bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract
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

Abstract

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 &gt; 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

Abstract
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

Abstract
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

Abstract
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&lt;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&lt;0.05). These complementary mechanisms of action synergize to induce high rates of cell death (MUSE ANNEXIN V assay, ANOVA p&lt;0.05, C-PARP western blot, Compusyn Synergy analysis CI&lt;1.0) and slow cell growth (MUSE Cell viability, ANOVA p&lt;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&lt;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

Abstract
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

Abstract

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

Abstract

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

Abstract

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, &lt;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&lt;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.