bluuebunny/crossref_metadata_2025_split huggingface dataset:
TMOD-39. EX-VIVO 3-DIMENSIONAL MODELS OF POST-SURGICAL RESIDUAL DISEASE IN HUMAN GLIOBLASTOMA
Authors: Rominiyi Ola , Myers Katie , Vanderlinden Aurelie , Dar Dawoud , Bagga Veejay , Gomez-Roman Natividad , Jellinek David , Carroll Thomas , Chalmers Anthony , Al-Tamimi Yahia , Collis Spencer 
Published: November 2019

Abstract
Translation of novel therapies for glioblastoma from laboratory to clinical trials has relied heavily on cells derived from within patient tumours. However, it is clear from over 40 years of limited improvement in survival rates, that the traditional paradigm of 2-dimensional in-vitro studies using these cells followed by implantation into mouse models poorly predicts the treatment response of glioblastoma cells left behind after surgery in patients. Additionally, recent increases in the number of new therapies requiring pre-clinical evaluation emphasise a need to apply disease models that faithfully and efficiently reproduce biological features of post-surgical residual glioblastoma in patients. Dependent on the anatomical considerations of individual cases, surgical resection occasionally provides an en-bloc specimen (e.g. partial lobectomy), which includes portions of infiltrated brain that would not otherwise be resected. Such specimens provide crucial material to model and understand residual (typically left behind) disease in glioblastoma. Using such specimens, we have developed a pragmatic methodology to liberate glioblastoma stem cells (GSC) from the tumour core and adjacent infiltrated brain to model resected and residual disease, respectively. Imperative considerations include careful patient selection and intraoperative clinical-academic collaboration, with immediate ex-vivo hemi-section and processing of suitable specimens. Initial biological characterisation of our resected and residual models reveals numerous divergent properties including morphological differences and elevated stem cell marker expression in residual models (p=0.0021). Importantly, although GSC within recently derived 2-dimensional residual disease models are frequently too migratory to reliably form discrete colonies, we are able to perform robust clonogenic survival studies using the same GSC within a novel customised 3-dimensional scaffold-based architecture (3.4-fold greater clonogenic potential, p=0.0010). In conclusion, we believe that our models provide a biologically relevant and cost-effective tool to investigate the nuances of residual glioblastoma and assess the potential of therapies to tackle disease normally left behind following surgery in patients.
TMOD-40. IN VIVO EVALUATION OF O6-METHYLGUANINE-DNA-METHYLTRANSFERASE (MGMT) PROMOTER METHYLATION STATUS FOR DE NOVO GLIOBLASTOMA PATIENTS USING DEEP LEARNING FEATURES
Authors: Rathore Saima , Nasrallah MacLean , Akbari Hamed , Shukla Gaurav , Bagley Stephen , Watt Christopher , Min Ha Sung , Mamourian Elizabeth , Sako Chiharu , Binder Zev , O’Rourke Donald , Davatzikos Christos 
Published: November 2019

Abstract

BACKGROUND
High expression of O6-methylguanine-DNA methyltransferase (MGMT) in glioblastoma is associated with resistance to temozolomide, as tumor cells lacking MGMT activity are significantly more sensitive to the cytotoxic effects of temozolomide. The MGMT promoter methylation status (MGMTpms) is typically determined as MGMT-methylated or MGMT-unmethylated. Some single-center studies have reported results ranging from 70–95% detection rates using MRI. We aim to further validate these findings using a multi-institutional data set. We hypothesize that transfer learning based features when integrated via machine learning may lead to non-invasive determination of MGMTpms.

METHODS
A total of 270 patients were included across the 3 institutions (Hospital of the University of Pennsylvania (HUP), Jefferson University Hospital (JUH); the TCIA). JUH and TCIA datasets comprised conventional modalities (T1,T2,T2-FLAIR,T1-Gd), whereas HUP dataset had additional modalities (DSC,DTI) as well. We used transfer learning and adapted a convolutional neural network (CNN) model pre-trained on 1.2 million 3-channel images of the ImageNet to extract deep learning features from the given images. A support vector machine multivariately integrated these features towards a non-invasive marker of MGMTpms.

RESULTS
The cross-validated accuracy of our MGMT marker in classifying the mutation status in individual patients was 86.95%, 81.56%, and 82.43%, respectively, in HUP, JUH, and TCIA. Our marker revealed MGMT-methylated tumors with lower neovascularization and cell density, when compared with MGMT-unmethylated tumors. MGMT-unmethylated tumors were found to be more lateralized to the right hemisphere, when compared with MGMT-methylated tumors.

CONCLUSION
Our findings suggest that transfer learning features when integrated via machine learning allow robust prediction of MGMTpms on mpMRI acquired within multiple institutions. The proposed non-invasive MGMT marker may contribute to (i) MGMTpms determination for patients with inadequate tissue/inoperable tumors, (ii) stratification of patients into clinical trials, (iii) patient selection for targeted therapy, and (iv) personalized treatment planning.
ANGI-03. PHARMACOLOGICAL TARGETING OF APELIN/APLNR SIGNALING BLUNTS THERAPY RESISTANCE TO VEGFA/VEGFR2 ANTI-ANGIOGENIC TREATMENT IN GLIOBLASTOMA
Authors: Kälin Roland , Mastrella Giorgia , Hou Mengzhuo , Li Min , Stoecklein Veit , Zdouc Nina , Volmar Marie , Miletic Hrvoje , Reinhard Sören , Herold-Mende Christel , Kleber Susanne , Eisenhut Katharina , Gargiulo Gaetano , Synowitz Michael , Vescovi Angelo , Harter Patrick , Penninger Josef , Wagner Ernst , Mittelbronn Michel , Bjerkvig Rolf , Hambardzumyan Dolores , Schüller Ulrich , Tonn Joerg-Christian , Radke Josefine , Glass Rainer 
Published: November 2019

Abstract
Anti-angiogenic therapy of glioblastoma with bevacizumab, a vascular endothelial growth factor-A (VEGFA) blocking antibody, may accelerate tumor cell invasion and induce alternative angiogenic pathways. We investigated the roles of the pro-angiogenic receptor APLNR and its cognate ligand apelin in VEGFA/VEGFR2 anti-angiogenic therapy against distinct subtypes of glioblastoma. In proneural glioblastoma, apelin levels were downregulated by VEGFA or VEGFR2 blockade by use of bevacizumab or ramucirumab, respectively. A central role for apelin/APLNR in controlling glioblastoma vascularization was corroborated in a serial implantation model of the angiogenic switch that occurs in human glioblastoma. Apelin and APLNR are broadly expressed in human glioblastoma, and knockdown or knockout of APLN in orthotopic models of proneural or classical glioblastoma subtypes massively reduced glioblastoma vascularization as compared with controls. What is more, direct infusion of the bioactive peptide apelin-13 was able to rescue this vascular loss-of-function phenotype, demonstrating the specific control of tumor vascularization by apelin/APLNR signaling. While high levels of apelin correlated with reduced tumor cell invasiveness, the reduction in apelin expression led to accelerated glioblastoma cell invasion. Analysis of stereotactic glioblastoma biopsies from patients as well as from in vitro and in vivo experiments revealed increased dissemination of APLNR-positive tumor cells when apelin levels were reduced. Most interestingly, application of apelin-F13A, a mutant APLNR ligand, blocked both tumor angiogenesis and glioblastoma cell invasion. Furthermore, co-targeting VEGFR2 and APLNR synergistically improved survival of mice bearing proneural glioblastoma. In summary, we show that apelin/APLNR signaling controls glioblastoma angiogenesis and invasion directly, and that both pathological features are blunted by apelin-F13A. We suggest that apelin-F13A can improve the efficiency and reduce the side effects of established anti-angiogenic treatments for distinct glioblastoma subtypes.
TMOD-41. ORTHOTOPIC PATIENT-DERIVED XENOGRAFT MODELS OF BRAIN METASTASIS: PLATFORMS FOR PRECISION ONCOLOGY AND UNDERSTANDING TUMOR BIOLOGY
Authors: Dankner Matthew , Savage Paul , Rose April , Lajoie Mathieu , Diaz Roberto , Park Morag , Watson Ian , Guiot Marie-Christine , Petrecca Kevin , Siegel Peter 
Published: November 2019

Abstract

RATIONALE
Brain metastasis (BrM) occurs in 10–20% of cancer patients and results in median survival times of less than 1 year. In order to accurately develop novel treatment strategies, there is an urgent need to establish animal models of BrM that resemble the human disease. OBJECTIVES: We sought to establish orthotopic patient-derived xenografts (PDX) models of BrM from diverse solid cancers to understand biological characteristics of BrM and to test novel drug candidates in their ability to treat BrM.

METHODS
35 PDXs were established by subcutaneous or mammary fat pad implantation and by intracranial injection. PDXs were validated by immunohistochemistry of routine pathological markers in patient specimens and matched primary and intracranial PDXs. PDXs were applied for precision medicine in class II BRAF mutant tumours treated with targeted therapy and in the pre-clinical development of a novel therapeutic agent, DZ-2384, which may have applications in treating BrM. They were also used to understand the underlying biology of leptomeningeal dissemination from parenchymal BrM.

RESULTS
PDXs reveal strong similarity to patient specimens by IHC staining. Class II BRAF mutant PDXs are optimally sensitive to BRAF and MEK inhibitors compared to either agent alone. DZ-2384 is effective in slowing the progression of breast cancer BrM. PDXs that most efficiently invade the leptomeninges display loss of E-Cadherin expression, suggesting the role of an epithelial-mesenchymal transition in this process.

CONCLUSIONS
PDXs of BrM represent important models that can be employed to test novel therapeutics and to improve understanding of molecular mechanisms engaged by BrM.
TMOD-42. PROSPECTIVE VALIDATION OF AN EX VIVO 3D ASSAY FOR PREDICTION OF TEMOZOLOMIDE RESPONSE IN GLIOBLASTOMA
Authors: Smith Ashley , Holmes Lillia , Shuford Stephen , Kanos Charles , Gardner Stephen , Hodge Philip , Lynn Michael , Edenfield Jeff , DesRochers Teresa 
Published: November 2019

Abstract
Standard treatment for newly diagnosed glioblastoma (GBM) is surgical resection followed by radiation with concurrent temozolomide (TMZ). For those who do not respond there are few clinical options, survival is low, and there no biomarkers to direct the decision of second-line treatment. We have developed a 3D cell culture assay to predict response to TMZ and 11 other potential therapies for GBM. Our assay uses GBM tissue obtained at surgical resection and the test’s 7-day turnaround maximizes clinical actionability of results. We performed a small, prospective study examining the ability of the assay to predict response to TMZ. Ten newly diagnosed GBM patients were enrolled over 12 months. Two patients were removed due to refusal of treatment, and three failed the assay (3/8, 62.5% success). The remaining five patients received radiation and concurrent TMZ following surgical resection. Using progression-free survival (PFS) measured from the completion of radiation therapy and setting 4 months as the cutoff for response, we were able to determine the ability of our assay to predict TMZ response. The assay correctly predicted all five patients (100%). The average PFS for the two predicted responders was 8 months compared to the three predicted non-responders at 3 months, p = 0.0634. In this limited dataset, MGMT methylation did not appear to play a role as two of three predicted non-responders were methylated along with one of two predicted responders. Average overall survival of the predicted TMZ responders was 13 months compared to 6 months for the predicted non-responders, p = 0.0634. This early data indicates the potential for this assay to inform clinicians of the best course of action for their patients. Further enrollment of patients into the 3D-PREDICT clinical trial will provide a larger dataset for better validation of the predictive value of this new assay.
SCIDOT-02. A PHASE I STUDY OF CONVECTION-ENHANCED DELIVERY OF LIPOSOMAL-IRINOTECAN (ONIVYDE) USING REAL-TIME IMAGING WITH GADOLINIUM IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMAS: RESULTS THUS FAR
Authors: Kumar Karishma , Butowski Nicholas , Aghi Manish , Bankiewicz Krystof , Bringas John , Ann Oberheim Bush Nancy , Chang Susan , Clarke Jennifer , Taylor Jennie , Martin Alastair , Berger Mitchell 
Published: November 2019

Abstract

BACKGROUND
Chemotherapy for high grade gliomas (HGG) is limited by the blood-brain-barrier (BBB). Convection enhanced delivery (CED) improves chemotherapy delivery by utilizing fluid convection obviating the challenges of crossing the BBB while minimizing systemic toxicity. CED of nanoliposomal-irinotecan (Onivyde) showed to be a superior delivery route for anti-tumor activity in animal models. An advance of this trial is the development and use of real time CED, which utilizes MRI to visualize the CED process with the aid of co-convected contrast agents, monitoring delivery into the brain and affording for corrective action.

METHODS
This is a 3 + 3 single dose escalation trial with 2 cohorts: 20mg/ml and 40mg/ml. Onivyde and GAD were co-infused via the same catheters in a one-time delivery. The total dose was personalized based on the patient’s tumor volume, and ranged from 20–680 mg of Onivyde, given via up to 4 catheters. Tumor diameters were allowed to be 1 – 4 cm, with injection volumes ranging from 2 – 17 mL of infusate.

RESULTS
13 patients have been treated on this protocol, all in under 5 hours. There were 9 GBs, 1 gliosarcoma, 2 AAs, and 1 oligoastrocytoma. Utilizing imaging software, we correlated pre-infusion modeling of the drug distribution with post-infusion imaging. A number of technical challenges were overcome by real time monitoring; the total volume of distribution (Vd), and the Vd to volume infused (Vi) ratio for each infusion was ~2. Of all patients, the only notable AE was encephalopathy, which was resolved.

CONCLUSIONS
Image-guided distribution allows for safe real-time placement and adjustment of CED cannula of Onivyde into patient’s brains. Such methods allow for maximum tumor coverage and warrant further studies with repeat dosing.
SCIDOT-04. REPLACEMENT OF MICROGLIA BY BRAIN-ENGRAFTED MACROPHAGES PREVENTS MEMORY DEFICITS AFTER THERAPEUTIC WHOLE-BRAIN IRRADIATION
Authors: Feng Xi , Gupta Sonali , Chen David , Boosalis Zoe , Liu Sharon , Gupta Nalin , Rosi Susanna 
Published: November 2019

Abstract
Microglia have a distinct origin compared to blood circulating myeloid cells. Under normal physiological conditions, microglia are maintained by self-renewal, independent of hematopoietic progenitors. Following genetic or pharmacologic depletion, newborn microglia derive from the local residual pool and quickly repopulate the entire brain. The depletion of brain resident microglia during therapeutic whole-brain irradiation fully prevents irradiation-induced synaptic loss and recognition memory deficits but the mechanisms driving these protective effects are unknown. Here, we demonstrate that after CSF-1R inhibitor-mediated microglia depletion and therapeutic whole-brain irradiation, circulating monocytes engraft into the brain and replace the microglia pool. These monocyte-derived brain-engrafted macrophages have reduced phagocytic activity compared to microglia from irradiated brains, but similar to locally repopulated microglia without brain irradiation. Transcriptome comparisons reveal that brain-engrafted macrophages have both monocyte and embryonic microglia signatures. These results suggest that monocyte-derived brain-engrafted macrophages represent a novel therapeutic avenue for the treatment of brain radiotherapy-induced cognitive deficits.
SCIDOT-06. TOWARDS EXCLUSIVELY LOCAL THERAPY OF GLIOBLASTOMA - ENGINEERING IL-12Fc WITH SUPERIOR TISSUE RETENTION AND MINIMAL SYSTEMIC EXPOSURE AFTER CNS ADMINISTRATION
Authors: Beffinger Michal , Schellhammer Linda , Pantelyushin Stanislav , Zimmermann Iwan , Egloff Pascal , Buch Thorsten , Seeger Markus , vom Berg Johannes 
Published: November 2019

Abstract
Intratumoral application of IL-12 overrides the prevailing glioblastoma (GB) associated immunosuppression and can trigger efficient anti-tumor responses. With clinical studies currently testing local expression of IL-12 in brain tumors, concerns on IL-12 systemic toxicity via leakage resurface. The fusion to an immunoglobulin heavy chain constant region (“Fc tag”) should increase tissue retention of IL-12. However, export of IL-12Fc into the blood via the neonatal Fc receptor (FcRn) could nevertheless lead to systemic exposure. Subsequent systemic recycling via FcRn could lead to gradually increasing and eventually toxic serum concentrations.
We analysed the effect of the Fc-tag on IL-12 tissue retention and evaluated whether FcRn also is involved in brain export and systemic recycling of IL-12Fc upon local delivery. Human or murine IL-12Fc was delivered in GB-bearing or naïve wt or FcRn-humanized mice (mFcRn-/- hFcRn tg) continuously via mini osmotic pumps or as bolus via convection-enhanced delivery (CED). Brain and blood concentration levels were assessed via ELISA. FcRn affinity of IL-12Fc mutants was assessed via ELISA and surface plasmon resonance.
We observed much higher tissue retention of IL-12Fc compared to unmodified IL-12, but also an FcRn-dependent gradual increase of IL-12Fc serum levels. Testing a battery of amino acid substitutions at the FcRn interaction interface, we discovered unique substitutions that largely abolish brain export and systemic accumulation while preserving IL-12Fc functionality, leading to an over 100-fold higher brain to blood ratio than unmodified IL-12. We currently test the impact on efficacy of local IL-12Fc and checkpoint brain tumor treatment in vivo.
Achieving high local concentrations at low to absent systemic exposure is an important prerequisite for a large therapeutic window for local treatment of neurologic diseases. The novel Fc-modifications present a promising platform for reducing systemic leakage of Fc-containing therapeutics in the context of continuous or intermittent CNS delivery beyond brain cancer therapy.
SCIDOT-07. ULTRASOUND DELIVERED ALBUMIN BOUND PACLITAXEL EXTENDS SURVIVAL IN MALIGNANT GLIOMA MODELS AND OUTPERFORMS ULTRASOUND DELIVERED CREMOPHOR PACLITAXEL IN BIO-DISTRIBUTION AND SAFETY
Authors: Sonabend Adam , Dmello Crismita , Chen Li , Arrieta Victor A , Gonzalez Edgar , Robert Kane J , Magnusson Lisa , Braun Aneta H , David James C , Horbinski Craig , Canney Michael , Carpentier Alexandre , Sottilini Frédéric , Desseaux Carole , Muzzio Miguel , Stupp Roger 
Published: November 2019

Abstract
Paclitaxel is anti-neoplastic agent shown to be extremely potent against glioblastoma in-vitro; however, it has yet to demonstrate antitumor activity in the clinic due to its inadequate brain penetration. Ultrasound-mediated drug delivery is an emerging new technology that transiently disrupts the blood-brain barrier to allow the passage of larger molecules that under physiological conditions would not reach the brain tissue. In this preclinical study, we investigated the ability of low intensity pulsed ultrasound (LIPU), delivered with the SonoCloud System (CarThera), to increase brain paclitaxel concentrations in a murine model. LIPU increased paclitaxel concentrations in the brain 300–500% after systemic administration of two different commercially available formulations of paclitaxel; paclitaxel dissolved in Cremophor (Taxol®) and albumin-bound paclitaxel (Abraxane®). The two formulations differed in their toxicity and biodistribution profiles with albumin-bound paclitaxel exhibiting increased tolerability and brain penetration. After sonication, albumin-bound paclitaxel increased survival in an orthotropic glioma model, whereas cremophor-paclitaxel induced central nervous system toxicity. Our experiments suggest that increased paclitaxel drug delivery by opening the BBB is feasible, and an effective anti-glioma treatment. Albumin-bound paclitaxel is the preferred formulation for further investigation with the SonoCloud system in the clinical setting.
SCIDOT-18. NANOTHERAPEUTICS FOR NEUROSURGICALLY-APPLIED DRUG DELIVERY
Authors: Vasey Catherine , Taresco Vincenzo , Smith Stuart , Alexander Cameron , Rahman Ruman 
Published: November 2019

Abstract
Design and implementation of innovative local drug delivery systems (DDS) may overcome current limitations in GBM treatment, such as the lack of therapeutic drug concentrations reaching residual GBM cells following surgery. Here we describe a novel DDS which utilises a bespoke mechanically engineered spray device, designed for safe surgical use, to deliver a mucoadhesive hydrogel containing chemotherapeutic nanoparticles (NPs) into the tumour resection margins. The overall aim is to spray a NP and polymer solution onto the resection cavity and potentially increase penetration of anti-cancer drugs within the 2 cm reoccurrence zone beyond the infiltrative margin. The mucoadhesive gel of choice, pectin, is currently used in other in vivo applications; however we have repurposed this for the brain. Pectin is biocompatible with GBM and human astrocyte cells in vitro and showed neither toxicity nor inflammation for up to 2 weeks upon orthotopic brain injection. Pectin is biodegradable in artificial CSF and is capable of being sprayed from the engineered device. A panel of polymeric, oil-based and polymer-coated NPs have been developed and optimised to maximise drug encapsulation of etoposide and olaparib as proof-of-concept for combination drug delivery. Etoposide/olaparib was chosen due to cytotoxicity from 5 GBM cell lines, including primary lines isolated from the invasive tumour margin (Mean IC50 of 1.1 µM and 8.3 µM respectively). The optimal NP/drug formulation (based on drug encapsulation, spray capability and bio-adhesiveness) will ultimately be assessed for tolerability and efficacy using orthotopic allograft and xenograft high-grade glioma models, including measurement of penetration of drug/nanoparticle in ex vivo murine and porcine brain using novel hybrid time-of-flight/Orbitrap TM secondary ion mass spectrometer (orbiSIMS) technology.