These results introduce a novel interaction between GSCs and platelets and elucidate a novel therapeutic approach specifically targeting GSCs by disrupting the GSC-platelet interaction.
STEM-06. THE ROLE OF IFITMs IN MAINTAINING GLIOMA STEM CELLS
Authors: Nita Erisa , Nekulova Marta , Brennan Paul M , Ball Kathryn 
Published: December 2020

Abstract
Glioblastoma, one of the most lethal and heterogeneous primary brain tumours, contains cellular hierarchies with both quiescent and self-renewing glioblastoma stem cells (GSCs). GSCs contribute to a lack of progress in patient survival as they appear to have an innate resistance to both chemotherapy and radiotherapy. The aim of this study is to elucidate how constitutive expression of interferons (IFNs) and their downstream signalling pathways maintain GSCs thereby supporting treatment resistance and tumour reoccurrence. To understand the mechanism of action of a subset of IFN regulated genes, originally characterized as a signature for radiation and chemotherapy resistance (IRDS), a panel of patient derived GSCs was generated and manipulated using CRISPR/Cas9 gene-editing. Phenotypic changes in growth, viability and drug resistance were characterised and linked to molecular level events using transcriptomic and proteomic techniques. Using this approach, in conjunction with patient tissue analysis, signalling under basal as well as IFN-activated conditions was studied in the context of GSC status. Immunohistopathology of a glioma tissue micro-array identified an increased expression of IFN induced transmembrane receptors (IFITMs), which co-localised with Nestin, around the blood vessels suggesting that IFITM positive cells were in the stem cell niche. Further analysis showed the presence of IFITM1 and IFITM3 in GSCs and established that loss of IFITMs function impacted on growth rate and cell cycle progression as well as treatment sensitivity. By using wild-type and gene-edited GSC to focus on the relationship between IFITM1 and IFITM3, we have compelling phenotypic and molecular evidence that IFN-induced changes in the localisation of IFITMs impact on the ability of stem cells to ‘escape’ normal growth control mechanisms. Taking into consideration the constitutive expression of interferons in the tumour microenvironment, our study provides evidence that IFITMs regulate GSC self-renewal and are involved in maintaining a quiescent population which can escape chemotherapy.