bluuebunny/crossref_metadata_2025 huggingface dataset:
RTID-10. SURGEONS TRIAL OF PROPHYLAXIS FOR EPILEPSY IN SEIZURE NAÏVE PATIENTS WITH MENINGIOMA: A RANDOMIZED CONTROLLED TRIAL (STOP ‘EM)
Authors: Jenkinson Michael , Helmy Adel , Huckey Helen , Mills Samantha , Grant Robin , Hughes Dyfrig , Marson Tony , Tangney Rebecca , Bulbeck Helen , Ali Usama , Gamble Carrol
Published: December 2020

BACKGROUND

Meningioma is the commonest primary brain tumour. 70% of patients are seizure-free at presentation, but approximately 12% will have seizures within 12 months of surgery. Seizures impact quality of life. Neurosurgeons administer prophylactic anti-epileptic drugs (AED) to prevent seizures despite a lack of evidence to support this. A meta-analysis of RCTs in brain tumours suggests that older AED may prevent seizures in the first week after surgery but not thereafter. There are no studies assessing newer AEDs in the prophylactic setting.

RESEARCH QUESTION

In patients with meningioma who have never had a seizure and are undergoing surgical resection, does prophylactic levetiracetam reduce the risk of developing seizures?

DESIGN

multi-centre, double-blind RCT in 20 UK centres. 1:1 randomisation of 14 days levetiracetam 500mg bd started one day before surgery compared to placebo.

PRIMARY OBJECTIVE

Determine whether 2 weeks prophylactic levetiracetam reduces the risk of developing seizures within 12 months of surgery compared to placebo.

ECONOMIC OBJECTIVE

Estimate cost-effectiveness of prophylactic levetiracetam.

SECONDARY OBJECTIVES

Determine effect of prophylaxis on time to first seizure and first convulsive seizure, whether prophylaxis affects quality of life and influences return to driving, safety of prophylaxis.

POPULATION

seizure-naïve meningioma undergoing surgery.

SAMPLE SIZE

seizure rate at 12 months is 12.3%. A 50% reduction is clinically beneficial. A two-group chi-squared test with 5% two-sided significance level will have 90% power to detect the difference between a Group 1 proportion of 0.12 and a Group 2 proportion of 0.06 when the sample size in each group is 477. Allowing for 5% dropout, 1004 patients will be recruited.

FUNDING

NIHR (£1.64M) award June 2020. Study opens March 2021.

TRANSLATIONAL RESEARCH

MRI, blood and tissue will be collected to explore risk factors for seizures.

CONCLUSIONS

study will provide class I evidence of the role of prophylactic levetiracetam in meningioma surgery.
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

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< 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 >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 >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

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

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

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 (>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 >/=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

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

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<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

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

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

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

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.
TMOD-09. GLIOBLASTOMA BIOPHYSICAL GROWTH ESTIMATION USING DEEP LEARNING-BASED REGRESSION
Authors: Pati Sarthak , Sharma Vaibhav , Aslam Heena , Thakur Siddhesh , Akbari Hamed , Mang Andreas , Subramanian Shashank , Biros George , Davatzikos Christos , Bakas Spyridon
Published: December 2020

BACKGROUND

Glioblastomas are arguably the most aggressive, infiltrative, and heterogeneous adult brain tumor. Biophysical modeling of glioblastoma growth has shown its predictive value towards clinical endpoints, enabling more informed decision-making. However, the mathematically rigorous formulations of biophysical modeling come with a large computational footprint, hindering their application to clinical studies.

METHODS

We present a deep learning (DL)-based logistical regression model, to estimate in seconds glioblastoma biophysical growth, defined through three tumor-specific parameters: 1) diffusion coefficient of white matter (Dw), which describes how easily the tumor can infiltrate through the white matter, 2) mass-effect parameter (Mp), which defines the average tumor expansion, and 3) estimated time (T) in number of days that the tumor has been growing. Pre-operative multi-parametric MRI (mpMRI) structural scans (T1, T1-Gd, T1, T2-FLAIR) from 135 subjects of the TCGA-GBM imaging collection are used to quantitatively evaluate our approach. We consider the mpMRI intensities within the region defined by the abnormal T2-FLAIR signal envelope, for training three DL models for the three tumor-specific parameters. Each of our DL models consist of two sets of convolution layers followed by a single max-pooling layer, with a normalized root mean squared error as the minimization metric and evaluated using 10-fold cross validation. We train and validate the DL-based predictions against parameters derived from biophysical inversion models.

RESULTS

Pearson correlation coefficients between our DL-based estimations and the biophysical parameters were equal to 0.85 for Dw, 0.90 for Mp, and 0.94 for T.

CONCLUSION

This study unlocks the power of tumor-specific parameters from biophysical tumor growth estimation, paving the way towards their utilization in more clinical studies, while opening the door for leveraging advanced radiomic descriptors in future studies, as well as allowing for significantly faster parameter reconstruction compared to biophysical growth modeling approaches.

*denotes equal senior authorship.
TMOD-13. RESEARCH RESOURCES FOR OLIGODENDROGLIOMA NOW AVAILABLE TO RESEARCH COMMUNITY
Authors: Greene Brock , Suva Mario , Cahill Daniel , Monje Michelle , Rich Jeremy , Mitchell Duane , Verhaak Roel , Abraham Bob
Published: December 2020

There are ~1,400 oligodendroglioma diagnoses in the U.S. annually, with up to 15,000 persons living with this disease today. However, there have not been any new treatments approved for oligodendroglioma in the past 25 years. A lack of funding and advocacy has contributed to this, but the lack of reagents allowing researchers to study the disease may be the most critical factor. Oligodendroglioma tissue and disease models, including cell lines and xenograft models, are crucial resources needed for researchers to understand oligodendroglioma biology, identify new treatment strategies, and perform preclinical research. Oligo Nation has created a collection of oligo tissue large enough to enable adequately-sized studies and meet the needs of researchers interested in studying Oligodendroglioma. Oligo Nation is also investing in developing new models of the disease as well as acquiring existing models to make them easily accessible to the research community. A number of resources are now available to support academic researchers: An oligodendroglioma biobank with over 100 patient tissue samples; WGS and RNA sequencing data, including long reads for these samples; An oligodendroglioma cell line repository with 3 lines available (to date) to researchers; An oligodendroglioma PDX repository will be available in the coming year through the NCI Patient Derived Model Repository; GEMM models that include both IDH1 (R132) and CIC mutations, two of the most common mutations in oligodendroglioma, will be available by the end of 2020. Extensive analysis including high-throughput and CRISPR knockout screens will be performed on all existing and new cell lines. The data generated on these models will be stored in a public repository and made available to the research community. Making these reagents available to the research community will hopefully increase research in oligodendroglioma, and will set us on a path to discover improved and ultimately curative treatments for this disease.
LTBK-04. PHASE 2 MULTICENTER STUDY OF THE ONCOLYTIC ADENOVIRUS DNX-2401 (TASADENOTUREV) IN COMBINATION WITH PEMBROLIZUMAB FOR RECURRENT GLIOBLASTOMA; CAPTIVE STUDY (KEYNOTE-192)
Authors: Zadeh Gelareh , Daras Mariza , Cloughesy Timothy F , Colman Howard , Kumthekar Priya U , Chen Clark C , Aiken Robert , Groves Morris D , Ong Shirley , Ramakrishna Rohan , Vogelbaum Michael A , Khagi Simon , Kaley Thomas , Melear Jason M , Peereboom David M , Rodriguez Analiz , Yankelevich Maxim , Nair Suresh G , Puduvalli Vinay K , Nassiri Farshad , Sonabend Adam M , Agensky Laura , Ewald Brett , Levisetti Matteo , Lang Frederick F
Published: December 2020

BACKGROUND

A Phase 2 multi-center study was conducted to evaluate the replication-competent oncolytic adenovirus, DNX-2401 (tasadenoturev), in combination with the anti-PD-1 antibody, pembrolizumab, in subjects with recurrent glioblastoma.

METHODS

Subjects ≥ 18 years with glioblastoma at first or second recurrence were treated with a single intratumoral injection of 5e8-5e10 vp DNX-2401 at the time of biopsy, followed by 200 mg pembrolizumab infusions every 3 weeks until progression or toxicity.

RESULTS

Forty-nine subjects were enrolled at first (79.6%) or second (20.4%) recurrence after prior surgery (89.8%), radiotherapy (100%), and temozolomide (100%). Forty-eight of 49 (98%) were treated with 5e8 vp (n=3), 5e9 vp (n=3), or 5e10 vp (n=42) DNX-2401 and pembrolizumab. Median treatment duration was 7 cycles (range 1–35) with one subject remaining on treatment (cycle 31). Adverse events were primarily mild to moderate, consistent with underlying disease, and manageable. Headache, brain edema, and fatigue are the most common events reported as related to the treatment regimen. Of subjects treated with full dose DNX-2401 and pembrolizumab (n=42), 5 subjects (11.9%) had confirmed responses, including 2 durable ongoing complete responses and 3 partial responses. One subject remains tumor free > 12 months after completing the planned 24 months of pembrolizumab. Median overall survival was 12.5 months; OS-12 and OS-18 were 54.5% and 20.8%, respectively. Four subjects, all of which have survived more than 21 months, continue to be followed for survival.

CONCLUSIONS

DNX-2401 plus pembrolizumab provides encouraging activity and is safe in patients with recurrent glioblastoma. A global, randomized, controlled Phase 3 study is planned.
ATRT-05. RESULTS OF MULTICENTER TRIAL CONCERNING THE TREATMENT OF CHILDREN WITH ATYPICAL TERATOID/RHABDOID TUMORS (ATRT) OF THE CENTRAL NERVOUS SYSTEM
Authors: Zheludkova Olga , Olkhova Lyudmila , Kushel’ Yuri , Melikyan Armen , Ryzhova Marina , Kislyakov Alexey , Shultz Evgeniy , Borodina Irina , Gorbatykh Svetlana , Popov Vladimir , Mushinskaya Marina , Polushkina Olga , Inyushkina Eugenia , Yudina Natalya , Privalova Lyudmila , Minkina Lyudmila , Zaichikov Artem , Matsekha Eugenia , Fisyun Ivan , Sakun Daniil , Dunaeva Nadezhda , Mitrofanov Vladislav , Kovalenko Sergey , Grishina Ekaterina , Chulkov Eduard , Pishchaeva Nadezhda , Gevorkyan Asmik , Nechesnyuk Evgeniy , Slobina Elena , Popova Natalya , Pogorelov Dmitriy , Matitsyn Alexander , Shapochnik Alexander , Timofeeva Valentina , Korchunov Andrey , Vorobiev Nikolay
Published: December 2020

We analyzed 105 patients under 18 years. The median age was 21 months. There were 54 boys and 51 girls. The supratentorial tumors were in 53 patients, infratentorial in 48, and in spinal cord in 4. 60 had stage M0,29-М+and 16-Mx. All the patients got surgical treatment:total tumor removal in 34,subtotal in 37,partial in 30,and biopsy in 4;75 patients got chemoradiotherapy to ATRT-2006;6-CWS;13-EU-RHAB;5-HIT-SKK;individual schemes in 6. RESULTS: 47 are alive,1 was LFU, and 57 died. PFS was 32%±0.05; the five-year OS 40%±0.05. The median survival-30 months, the median progression-free survival-12 months, and the median of follow-up-23 months. PFS was significantly better in patients more than 12 months compared to patients younger than 12 months:40 and 12%;p=0.00161.After total resection PFS was higher compared to subtotal resection, partial resection, and tumor biopsy:48,38,0,and 0%(p=0.025). After chemoradiotherapy, PFS was higher compared to patients without radiotherapy: 49and 0%(р=0.0000000).PFS for stage M0 was higher compared to stage M+and stage Mx:41,15,and 27%,respectively(р=0.00032).PFS was better for the tumors in the spinal cord and infratentorial location compared to the supratentorial location:67,37,and 25%(p=0.0876).The survival rate was higher among the patients who got treatment according to the ATRT-2006 protocol compared to EU-RHAB, individual regimens, CWS, and HIT-SKK:39,19,17,17,and 0% respectively;p=0.00159.The survival was higher among the patients who got intraventricular/intrathecal Methotrexate,Cytarabine, Prednisolone than among the patients who got only Methotrexate or none at all:40,0,and 5%, respectively; p=0.00015. CONCLUSIONS: Survival was significantly better in patients more than 12month, without metastases, with total removal tumor, chemotheradiotherapy by ATRT-2006 protocol with i/t, i/v Methotrexate/Cytarabine/Prednisolone.
ATRT-20. CDK7 INHIBITION IN AT/RT
Authors: Morin Andrew , Veo Bethany , Fosmire Susan , Crespo Michele , Zahedi Shadi , Vibhakar Rajeev , Levy Jean M Mulcahy
Published: December 2020

Atypical teratoid/rhabdoid tumors (AT/RT) are characterized by loss-of-function mutations in the SMARCB1 component (and less commonly SMARCA4) of the SWI/SNF chromatin-remodeling complex. AT/RT demonstrate an overall silent genomic landscape with epigenetic dysregulation of the genome. CDK7 is a key transcriptional regulator that preferentially phosphorylates the Ser5 and Ser7 positions on RNA Polymerase C terminal domain and is involved early in transcription. In tumor cells, CDK7 is enriched at super enhancers which preferentially regulate genes involved in cell transformation, and expressed at significantly higher levels in transformed tissues than the surrounding normal brain. Our preliminary data shows that CDK7 is expressed in a number of AT/RT tumor cell lines and patient-derived tumor cultures, and that loss of CDK7 function though exposure to the novel CDK7 inhibitor THZ2 results in lack of proliferation at lower doses, and caspase-mediated apoptosis at higher concentrations. shRNA-based inhibition confirms that this effect is due specifically to loss of CDK7. RNA sequencing of cells treated with lower doses of THZ2 show significant alterations in transcript expression consistent with altered balance between antagonistic SWI/SNF and PRC2 chromatin-modeling complex activities, as well as alterations in DNA damage response pathways, cell cycle checkpoints, miRNA transcription, and numerous proliferative factors. THZ2 penetrates the blood brain barrier (BBB), is well tolerated, and results in prolonged survival in murine xenograft models of AT/RT. CDK7 inhibition also synergizes with a number of currently-approved oncology drugs, as well as with ionizing radiation, in order to inhibit AT/RT growth and viability.
ATRT-23. THE DUAL mTORC1/2 INHIBITOR SAPANISERTIB DISRUPTS THE NRF2-MEDIATED STRESS RESPONSE AND COMBINES SYNERGISTICALLY WITH THE BH3 MIMETIC OBATOCLAX TO EXTEND AT/RT SURVIVAL
Authors: Parkhurst Ashlyn , Wang Sabrina , Alt Jesse , Arnold Antje , Kaur Harpreet , Slusher Barbara , Eberhart Charles , Raabe Eric , Rubens Jeffrey
Published: December 2020

Atypical teratoid/rhabdoid tumors are aggressive infantile tumors highly resistant to intensive therapies. We aim to identify and target critical factors driving this therapy resistance to improve AT/RT survival. Analysis of publically available RNASeq on 32 AT/RT identified elevated expression of NRF2 (median expression 40.78, normal brain 18.81). NRF2 is a master regulator of cell’s stress response whose expression is correlated with therapy resistance and poor survival. NRF2 activation is sensitive to mTOR activity and is a biomarker predicting response to the dual mTORC1/2 inhibitor, Sapanisertib (TAK228, INK128). We performed RNASeq on 4 human-derived AT/RT cell models after Sapanisertib treatment. Pathway analysis reveals disruption of the NRF2-mediated stress response (-log p value 0.39, Z-score 1.0). As a result, Sapanisertib decreases ROS scavengers like glutathione (Metabolite analysis UHPLC-MS, t-test p<0.05) and induces a pro-death phenotype (decreased MCL-1 expression, western blot; gene-expression analysis, RNASeq). The brain-penetrant BH3 mimetic Obatoclax increases ROS generation and induces apoptosis (MUSE oxidative stress and ANNEXIN V assays, t-test p<0.05). These complementary mechanisms of action synergize to induce high rates of cell death (MUSE ANNEXIN V assay, ANOVA p<0.05, C-PARP western blot, Compusyn Synergy analysis CI<1.0) and slow cell growth (MUSE Cell viability, ANOVA p<0.05). Once-weekly treatments of Sapanisertib combined with Obatoclax in orthotopic mouse models of AT/RT are well tolerated, slow tumor growth (bioluminescence imaging) and significantly extend median survival from 35 to 55 days (Log-rank p<0.05). These findings support a new clinical trial aimed at improving AT/RT survival.
ATRT-31. SUCCESSFUL MULTIMODALITY MANAGEMENT OF ATRT OF THE LOWER DORSAL SPINE WITH SPINAL DROP METASTASIS
Authors: Biswas Ahitagni , Velu Umesh , Kumari Kalpana , Jain Deepali , Bakhshi Sameer
Published: December 2020

A 6 year old boy presented with low backache for the last 5 months. MRI of the spine showed a 1.5x1.5x4.7cm intradural mass extending from D10-D12, causing compression of the conus medullaris. With a preoperative diagnosis of intradural ependymoma, a gross total resection (GTR) of tumour was performed. Post-operative histopathology showed a markedly cellular, malignant tumour with frequent mitotic figures. Cells were round to polygonal with vesicular nuclei, prominent nucleoli and were immunopositive for CK,EMA,p53 and immunonegative for MIC2,desmin,SMA,GFAP,INI-1(MIB1 labeling index-35–40%). The overall impression was spinal atypical teratoid rhabdoid tumour(ATRT). Post-operative neuraxis MRI revealed post-operative changes(D10-D12) with a 9 mm enhancing lesion at L5-S1 junction suggesting drop metastasis. There was no brain lesion. CSF cytology did not show any malignant cell. The metastatic work-up was normal. He was started on chemotherapy with ICE regimen (Ifosfamide-2g/m2IVD1–D3,Carboplatin-500mg/m2IVD3,Etoposide-100mg/m2IVD1–D3q3weeks). Subsequently he received craniospinal irradiation (CSI)-36Gray/20fractions/4weeks→ focal boost to primary tumour bed and spinal drop metastasis-14.4Gray/8fractions/1.5 weeks. Thereafter he received 3 more cycles of ICE regimen. End-of-treatment MRI spine showed post-op changes(D10-D12) and 38.9%reduction of the L5-S1 lesion suggesting partial response. Six monthly spinal MRI showed serial reduction of the metastatic lesion leading to complete response (CR) 1 year after completion of treatment. On last follow-up (30 months from initial diagnosis), he was neurologically intact and in CR. Multimodality management comprising GTR,CSI followed by focal boost and multiagent chemotherapy(ICE) can lead to successful outcome in patients with this rare and aggressive spinal tumour.
DDEL-16. UNDERSTANDING OPTIMAL CONVECTION-ENHANCED DELIVERY PHYSICO-CHEMICAL INFUSION PARAMETERS: THE ROLE OF BBB EFFLUX PUMPS IN DRUG DISTRIBUTION AND CLEARANCE
Authors: Power Erica , Zhang Liang , Daniels David
Published: December 2020

BACKGROUND

Diffuse midline gliomas harboring the H3K27M mutation are aggressive and universally fatal brain tumors that primarily occur in children. The blood-brain barrier (BBB) prevents many drugs from reaching the tumor at cytotoxic concentrations and efflux pumps found on the epithelial cells of the BBB rapidly pump drugs out of the brain. Convection enhanced delivery (CED) is a drug delivery technique that bypasses the BBB by directly injecting the drug into the tumor site under a pressure gradient. Further clinical implementation of CED requires understanding drug distribution, as optimal drug physico-chemical properties have never been evaluated.

METHODS

Sprague Dawley rats underwent a single injection of drug by CED to the brainstem with and without an efflux pump inhibitor. Animals were euthanized at 0, 2, 4, 8, 12 and 24 hours. Their brain drug concentration/distribution was analyzed by MALDI-MSI and plasma drug concentration was measured by LC-MS/MS.

RESULTS

Drug distribution and brainstem concentration were increased following BBB efflux pump inhibition compared to no pump inhibition controls. Additionally, efflux pump inhibition resulted in slower drug clearance for those drugs that are known pump substrates.

CONCLUSIONS

BBB efflux pump inhibition resulted in a larger volume of distribution, increased drug concentration and slower drug clearance following CED to the brainstem of known efflux substrates.
DIPG-39. NOVEL PROTEOMIC ANALYSIS REVEALS EPIGENETIC THERAPEUTIC TARGETS IN PEDIATRIC GLIOMA
Authors: Li Daphne , Huang Tina , Camarillo Jeannie , Piunti Andrea , Qi Jin , An Shejuan , Nazarian Javad , Thomas Paul , Saratsis Amanda
Published: December 2020

INTRODUCTION

Diffuse midline glioma is a highly morbid pediatric cancer. Up to 80% harbor Histone H3K27M mutation, which alters Histone H3 post-translational modifications (PTMs) and genomic enrichment patterns, affecting chromatin structure and transcription. We previously identified tumorigenic patterns of H3K27Ac/bromodomain co-enrichment and pre-clinical efficacy of bromodomain inhibition (JQ1) in DMG. Here, we employ a novel proteomics approach developed at our institution to further elucidate the impact of H3K27M mutation on glioma epigenetic signatures and treatment response.

METHODS

Epiproteomic analysis was performed on pediatric glioma cells (H3K27 WT n=2, H3K27M n=2) to characterize 95 distinct Histone H3 N-terminal tail modification states. Cells were treated with JQ1 or DMSO, and collected at 0h, 24h, 48h, Histones extracted from isolated nuclei and immunopurified, then analyzed by LC-MS/MS. Results were integrated with RNA-Seq and ChIP Seq (H3.3K27M, H3.3, H3K27Ac, H3K27me3, H3K4me1, H3K4me3) from the same cell lines. Pediatric glioma tissues (H3K27M WT n=3, H3K27M n= 9) were similarly analyzed to validate cell line results.

RESULTS

Cell PTM profiles cluster by H3 mutation status on unsupervised analysis. Significant differential PTM abundance and genomic enrichment H3K27M, H3.3 WT, H3K27Me3 and H3K27Ac was observed between mutant and wild type cell lines with epigenetic-targeted therapy, correlating with cell transcriptomes.

CONCLUSIONS

Histone H3 tail analysis reveals the effects of H3K27M mutation and bromodomain inhibition on the tumor epigenetic landscape, providing insight into mechanisms of tumorigenesis and therapy response. Further investigation of the utility of these signatures as biomarkers for diagnosis and monitoring treatment response are therefore underway.
DIPG-46. NON-DIPG PATIENTS ENROLLED IN THE INTERNATIONAL DIPG REGISTRY: HISTOPATHOLOGIC EVALUATION OF CENTRAL NEURO-IMAGING REVIEW
Authors: Lazow Margot A , Fuller Christine , Lane Adam , DeWire-Schottmiller Mariko D , Bandopadhayay Pratiti , Bartels Ute , Bouffet Eric , Cheng Sylvia , Cohen Kenneth J , Cooney Tabitha M , Coven Scott L , Dholaria Hetal , Diez Blanca , Dorris Kathleen , El-Ayadi Motasem , El-Sheikh Ayman , Fisher Paul G , Lombardi Mercedes Garcia , Greiner Robert J , Goldman Stewart , Gottardo Nicholas , Gururangan Sridharan , Hansford Jordan R , Hassall Tim , Hawkins Cynthia , Kilburn Lindsay , Koschmann Carl J , Leary Sarah E , Ma Jie , Minturn Jane E , Monje-Deisseroth Michelle , Packer Roger J , Samson Yvan , Sandler Eric S , Sevlever Gustavo , Tinkle Christopher , Tsui Karen , Wagner Lars M , Zaghloul Mohamed , Ziegler David S , Chaney Brooklyn , Black Katie , Asher Anthony , Drissi Rachid , Fouladi Maryam , Jones Blaise V , Leach James L
Published: December 2020

INTRODUCTION

The role of diagnostic biopsy in diffuse intrinsic pontine glioma (DIPG) remains in question. Distinguishing radiographically between DIPG and other pontine tumors with more favorable prognosis and different therapy is critically important.

METHODS

Cases submitted to the International DIPG registry with histopathologic data were analyzed. Central imaging review was performed by two neuro-radiologists; all cases with imaging features or histopathology suggestive of alternative diagnoses were re-reviewed. Imaging features suggestive of alternative diagnoses included non-pontine origin, <50% pontine involvement (without typical DIPG pattern on follow-up), focally exophytic morphology, sharply-defined margins, or marked diffusion restriction throughout.

RESULTS

Among 297 patients with pathology from biopsy and/or autopsy available, 27 (9%) had histologic diagnoses not consistent with DIPG, commonly embryonal tumors (n=9) and pilocytic astrocytomas (n=11). 163 patients had diagnostic MRI available for central neuroimaging review. Among 81 patients classified as characteristic of DIPG, 80 (99%) had histopathology consistent with DIPG (diffuse midline glioma, H3K27M-mutant, glioblastoma, anaplastic astrocytoma, diffuse astrocytoma). Among 63 patients classified as likely DIPG, but with unusual imaging features, 59 (94%) had histopathology consistent with DIPG. 19 patients had imaging features suggestive of another diagnosis, including 13 with non-pontine tumor origin; the remaining 6 all had histopathology not consistent with DIPG. Association between central imaging review and histopathology was significant (p<0.001).

CONCLUSIONS

The important role and accuracy of central neuroimaging review in diagnosing or excluding DIPG is demonstrated. In patients with pontine tumors for which DIPG is felt unlikely radiographically, biopsy may be considered to guide diagnosis and treatment.