bluuebunny/crossref_metadata_2025_split huggingface dataset:
TMOD-35. PREDICTION OF OVERALL SURVIVAL, AND MOLECULAR MARKERS IN GLIOMAS VIA ANALYSIS OF DIGITAL PATHOLOGY IMAGES USING DEEP LEARNING
Authors: Rathore Saima , Iftikhar Muhammad , Nasrallah MacLean , Gurcan Metin , Rajpoot Nasir , Mourelatos Zissimos 
Published: November 2019

Abstract

BACKGROUND
Microscopic features of brain tumors, such as tumor cell morphology, type/degree of microvascular hyperplasia, mitotic activity, and extent of zonal/geographic necrosis, among many others, are measurable and reflect underlying molecular markers that are predictive of patient prognosis, signifying that quantitative analysis may provide insight into disease mechanics. We developed a computational method to predict overall-survival and molecular markers for brain tumors using deep learning on whole-slide digital images (WSDI).

METHODS
The WSDI were acquired from TCGA for 663 patients [IDH:333 wildtype, 330 mutants, 1p/19q:201 non-codeleted, 129 codeleted]. A set of 100 region-of-interest each comprising 1024x1024 that contained viable tumor with descriptive histologic characteristics and that were free of artifacts were extracted. A modified version of ResNet with architecture of 50 convolutional layers was used. The network was optimized using stochastic gradient decent optimization method with binary cross-entropy loss. Sigmoid- and linear-activation were, respectively, used as final layer for mutation and survival prediction. Data was divided into training (50%), testing (25%), and validation (25%).

RESULTS
The model predicted IDH and 1p/19q with an accuracy of 88.92%[sensitivity(se)/ specificity(sp)=87.77/84.35] and 88.23%(se/sp=87.38/88.58), respectively. The accuracy was further improved, when classification was done within homogeneous grades, for IDH [II=90.50%(se/sp=91.52/78.57), III=91.21%(se/sp=91.89/89.47), IV=92.77%(se/sp=77.78/93.51)] and 1p/19q [II=91.51%(se/sp=91.30/91.66), III=92.56(se/sp =93.33,92.04)]. The Pearson correlation coefficient between the predicted scores and overall-survival was 0.79 (p< 0.0001).

CONCLUSION
Our findings suggest that deep learning techniques can be applied to WSDI for objective, and accurate prediction of mutations and survival. Our approach, when compared with expensive molecular based assays that invariably capture molecular markers from a small part of the tumor and also destroy the tissue, could (i) offer the same service at a reduced price, (ii) enable disease characterization across the entire landscape of the tissue, (iii) be beneficial for tissues inadequate for molecular testing, and (iv) does not need physical shipping of the tissue.
SCIDOT-01. NANOPARTICLE DELIVERY OF MIRNAS TO INHIBIT GBM STEM CELLS
Authors: Lopez Hernando 
Published: November 2019

Abstract
Options for treating high-grade brain tumors remain limited. Recent developments in nanomedicine provide new and exciting opportunities to treat and manage brain tumors. Epigenetic modifications, involving deregulation of non-coding RNAs, in particular miRNAs, are emerging as critical determinants of gene expression and essential drivers of neoplastic phenotypes. Cationic polymers are a class of biomaterials with great promise for targeted molecular therapeutics. We combined this cutting-edge technology with our newly discovered stem cell inhibiting miRNAs to develop nano/miR to treat gliomas. We show these nano/miR distribute throughout an established tumor in vivo, and more importantly, delivering these tumor-suppressing miRNAs using PBAE polymers inhibits the growth of established GBM tumor in mouse models. Our findings demonstrate that identifying and validating stem cell-inhibitory in combination with current advances in nanomedicine will undoubtedly impact the development of novel therapies for targeting the CSC population and treating GBM.
SCIDOT-03. HYPERLOADED POLY(2-OXAZOLINE) MICELLES AS PERSONALIZED DRUG CARRIERS FOR BRAIN TUMORS
Authors: Hwang Duhyeong , Dismuke Taylor , Rosen Elias , Kagel John , Lim Chaemin , Zamboni William , Kabanov Alexander , Gershon Timothy , Sokolsky-Papkov Marina 
Published: November 2019

Abstract
Systemic therapies for brain tumors are complicated by dose-limiting extraneural toxicity, serum protein binding and restricted blood-brain barrier (BBB) permeability. For patients with SHH-subgroup medulloblastoma, SHH-pathway inhibition may be more effective and less toxic than current non-targeted therapy. However, vismodegib, which effectively targets SHH-driven basal cell carcinoma, has limited benefit for patients with SHH-driven medulloblastoma. Formulating vismodegib in poly(2-oxazoline) micelles (POx-vismo) improved delivery and efficacy, using medulloblastoma-prone hGFAP-Cre/SmoM2 (G-Smo) mice for a preclinical model. Compared to conventional vismodegib (c-vismo), POx-vismo increased maximum tolerated dose (MTD), tumor:serum ratio and penetration to brain and tumor. Further studies have shown the ability of POx micelles to load CDK4/6 inhibitor. Loading into POx micelles improved MTD and efficacy of palbociclib. Taken together, our results show the potential for poly(2-oxazoline) micelles delivery to make failed brain tumor treatments newly effective. This work was supported by the NCI Alliance for Nanotechnology in Cancer (U54CA198999, Carolina Center of Cancer Nanotechnology Excellence), by NINDS (R01NS088219, R01NS102627) and by the St. Baldrick’s Foundation. References: 1 H. Bader et al. Angew. Macromol. Chem. 1984, 123/124:457; A. Kabanov et al. FEBS Lett. 1989, 258:343; M. Yokoyama et al. Cancer Res. 1990, 50:1693. 2 M. Yokoyama et al. J. Exp. Clin. Med. 2011, 3:8. 3 T. Lorson et al. Biomaterials. 2018, 178:204. 4 R. Luxenhofer et al. Biomaterials 2010, 31:4972; A. Schulz et al. ACS Nano 2014, 8 (3):2686; Z. He et al. Biomaterials 2016, 101:296
SCIDOT-16. T2-WEIGHTED IMAGING MAY BE INDICATIVE OF DRUG DISTRIBUTION IN GLIOBLASTOMA PATIENTS
Authors: Jackson Pamela , Kim Minjee , Hawkins-Daarud Andrea , Singleton Kyle , Mohammad Afroz , Burns Terence , Parney Ian , Hu Leland , Kaufmann Timothy , Elmquist William , Sarkaria Jann , Swanson Kristin 
Published: November 2019

Abstract

OBJECTIVES
Dogma suggests that for brain tumors, regions of enhancement on T1-weighted gadolinium contrast enhanced (T1Gd) magnetic resonance imaging (MRI) correlate with intravenously delivered drug distribution as enhancement indicates a compromised blood-brain barrier (BBB). However, poor response to intravenous therapies highlights the importance of the diffuse disease beyond enhancing regions. This study investigated whether imaging features can provide an accurate prediction of drug distribution.

METHODS
Eight brain tumor patients (7 gliomas and 1 metastatic adenocarcinoma) were included in this Phase 0 trial. Presurgery T1-weighted, T1Gd, T2-weighted gadolinium contrast enhanced (T2Gd), and T2-weighted Fluid Attenuated Inversion Recovery (T2FLAIR) MRIs were acquired. All images underwent bias correction using the N4 algorithm, standardization of intensities, and registration. Prior to incision, patients received both an antibiotic cefazolin (6% BBB penetrance) and levetiracetam (80% BBB penetrance), an anti-seizure drug. Subsequently, multiple blood samples and image-guided biopsies were taken and analyzed for drug concentration using liquid chromatography mass spectrometry. Biopsy drug levels are reported as Brain-Plasma Ratio (BPR), the ratio of biopsy concentration relative to plasma concentration. Mean image intensity was extracted from an 8x8 mm window surrounding each biopsy location. Regression analysis was performed to determine which combination of image types were linearly predictive of BPR for both drugs. Correlations were also analyzed according to the biopsy location radiographic appearance.

RESULTS
Regression analysis revealed that T2Gd intensity was linearly predictive of cefazolin BPR and FLAIR intensity was linearly predictive of levetiracetam BPR (p=0.009 and 0.041, respectively). Grouping samples according the the radiographic appearance revealed that levetiracetam BPR had a similar pattern of values to that of FLAIR intensities and cefazolin BPR had a similar pattern to T2, further supporting the regression analysis results.

CONCLUSIONS
Local concentrations of drug may be related to T2-weighted signals (T2Gd and T2FLAIR) rather than the gadolinium distribution on T1Gd images.
SCIDOT-24. INCREASING INDUCED NEURAL STEM CELL PERSISTENCE IN THE TUMOR RESECTION CAVITY
Authors: Bomba Hunter , Sheets Kevin , Carey-Ewend Abigail , Goetz Morgan , Bago Juli , Khagi Simon , Hingtgen Shawn 
Published: November 2019

Abstract
Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults. Afflicted patients have a median survival rate of only 15 months, and patient survival statistics have remained stagnant for over three decades. Current standard of care includes maximal safe tumor resection, chemotherapy, and radiation. Nevertheless, GBM is aggressive, making recurrence and deeper tumor infiltration inevitable. Neural stem cells transdifferentiated from a skin biopsy, i.e. induced neural stem cells (iNSCs), have the innate ability to home to tumors, and, when engineered with cytotoxic proteins, can actively kill cancer cells. However, direct injection of these cells into the hostile immune environment of the tumor resection cavity results in an accelerated clearance rate and therefore a shortened therapeutic window. To combat this clearance issue, we investigated the FDA-approved hemostatic matrix, Floseal, as a cell delivery platform to increase iNSC persistence. In vitro, SEM imaging showed homogeneous iNSC distribution throughout Floseal. Using our surgical resection model of GBM in mice, we delivered iNSCs into the post-surgical cavity in Floseal and by direct injection to model current clinical delivery strategies. Serial kinetic imaging showed that human iNSC persistence delivered into the cavity in Floseal persisted over 90 days, while cells directly injected into the brain parenchyma persist less than 20 days. When we investigated the impact on tumor kill, we found the increase in persistence increased survival of GBM-bearing mice more than 30 days compared to control cells. Light-sheet microscopy showed wild-type neural stem cells migrate into invasive GBM-8 tumors in the contralateral hemisphere, and we are now using this approach to validate the homing of iNSCs delivered via Floseal. Administration of iNSCs encapsulated in the biocompatible Floseal matrix offers a promising, clinically-translatable therapeutic strategy for GBM.
SCIDOT-30. GLITIPNI: A PHASE 1B CLINICAL TRIAL COMBINING SURGICAL RESECTION WITH DIRECT INTRACEREBRAL INJECTION OF IMMUNE CHECKPOINT INHIBITORS IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Duerinck Johnny , Awada Gil , Katharina Schwarze Julia , Dufait Ines , Peeters Stephanie , Seynaeve Laura , Van Binst Anne-Marie , Everaert Hendrik , Michotte Alex , Rogiers Anne , Van Velthoven Vera , Neyns Bart 
Published: November 2019

Abstract

INTRODUCTION
Intravenous (iv) administration of PD-1 blocking mAb is largely ineffective for the treatment of recurrent glioblastoma (rGB). Combination of iv-ipilimumab (IPI) plus nivolumab (NIVO) is associated with a high incidence of irAE. Intracerebral (ic) administration of immune-checkpoint inhibiting mAb following the resection of rGB could be a more effective and safer alternative to iv-dosing.

METHODS
Patients underwent maximal safe resection of their rGB followed by ic-injection of 10mg IPI (cohort-1) or 5mg IPI plus 10mg NIVO (cohort-2) in the wall of the resection cavity. In both cohorts 10mg nivolumab was administered iv for a max of 6 doses, starting 1 day pre-operatively.

RESULTS
21 pts were included (3 in C-1, 18 in C-2; 8F/13M; median age 56y [range 38–72]; 17 de novo GB, 4 secGB). All patients underwent maximal safe surgical resection followed by ic-injection of IPI and NIVO as planned. Median number of iv-administrations of NIVO was 5 (range 1–8). Treatment was generally well tolerated. Postoperatively, 2 patients experienced a G3 symptomatic increase in perilesional cerebral edema with neurological deterioration, reversible upon steroid treatment. One patient had worsening neurological symptoms related to an inflammatory intracerebral cyst at the resection site, requiring surgical decompression 4 months post-study treatment. Most frequent AEs were fatigue (2pts G3, 8pts G2), postoperative fever (11pts G1) and headache (3pts G2); 1pt developed G3 pneumonitis. No other immune-related AEs or treatment-related deaths occurred. After median follow-up of 60 weeks, median PFS is 14.4 weeks (95% CI 11.2–17.6); 11/21 patients are alive, and 1- and 2y-OS% are respectively 46% (95% CI 19- 73%), and15% (95% CI 0–42%).

CONCLUSION
This is the first study demonstrating the safety and activity of combined surgical resection of rGB with local intracerebral administration of immune checkpoint-inhibiting mAb. Survival compares favorably to historical controls justifying further investigation of this experimental therapy.
SCIDOT-46. MicroRNA NANOCELL THERAPY FOR GLIOBLASTOMA
Authors: Babar Khan Muhammad , Ruggieri Rosamaria , Tran Nhan , Sarkaria Jann , MacDiarmid Jennifer , Brahmbhatt Himanshu , Boockvar John , Symons Marc 
Published: November 2019

Abstract
Therapeutic resistance stemming from inter and intra-tumoral heterogeneity is a significant impediment towards development of effective therapeutics for glioblastoma. We hypothesized that microRNAs can potentially counteract resistance emanating from such heterogeneity as they simultaneously modulate the expression of multiple proteins. We identified microRNA-34a as a unique microRNA which modulates multiple oncoproteins in GBM using two different in silico approaches. We investigated the therapeutic effects of microRNA-34a in three primary patient-derived xenografts (PDX) representing classical (GBM6), proneural (GBM118) and mesenchymal (GBM118) subtypes; four established cell lines (T98G, U251, A172, LN229) and two cell lines with acquired resistance to temozolomide (A172-TR, LN229-TR) in vitro. Glioblastoma cell cultures showed variable responses to temozolomide but microRNA-34a inhibited proliferation in all cell cultures. Furthermore, microRNA-34a also sensitized all tested cell lines to temozolomide (combination index < 0.8, p=.03) and radiation treatment (dose enhancement factor 1.7–2.2, p=0.02). Mechanistically, microRNA 34a down-regulates at least six distinct therapeutic resistance proteins. Importantly, these resistance proteins are expressed in distinct spatial niches and are prognostic for patient survival based on our analysis of the cancer genome atlas (TCGA) data. For in vivo delivery of microRNA-34a, we utilized nanocells which are derived from genetically modified bacteria, loaded with microRNA-34a and tagged with a bispecific antibody targeting EGFR. Nanocells were injected intravenously while temozolomide was administered by oral gavage in an orthotopic PDX model. We confirmed delivery of microRNA-34a to tumor by observing down-regulation of cMet and phosphorylated Akt in treated mice. Importantly, microRNA-34a nanocells resulted in significant reduction in tumor growth (p=0.021), increased survival (p<0.001) with microRNA-34a monotherapy and synergy in combination with temozolomide in vivo. Taken together, our results suggest that delivery of miR-34a may be a powerful new adjuvant for the treatment of glioblastoma in combination with temozolomide that can mitigate both inter- and intra-tumor heterogeneity.
SCIDOT-51. OVERPOWERING MULTIPLE INHIBITORY IMMUNE CHECKPOINTS WITH A SINGLE PEPTIDE INHIBITOR ENHANCED SURVIVAL IN A SPONTANEOUS HIGH-GRADE GLIOMA CANINE PILOT-TRIAL
Authors: Olin Michael , Moertel Christopher , Elisabeth Pluhar G 
Published: November 2019

Abstract
Given the modest effects current immune checkpoint-inhibitors have on patients with CNS tumors, we focused our studies on the novel CD200 immune checkpoint. The CD200 checkpoint suppresses the immune system through binding of the inhibitory CD200 protein to the inhibitory receptor (CD200R1) expressed on immune cells. In addition to CD200R1, the CD200 checkpoint includes activation receptors (CD200AR), which we are targeting with a peptide ligand (CD200AR-L) to reverse the inhibitory effects of the CD200 protein. We showed that spontaneous high-grade glioma dogs receiving a canine specific CD200AR-L in combination with autologous tumor lysate vaccine had an increased median overall survival of 9 months, compared to 6.3 months with lysate alone, resulting in an overall 36-month survival of 21%. However, we have a 45% event-free (progression-free) group of dogs that died of non-tumor related deaths with an extended median survival of 18 months. Six dogs remain on trial, 87% of the dogs receiving tumor lysate only died of tumor recurrence within 6 months. Serum chemistry profiles and physical examinations showed that the peptide did not induce any systemic toxicity. To determine how we obtained these unprecedented results, we focused on the mechanism of CD200AR-L/CD200AR binding. We discovered DAP10/12 signaling pathways and CD200ARs are upregulated, while the inhibitory CD200R1 is downregulated. We discovered the molecular connection between CD200, PD-1 and CTLA4. We demonstrated that our murine and human CD200AR-L downregulates the inhibitory PD-1 and PD-L1 and inhibits the upregulation of CTLA4. Therefore, we attribute the success of CD200AR-L to the ability to concurrently modulate multiple immune checkpoints. We have now developed human GMP grade CD200AR-L peptides to develop an immunotherapy approach for patients with CNS tumors; we will conduct a Phase I trial utilizing the peptide ligand concomitantly with an allogeneic GBM6-AD cell line as a tumor vaccine and the adjuvant imiquimod.
RARE-47. CHARACTERIZATION OF ADULT MEDULLOBLASTOMA; A RETROSPECTIVE REVIEW OF 200 PATIENTS AT MD ANDERSON CANCER CENTER
Authors: Majd Nazanin , Mastall Max , Hess Kenneth , Fuller Greg , Alfaro-Munoz Kristin , Gule-Monroe Maria , Huse Jason , Khatua Soumen , Rao Ganesh , Sandberg David I , Wefel Jeffrey , Yeboa Debra , Zaky Wafik , Mahajan Anita , Puduvalli Vinay , Suki Dima , Weathers Shiao-Pei , Harrison Rebecca , DeGroot John , Penas-Prado Marta 
Published: November 2019

Abstract

INTRODUCTION
Prospective studies for adult medulloblastoma (MB) are scarce and management guidelines are largely derived from pediatric experience and retrospective data. However, adult MB is a distinct disease for which limited data exist regarding clinical characteristic, prognostic factors, outcome based on upfront treatment, or patterns of recurrence.

METHODS
200 patients (≥18 years at diagnosis) were identified from 1978 to 2017. Survival analysis was performed using the Kaplan-Meier method.

RESULTS
Median age at diagnosis 29 (18–63); 111 (55.5%) standard-risk (SR), 59 (29.5%) high-risk (HR), 30 (15%) unknown. 188 (94%) and 97 (48.5%) underwent radiotherapy and upfront chemotherapy, respectively. Median PFS: 6.28 years (4.9–11.2); median OS: 8.8 (7.8–12.4) years. Median time to first recurrence: 8.2 (5.1-not reached); 5-year recurrence-free rate: 71% in SR and 45% in HR patients. Survival after first recurrence: 2 years (1.64–2.4). Documented recurrence and risk group were associated with survival (HR 30.4, p< 0.0001 and 2.33, p< 0.001), but metastatic status and local vs. distant recurrence were not. The effect of upfront chemotherapy on survival did not reach statistical significance in SR patients. The use of chemotherapy regimens with or without vincristine or containing cisplatin vs. carboplatin, did not alter the survival outcome. In a subgroup of 57 SR patients who were seen at initial diagnosis and for whom complete staging and treatment information were available 3 and 5-year PFS were 94% (88%, 100%) and 76% (66%, 86%); OS at 5 years, 94% (87%, 100%).

CONCLUSION
No statistically significant difference was noted in outcome of patients treated without vincristine or with carboplatin instead of cisplatin, suggesting attenuated upfront regimens could be considered to reduce toxicity. Adult MB patients recur late and have a poor post-recurrence survival, therefore long-term follow-up, development of molecular risk-adjusted upfront treatment, and optimization of rescue treatments are needed.
ANGI-10. CHEMOTHERAPEUTIC STRESS INDUCES TRANSDIFFERENTIATION OF GLIOBLASTOMA CELLS TO PROMOTE VASCULAR MIMICRY
Authors: Baisiwala Shivani , Auffinger Brenda , Caragher Seamus , Shireman Jack , Ahsan Riasat , Park Cheol , Ahmed Atique 
Published: November 2019

Abstract
Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor affecting adults, with a median survival of approximately 21 months after diagnosis. A key factor underlying the limited efficacy of current treatment modalities is the remarkable plasticity exhibited by GBM cells, which allows them to effectively adapt to changes induced by our current treatment strategies. In addition to their plasticity, GBM tumors are also highly vascularized with aberrant vessels that further promote its aggressiveness. Recent research has demonstrated that GBM cells have the ability to transdifferentiate into endothelial cells (ECs), which suggests that GBM cells may use their properties of plasticity and vascularity in concert, leading to the creation of tumor-derived blood vessels. The mechanism behind this transdifferentiation remains unclear. Here, we show that treatment with temozolamide (TMZ)-based chemotherapy (the current standard of care) induces time-dependent increases in expression of markers for glioma stem cells (GSCs) and immature and mature ECs over 8 days of treatment (p < .001) in multiple patient-derived xenograft (PDX) lines. In addition, GBM tumors growing as orthotopic xenografts in nude mice showed significantly increased expression of GSC markers (CD15 and CD133) and EC markers (CD105 and CD144) after 8 days of TMZ treatment (p < .01). Ex-vivo FACS analysis of these orthotopic xenografts showed the presence of immature and mature EC populations in addition to GSC populations. To assess the functionality of these increased EC populations, a tube forming assay was performed. Results showed that the tube forming capacity of PDX lines was significantly increased (p < .01) after therapy. Furthermore, immunofluorescence analysis revealed increased tumor-derived vessels in TMZ-recurrent tumors. Overall, this study identifies chemotherapeutic stress as a new driver of transdifferentiation of tumor cells to endothelial cells and highlights cellular plasticity as a key player in therapeutic resistance and tumor recurrence.
CBMT-04. MOLECULAR MECHANISM OF OLIG2-CDK2 INTERACTION IN GLIOMA CELLS
Authors: Saito Norihiko , Hirai Nozomi , Aoki Kazuya , Sato Sho , Suzuki Ryo , Hiramoto Yu , Nakayama Haruo , hayashi Morito , Sakurai Takatoshi , Iwabuchi Satoshi 
Published: November 2019

Abstract
Oligodendrocyte transcription factor 2 (OLIG2) promotes proliferation of normal neural stem/progenitor cells and glioma cells. However, the mechanisms underlying the regulation of OLIG2 remain largely unknown. Here we identified OLIG2 as a critical phosphorylation target for cyclin-dependent kinase 2 (CDK2). CDK2-mediated OLIG2 phosphorylation stabilizes OLIG2 protein from proteasomal degradation. Phosphorylated OLIG2 binds to the E-Box regions of p27 promoter and represses p27 transcription, which in turn activates CDK2 in positive feedback manner. CDK2-mediated OLIG2 phosphorylation promotes cell cycle progression, cell proliferation, and tumorigenesis. OLIG2 inhibition disrupted cell cycle control mechanism by decreasing CDK2 and elevating apoptosis-related molecules. Inhibition of CDK2 activity disrupted OLIG2-CDK2 interactions and attenuated OLIG2 protein stability. In addition, OLIG2-high glioma initiating cells are highly sensitive to CDK2 inhibitor treatment, indicating that OLIG2 can be a biomarker for personalized treatment for glioblastoma patients with CDK2 inhibitors. Further investigation on these mechanisms may lead to novel targeted therapy on GBMs with high OLIG2 expression.