bluuebunny/crossref_metadata_2025_split huggingface dataset:
RTID-12. PHASE 2 TRIAL OF TUMOR TREATING FIELDS (TTFIELDS) PLUS RADIATION THERAPY (RT) PLUS TEMOZOLAMIDE (TMZ) COMPARED TO RT PLUS TEMOZOLOMIDE IN NEWLY DIAGNOSED GLIOBLASTOMA (ndGBM)
Authors: Grossman Rachel , Limon Dror , Bokstein Felix , Harosh Carmit Ben , Blumenthal Deborah , Ram Zvi 
Published: December 2020

Abstract

OBJECTIVE
In the EF-14 phase 3 trial, TTFields 9200 kHz) added to maintenance TMZ increased median OS to 20.9 months versus 16.0 months with maintenance TMZ (p&lt; 0.001) in ndGBM. Preclinical investigations showed that TTFields/RT have a synergistic effect. A pilot study (N=10) in ndGBM demonstrated the feasibility and safety of TTFields combined with RT/TMZ (Grossman Front Onc 2020). The only TTFields-related adverse event was array-associated skin toxicity. Median PFS was 8.9 months. Based on these encouraging results, this prospective, randomized phase 2 study [NCT03869242] in 60 patients further investigates if the addition of TTFields TMZ/RT treatment in ndGBM patients improves treatment efficacy and delays disease progression.

METHODS
Following debulking surgery or biopsy, 60 patients (≥18 years) with histologically confirmed GBM, KPS≥70 and life expectancy &gt;3 months will be randomized 1:1 to: i) RT with concomitant TMZ/TTFields (200 kHz) for 6 weeks followed by up to 6 months of maintenance TMZ combined with TTFields (experimental arm) up to 24 months; or ii) RT with concomitant TMZ alone followed by maintenance TMZ combined with TTFields (control arm). Patients with early progressive disease, significant comorbidities precluding maintenance RT or TMZ or with implanted electronic devices will be excluded. The primary endpoint is the rate of progression free survival at 12 months (PFS12). Treatment with TTF will be continued until second progression or 24 months (the earlier of the two). All patients will be followed for survival. All adverse events will graded per CTCAE V5.0. The sample size of 60 patients provides 80% power with two-sided alpha level of 0.05 to detect a PFS12 of 46.5% with RT/TMZ/TTFields compared to 29.4% with RT/TMZ followed, respectively, by maintenance TMZ/TTFields (calculated from the RT/TMZ followed by maintenance TMZ/TTFields arm of the EF-14 trial). Follow-up will continue for &gt;12 months from recruitment of the last patient.
STEM-12. ZIKA VIRUS TARGETS GLIOBLASTOMA STEM CELLS THROUGH A SOX2-INTEGRIN α vβ 5 AXIS
Authors: Chen Clark , Dhawan Sanjay , Zhu Zhe , Mesci Pinar , Rich Jeremy 
Published: December 2020

Abstract

INTRODUCTION
Oncolytic virus hold great promise as a platform for glioblastoma therapeutic development. Zika virus (ZIKV) is an oncolytic virus with exquisite selectivity for infecting and killing glioblastoma stem cells (GSCs). Here, we delineate the molecular determinant of this selectivity.

METHODS
cell-based glioblastoma models, glioblastoma organoid assays, in vivo murine glioblastoma models, ZIKV infectivity assays, gene silencing, ChIP-seq studies.

RESULTS
In independent models, ZIKV preferentially infected and lysed SOX2+ GSCs. Silencing of SOX2 expression attenuated this preferential infectivity. Of note, ZIKV infection of GSCs was independent of AXL, its putative receptor in normal brain. ChIP-seq experiments revealed that SOX2 bound within the ITGAV locus (encoding the integrin av subunit), and this binding was associated with accumulation of the active chromatin mark H3K27ac. Silencing of SOX2 suppressed ITGAV expression as well as ZIKV infectivity against GSCs, indicating that integrin is required for ZIKV infection. Of integrin b units, only silencing of integrin b5 prevented the killing of GSCs by ZIKV infection, suggesting ZIKV infection required the avb5 integrin. Supporting this hypothesis, blockade of the avb5 integrin substantially reduced ZIKV infection of GSCs in glioblastoma organoid assays and in clinical glioblastoma specimens. Sox2 expression additionally suppress GSC expression of all members of the interferon-stimulated genes (ISG family), thereby suppressing innate anti-viral response to facilitate ZIKV infection.

CONCLUSIONS
Collectively, our results reveal that ZIKV infection of GSCs is mediated by integrin α vβ 5 leading to SOX2 expression which negatively regulates antiviral immunity thereby facilitating ZIKV infection.
STEM-24. RADIATION-INDUCED EXTRACELLULAR VESICLE (EV) RELEASE OF miR-603 PROMOTES IGF1-MEDIATED STEM CALL STATE IN GLIOBLASTOMAS
Authors: Ramakrishnan Valya , Xu Beibei , Akers Johnny , Nguyen Thien , Ma Jun , Dhawan Sanjay , Ning Jianfang , Mao Ying , Hua Wei , Kokkoli Efrosini , Furnari Frank , Carter Bob , Chen Clark 
Published: December 2020

Abstract

INTRODUCTION
Release of exosomes and extracellular vesicles (EV) by glioblastomas plays key roles in modulating the tumor microenvironment and therapeutic response. Studies to date have largely focused on the impact of EV and exosomes on the recipient cell. Here, we demonstrate that EV-mediated export of a master-regulatory miRNA has fate-determining impacts on the cell releasing the EVs.

METHODS
microRNA (miRNA) profiling was performed using clinical glioblastoma specimens from the same patients derived pre- and post-standard of care treatment. Mechanism mediating altered miRNA homeostasis were assessed.

RESULTS
While the levels of nearly all miRNAs remained unchanged after standard-of-care treatment, decreased levels of few, select miRNAs were observed, including miR-603. In response to ionizing radiation (IR), but not temozolomide (TMZ), glioblastoma cell lines exhibited a time-dependent decrease in miR-603 levels. While miR-603 biogenesis and degradation remained unchanged after IR, IR induced an increase in EV-mediated export of miR-603. Profiling of miR-603 targets revealed that miR-603 repressed the insulin-like growth factor 1 (IGF1) and IGF1 receptor (IGF1R), genes required to maintain the cancer stem cell (CSC) state, as well as MGMT, the gene encoding a DNA repair protein that detoxifies temozolomide (TMZ) induced DNA damages. IR induced export of miR-603 de-repress IGF1/IGF1R to promote radiation resistance and de-repress MGMT to promote cross-resistance to TMZ and CCNU. Ectopic miR-603 expression overwhelmed cellular capacity for miR-603 export and synergized with the tumoricidal effects of IR and temozolomide (TMZ).

CONCLUSIONS
Radiation stimulated EV-mediated export of miR-603 to facilitate acquired resistance to IR and cross-resistance to DNA alkylating agents.
SURG-01. RISK OF TRACT RECURRENCE WITH STEREOTACTIC BIOPSY OF BRAIN METASTASES: AN 18-YEAR CANCER CENTER EXPERIENCE
Authors: Carnevale Joseph , Winston Graham , Goldberg Jacob , Brennan Cameron , Tabar Viviane , Moss Nelson 
Published: December 2020

Abstract

BACKGROUND
Stereotactic biopsy is increasingly performed on brain metastases (BrM) as improving cancer outcomes drive aggressive multimodality treatment, however the risk of tract recurrence for such biopsies, in both the upfront and recurrent settings, are poorly defined in an era defined by focused-irradiation paradigms. As such, the rate of tract recurrence was evaluated.

METHODS
A retrospective review was performed to identify stereotactic biopsies performed for BrM at Memorial Sloan Kettering Cancer Center from 2002-2020. Data including surgical indications, tumor type, radiographic characteristics, stereotactic planning, pre- and post-operative CNS-directed and systemic treatments, and clinical courses were collected. Recurrence was evaluated using RANO-BM criteria.

RESULTS
Four-hundred-and-seventy-nine patients underwent stereotactic intracranial biopsy for any diagnosis (&gt;80% were for gliomas or CNS lymphoma). Twenty-two (4.5%) were for pathologically-confirmed viable BrM and 91% of these underwent postoperative irradiation with either stereotactic radiotherapy (14/20, 70%; SBRT) in plans that did not specifically target the biopsy tract, or whole-brain irradiation (6/20, 30%; WBRT). Eleven patients (50%) had &gt;/=3 months radiographic follow-up (median 11.9; 4.5-30.6), of which 6 (55%) developed discontinuous enhancement along the tract at a median 6.4 months (2.3-17.1) post-biopsy. Of these, 2 had previously been treated with SBRT and were sampled in the setting of diagnostic ambiguity (one additionally with WBRT for small cell carcinoma) and underwent intraoperative laser interstitial thermal therapy (LITT) immediately following biopsy. The remainder were treated with SBRT +/- LITT (n=3 and 4, respectively) following biopsy. Tract recurrences were treated with resection (n=2, both with pathologic confirmation), re-irradiation (n=1) or observation/systemic therapy.

CONCLUSIONS
In this largest reported series of biopsied BrM, we identify a nontrivial rate, higher than previously described, of recurrence along stereotactic biopsy tracts. As BrM are most commonly treated with focused radiotherapy centered on enhancing tumor margins, consideration should be made to include biopsy tracts where feasible.
SURG-35. INTRACRANIAL MYXOID MESENCHYMAL TUMOR WITH EWSR1-ATF1 GENE FUSION
Authors: Ward Benjamin , Wang Christopher , Macaulay Rob , Liu James 
Published: December 2020

Abstract
Intracranial myxoid mesenchymal tumors (IMMT) carrying an EWSR1-CREB gene family fusion are extremely rare and have only been identified in ten relatively recent reported cases. There is some question as to whether this is a novel entity, or a myxoid variant of angiomatoid fibrous histiocytoma (AFH), given certain histopathological similarities. Despite these similarities, the increasing number of cases reported appear to demonstrate clear histological differences that indicate IMMTs are a distinct and novel entity. Previous reports have focused on histological analysis but have lacked detailed long-term clinical follow-up and recommendations regarding treatment approach. In this case, we describe a 48-year-old female who presented with a left intraventricular mass that was identified histologically as an IMMT with an EWSR1-ATF1 gene fusion. Following initial resection, the tumor demonstrated local recurrence. Repeat resection was performed followed by immediate demonstration of local, as well as distant, tumor recurrence. Subsequent histological analysis of the tumor demonstrated a myxoid mesenchymal tumor clearly distinct from AFH. Fractionated stereotactic radiation therapy was administered following the second resection and tumor control was achieved at 1 year. This case is particularly remarkable as it is only the second reported IMMT case to occur in a middle-aged adult, with all other cases occurring in children or young adults. The two middle-aged adult cases share striking similarities in clinical presentation, including a history of breast cancer. Our findings indicate that an intracranial myxoid mesenchymal tumor is a novel and rare entity that may demonstrate rapid local and distant recurrence. Given the aggressive recurrence seen with the presented case, we recommend the treatment plan to be surgical resection followed by adjuvant radiation therapy to maintain tumor control.
SURG-36. THE EVALUATION OF POSTOPERATIVE MOTOR FUNCTION DEFICITS AFTER SUPRATENTORIAL BRAIN TUMOR SURGERY THROUGH THE ANALYSIS OF INTRAOPERATIVE MEP AND ISCHEMIC LESION ON POSTOPERATIVE DWI
Authors: Yang Seung Ho , Kil Hong Yong , Kim Young Il 
Published: December 2020

Abstract

BACKGROUND
The authors investigated the incidence of ischemic lesions on immediate postoperative diffusion-weighted imaging (DWI) according to the findings of intraoperative motor evoked potential (MEP) and the correlation with postoperative motor function deficits.

METHODS
From January 2016 to June 2018, total 127 supratentorial brain tumor patients were enrolled in this study. The intraoperative MEP results were analyzed in the following three groups: no decline below 50 % of baseline (A), transient decline below 50 % of baseline (B), no recovery until end stage of surgery (C). Postoperative magnetic resonance imaging was performed within 48 hours after surgery.

RESULTS
Of the total 127 patients, MEP changes (group B&C) were observed in 25 patients (25/127, 19.7%), DWI positive findings were identified in 31 patients (31/127, 24.4%) and motor function deficits were observed in 19 patients (19/127, 15%), respectively. DWI positive finding rate was higher in gliomas (14/43, 32.6%) than meningiomas (8/51, 15.7%) or other tumors including metastasis (6/32, 18.8%), however, there was no statistical significance. In MEP changes, group B&C (16/25, 64%) showed higher DWI positive rate than group A (13/102, 12.7%). In DWI findings, the DWI positive cases (16/31, 51.6%) showed a higher motor function deficit rates than the DWI negative cases (3/96, 3%). These two results were all statistically significant (P&lt;0.01). In group A, motor function deficits were presented in 3 of 13 DWI positive case, all of which were transient. In group B, motor function deficits were presented in 9 out of 13 DWI positive cases with permanent 4 and transient 5. In group C, motor function deficits were presented in 4 out of 5 DWI positive cases with permanent 3 and transient 1.

CONCLUSIONS
Both intraoperative MEP changes and postoperative DWI positive findings in supratentorial brain tumor surgery were significant related with postoperative motor function deficits. Even if intraoperative MEP changes occur during supratentorial brain tumor surgery, active and appropriate efforts to prevent irreversible MEP changes may reduce the occurrence of permanent postoperative motor function deficits.
SURG-42. SAFETY OF INTRA-ARTERIAL CHEMOTHERAPY WITH OR WITHOUT OSMOTIC BLOOD BRAIN BARRIER DISRUPTION IN TREATMENT OF BRAIN TUMORS
Authors: Uluc Kutluay , Tabb John Philip , Nerison Caleb S , Dogan Aclan , Priest Ryan A , Ambady Prakash , Neuwelt Edward 
Published: December 2020

Abstract

BACKGROUND
Intra-arterial route of drug delivery (IA) without or with osmotic blood brain barrier disruption (IA/BBBD) is one of the available techniques to overcome the blood-brain barrier and enhance drug delivery to brain tumors. We present a large single institution safety data of IA or IA/BBBD.

METHODS
This is a retrospective review of the electronic records, imaging and complications in patients who underwent IA or IA/BBBD in OHSU between December, 1997 and November, 2018. Procedural complications were documented prospectively and reviewed in the electronic medical records. Toxicities, attributed to chemotherapy, were reported when grade is either II or higher by Common Terminology Criteria for Adverse Events (CTCAE).

RESULTS
Complications related to chemotherapy and procedure were reported separately. Total of 4940 procedures (1102 IAC and 3838 oBBBD) were performed on 436 patients (190 female and 246 male). Pathologies were primary central nervous system lymphoma (PCNSL) (n=115, 26%), secondary central nervous system involvement (SCNSL) (n=37, 8%), glioblastoma (n=79, 18%), astrocytoma (grade II/III) (n=34, 7%), oligodendroglioma (n=64, 14%), pilocytic astrocytoma (n=10, 2%), metastatic (n=38, 8%), embryologic (n=37, 8%), others (n=22, 5%). Procedural complications: groin related (n=16, 0.32%), transient neurological decline (n=57, 1.15%), subintimal arterial injury (n=13, 0.26%), asymptomatic imaging changes (T2 or DWI) (n=60, 1.21%), symptomatic stroke (n=21, 0.43%), myocardial infarction (n=3, 0.37%), cervical cord injury (n=6, 0.12%), death within 3 days (n=6, 0.12%). Minor complications are 2.86%, major complications are 1.12%. Eighty-four percent (n=369) of the patients experienced grade 2 or higher toxicities attributed to chemotherapy.

CONCLUSION
We present the largest safety data set to date from a single institution experience using IA and IA/BBBD for brain tumors. Our results suggest that IA and IA/BBBD is safe and can be performed multiple times in the same patients with acceptable procedure related complications. Efficacy of this approach is being evaluated in prospective clinical trials.
TAMI-39. AGE-DEPENDENT PHENOTYPIC CONVERSION FROM NEURONAL ACTIVITY TO NEURO-INFLAMMATION IN GLIOBLASTOMA PROGRESSION
Authors: Yamashita Daisuke , Flanary Victoria , Munk Rachel , Sonomura Kazuhiro , Ozaki Saya , Kawaguchi Riki , Suehiro Satoshi , Ghosh Sadashib , Chen Zhihong , Yamaguchi Shinobu , Komarova Svetlana , Bastola Soniya , Bernstock Joshua , King Gwendalyn , Kunieda Dr , Hambardzumyan Dolores , Kondo Toru , Kornblum Harley , Crossman David , Hackney James , Horvath Steve , Sato Taka-aki , Gorospe Myriam , Nakano Ichiro 
Published: December 2020

Abstract
The rise in population aging worldwide is causing an unparalleled increase in death from many cancers, including glioblastoma (GBM). Here, we have explored the impact of aging and rejuvenation on GBM tumorigenesis. Compared with neuro-inflammatory old GBM, young GBM displayed elevated neuronal/synaptic signaling via brain-derived neurotrophic factor (BDNF) and SLIT and NTRK like-family member 6 (SLITRK6), promoting favorable survival rates. These effects were attributed to the rise in nicotinamide adenine dinucleotide (NAD+) levels, as brain rejuvenation by parabiosis or administration of nicotinamide mononucleotide (NMN) in mice elicited a younger phenotype with activated neuronal/synaptic signaling and improved outcomes. Our data indicate that age-associated NAD+ loss contributes to the highly aggressive GBM by the shift from neuronal/synaptic activity to neuro-inflammation in the elderly brain. These findings have therapeutic and preventive implications in GBM and provide mechanistic insights into the exacerbation of GBM tumorigenesis by aging.
TAMI-48. ENGRAFTMENT PHENOTYPES IN PRECLINICAL MODEL SYSTEMS REVEAL A FUNCTIONAL SUBGROUP OF PATIENT TUMORS DEPENDENT ON THE BRAIN TUMOR MICROENVIRONMENT FOR GROWTH
Authors: Bayley Nicholas , Tse Christopher , Zhu Henan , Yan Weihong , Gosa Laura , Baufeld Lynn , Ta Lisa , Prins Robert , Yong William , Cloughesy Timothy , Liau Linda , Graeber Thomas , Nathanson David 
Published: December 2020

Abstract
The derivation of model systems from patient tumors is a requisite for reproducible and high throughput translational cancer research. However, not all tumors can form a model and those that do often fail to capture the molecular diversity specific to their cancer. The potential tumor-intrinsic underpinnings remain largely unknown. In gliomas, the brain tumor microenvironment (TME) is increasingly acknowledged as a regulator of tumor proliferation, invasion, and therapy response. The dissimilar environment of in vitro and heterotopic xenograft models could potentially play a role in the limited fidelity of these model systems. Here we established a culture-free workflow and biobank of 144 glioma direct-from-patient orthotopic xenografts (DPDOX) and 51 parallel gliomasphere cultures (GS). Our direct-from-patient workflow enabled the exclusive in vivo establishment of several gliomas – hereafter termed TME-dependent tumors – including low and high grade mtIDH gliomas and histone H3.3 G34 glioblastomas notoriously difficult to culture in vitro. Through molecular profiling of over 75 patient tumors and their matched derivative models, we find that DPDOX tumors preserve a gene expression signature of neural and glial interactions not found in GS and enriched in brain TME-dependent patient tumors. While these patient tumors span a diversity of clinical diagnoses, network-based inferred transcription factor activity suggests that they converge on shared master regulators of self-renewal driving proneural and OPC/NPC-like cellular state enrichment. Integrating multi-omic profiling from TCGA and other publicly available datasets reveals that this expression signature corresponds to a shared DNA methylation signature across disparate epigenetic subgroups. These findings suggest a brain TME dependence in patient tumors across multiple molecular and clinical classifications of glioma which leads to a lack of representation in model systems failing to recapitulate tumor-promoting components of the TME. Further this work provides a resource to guide translational investigations accounting for influences of the model environment.
TAMI-51. IDENTIFYING NEW TUMOR MICROENVIRONMENT (TME) CONTEXTS OF VULNERABILITY IN GLIOBLASTOMA
Authors: White Kieron , Meylan Maxime , Bougoüin Antoine , Connor Kate , Salvucci Manuela , Bielle Franck , Prehn Jochen H M , Verreault Maite , Idbaih Ahmed , Sautès-Fridman Catherine , Fridman Wolf H , Byrne Annette 
Published: December 2020

Abstract
Glioblastoma (GBM) is the most frequent and aggressive adult brain tumor with 85% of patients dying within two years. New effective precision medicine therapies are urgently required, especially for isocitrate dehydrogenase wild-type (IDHwt) disease. Despite efforts to subtype patients based on molecular profiles, this approach has yet failed to direct treatment strategies. Further interrogation of the tumor microenvironment (TME) across molecular subtypes and identification of new TME specific subtypes may guide new directions for future therapies. Here, we analysed transcriptomic data from selected GLIOTRAIN(www.gliotrain.eu)(n=120) and TCGA(n=69) IDHwt patients. Firstly, the microenvironment cell population (MCP)-counter method (a gene-expression-based TME deconvolution tool) was validated for use in the brain tumor setting using quantitative multiplex immunohistochemistry. In this context, immune markers (CD20/CD3/CD68/CD8) were significantly correlated with MCP-counter scores. We are currently optimizing and validating a vessel-density and microglial RNA-signature to provide a more robust representation of brain TME. Next, using MCP-counter, the TME composition of IDHwt tumors was assessed within proneural (24%), classical (38%) and mesenchymal (38%) subtypes. We initially classified the GLIOTRAIN cohort into 3 novel clusters characterised by differences in TME composition and validated our findings in the TCGA cohort. A TME-high group (37%) is characterized by elevated presence of lymphocytes and myeloid cells, and presents a high level of immune checkpoint genes: PDCD1(PD1) and CTLA4. In addition, the presence of tertiary lymphoid structures (TLS) is a feature of TMEhigh/mesenchymal+ patients. This finding has been validated by IHC and RNA-signature. TME-med (38%) displayed heterogenous immune populations and the TME-low (25%) represented an ‘immune-desert’ group. There was no significant difference in OS based on these TME subtypes(p=0.50). We hypothesise that PD1/CTLA4 blockade might be an effective treatment strategy in TME-high patients. These hypotheses will be tested (in the adjuvant setting) using appropriate syngeneic disease models which incorporate surgical resection.