tbuckley/cabot-search huggingface dataset:
Integrative cross-platform analyses identify enhanced heterotrophy as a metabolic hallmark in glioblastoma
Authors: Antony H Prabhu, Shiva Kant, Pravin Kesarwani, Kamran Ahmed, Peter Forsyth, Ichiro Nakano, Prakash Chinnaiyan
Journal: Neuro-Oncology (2018)

Although considerable progress has been made in understanding molecular alterations driving gliomagenesis, the diverse metabolic programs contributing to the aggressive phenotype of glioblastoma remain unclear. The aim of this study was to define and provide molecular context to metabolic reprogramming driving gliomagenesis.Integrative cross-platform analyses coupling global metabolomic profiling with genomics in patient-derived glioma (low-grade astrocytoma [LGA; n = 28] and glioblastoma [n = 80]) were performed. Identified programs were then metabolomically, genomically, and functionally evaluated in preclinical models.Clear metabolic programs were identified differentiating LGA from glioblastoma, with aberrant lipid, peptide, and amino acid metabolism representing dominant metabolic nodes associated with malignant transformation. Although the metabolomic profiles of glioblastoma and LGA appeared mutually exclusive, considerable metabolic heterogeneity was observed in glioblastoma. Surprisingly, integrative analyses demonstrated that O6-methylguanine-DNA methyltransferase methylation and isocitrate dehydrogenase mutation status were equally distributed among glioblastoma metabolic profiles. Transcriptional subtypes, on the other hand, tightly clustered by their metabolomic signature, with proneural and mesenchymal tumor profiles being mutually exclusive. Integrating these metabolic phenotypes with gene expression analyses uncovered tightly orchestrated and highly redundant transcriptional programs designed to support the observed metabolic programs by actively importing these biochemical substrates from the microenvironment, contributing to a state of enhanced metabolic heterotrophy. These findings were metabolomically, genomically, and functionally recapitulated in preclinical models.Despite disparate molecular pathways driving the progression of glioblastoma, metabolic programs designed to maintain its aggressive phenotype remain conserved. This contributes to a state of enhanced metabolic heterotrophy supporting survival in diverse microenvironments implicit in this malignancy.
INNV-34. INNOVATIVE, INDEPENDENT, PATIENT ADVOCATE ROLE ESSENTIAL THROUGHOUT DRUG DEVELOPMENT IN THE AGE OF SOCIAL MEDIA
Authors: Mary Lovely
Journal: Neuro-Oncology (2018)

A mid-sized biotech company recruiting for high-grade glioma (HGG) clinical trials used the internet for patient awareness. Many patients and families began contacting the company inquiring about trials. METHOD: To offer ethical, informative responses, the company engaged a dedicated, independent patient advocate consultant to interact with the patients and families. This role provides critical separation from the drug company, maintaining patient privacy and preventing recruitment bias. The patient advocate role has evolved into a position that influences all the patient-oriented aspects of the research process. The patient advocate reviews all patient facing documents and provides patient perspectives. The patient advocate informs patients and families about the trial and provides support resources when appropriate. This role requires experience with the brain tumor population and evidence-based knowledge of patient and family needs. The patient advocate communicates with patients and caregivers and helps them navigate through the clinical trials research process. Also, the patient advocate liaises between the drug company and brain tumor advocacy groups. Activities performed since 2014 by Tocagens patient advocate included: A) communicated with > 1200 patients and caregivers through email and phone inquiries; B) reviewed clinical trial protocols, consents and brochures for patient and caregiver suitability; C) participated in the clinical trial patient recruitment team; D) wrote blogs related to living with a brain tumor and understanding clinical trials placed on the company site; E) communicated with brain tumor advocacy groups. A patient advocate consultant embedded in a biotech firm provides essential patient-centered perspective throughout drug development. This innovative, independent position provides an interface for patients and families to receive quality, individualized responses to questions. Clinical trial protocols become patient-oriented at times leading to more efficient patient recruitment and trial design. People inquiring about clinical trials receive accurate information, resources with a humane touch.
Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition
Authors: Elena Deliu, Niccolò Arecco, Jasmin Morandell, Christoph P. Dotter, Ximena Contreras, Charles Girardot, Eva-Lotta Käsper, Alena Kozlova, Kasumi Kishi, Ilaria Chiaradia, Kyung-Min Noh, Gaia Novarino
Journal: Nature Neuroscience (2018)
ATIM-12. NEOADJUVANT ANTI-PD-1 IMMUNOTHERAPY PROMOTES INTRATUMORAL AND SYSTEMIC IMMUNE RESPONSES IN RECURRENT GLIOBLASTOMA: AN IVY CONSORTIUM TRIAL
Authors: Robert Prins, Aaron Mochizuki, Joey Orpilla, Alexander Lee, Tom Davidson, Sarah Gaffey, Catherine Sanders, Julie Rytlewski, Benjamin Ellingson, Gang Li, William Yong, Jennifer Clarke, Isabel Arrillaga-Romany, Howard Colman, David Reardon, Thomas Kaley, John de Groot, Linda Liau, Patrick Wen, Timothy Cloughesy
Journal: Neuro-Oncology (2018)

Glioblastoma is the most common malignant brain tumor in adults and is associated with poor survival. It is often resistant to standard-of-care chemotherapy and radiation, necessitating the development of more effective treatments. The Ivy Foundation Early Phase Clinical Trials' Consortium conducted a randomized, multi-institution clinical trial to evaluate the immune response and survival following neoadjuvant and adjuvant therapy with pembrolizumab, a PD-1 monoclonal antibody, in thirty patients with recurrent, surgically resectable glioblastoma. Patients who received neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that received adjuvant, post-surgical PD-1 blockade alone (HR=0.33, p<0.008, log-rank test). Survival was directly associated with an elevated IFN-g gene expression signature in the tumor, but only in patients who received neoadjuvant PD-1 blockade (HR=0.15, p<0.02, Wald test). Focal induction of PD-L1 in the tumor microenvironment was observed in the neoadjuvant group and linked with the IFN-g gene expression signature and extended survival. Similarly, neoadjuvant pembrolizumab was associated with expanded T cell receptor clones, increased markers of activation in CD8+ T cells that expressed PD-1, and a decreasing monocytic population in the peripheral blood (p<0.03, two-sided t-test). These findings suggest that the neoadjuvant timing of PD-1 blockade enhances the local and systemic immune response, and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.
NIMG-33. MULTICENTER, PROSPECTIVE VALIDATION OF AUTOMATED INTRAOPERATIVE NEUROPATHOLOGY USING STIMULATED RAMAN HISTOLOGY AND CONVOLUTIONAL NEURAL NETWORKS
Authors: Todd Hollon, Balaji Pandian, Jason Heth, Oren Sagher, Cormac Maher, Steve Sullivan, Hugh Garton, Greg Thompson, Akshay Save, Tamara Marie, Deborah Boyett, Petros Petridis, Guy McKhann, Karin Muraszko, Jeffrey Bruce, Sandra Camelo-Piragua, Peter Canoll, Daniel Orringer
Journal: Neuro-Oncology (2018)

Accurate intraoperative diagnosis is essential for providing optimal neurosurgical care. In many centers caring for brain tumor patients, neuropathology resources are limited. To augment existing neuropathology resources, we developed and validated a new paradigm combining optical histology and artificial intelligence (AI) to accurately predict diagnosis during brain tumor surgery. A total of 1026 specimens from 501 patients undergoing brain tumor resection at two tertiary hospitals were imaged using an optical technique, called stimulated Raman histology (SRH). SRH images were used to train and validate a convolutional neural network (CNN) for state-of-the-art computer vision. We redesigned the GoogleNet InceptionV3 CNN architecture to optimize performance on SRH histologic image fields of view (FOVs) and trained the network using 466 patients (3.1 million unique 300m2 FOVs) to classify into 13 common brain tumor subtypes. Final intraoperative diagnosis was determined using the most commonly predicted FOV diagnosis within each specimen. Model testing was completed on 1 million unique FOVs from 35 prospectively enrolled patients whose data was not included in the training set. In the validation set, our trained CNN differentiated lesional from normal tissue with 100% accuracy, surgical from nonsurgical lesions with 100% accuracy, glial from non-glial tumors with 100% accuracy. When evaluating our model for tumor subtype classification, we achieved an accuracy of 97% (35/36 patients) compared to final clinical diagnosis. Corresponding clinical frozen section diagnostic accuracy was 97% and interrater agreement between CNN and clinical frozen section diagnosis was near-perfect (k>0.96). The sole CNN error was misclassification of a WHO grade 1 pilocytic astrocytoma as a WHO grade II astrocytoma. Our prospective, multi-institutional validation suggests that AI can be applied to predict diagnosis in neurosurgical specimens in an automated fashion. AI-based diagnosis may ultimately be used to augment the current neuropathology workflow where resources are limited.
ATIM-05. INTRATUMORAL DELIVERY OF MDNA55, AN INTERLEUKIN-4 RECEPTOR TARGETED IMMUNOTHERAPY, BY MRI-GUIDED CONVECTIVE DELIVERY FOR THE TREATMENT OF RECURRENT GLIOBLASTOMA
Authors: Achal Achrol, Martin Bexon, Krystof Bankiewicz, Andrew J Brenner, Nicholas Butowski, Santosh Kesari, Fahar Merchant, Rosemina Merchant, Dina Randazzo, Michael Vogelbaum, Miroslaw Zabek, John Sampson
Journal: Neuro-Oncology (2018)

While intratumoral delivery of immunotherapies allows for targeted distribution and minimal systemic toxicity, optimal spatial distribution of therapeutic agents remains a challenge. MR-guided convection-enhanced delivery of MDNA55, interleukin-4 cytokine fused to Pseudomonas exotoxin, is currently being explored in a Phase 2 open label study in up to 52 patients with recurrent glioblastoma. MDNA55 is coinfused with a Gadolinium-based contrast agent (GdDTPA) and delivered as a single infusion using implantable flexible catheters. MRI was employed to monitor initial infusion, allowing adjustment of catheter depth as needed. The bulk of the delivery was performed outside the MRI scanner while patients were awake. MRI confirmation of distribution was performed within 4 hours post-infusion. Here we report preliminary results of tumor distribution in 23 subjects. Total volume of MDNA55 (ranging from 12 mL to 66 mL) was initially administered to subjects (n=12) based on tumor size. This achieved a mean coverage of 75% (range 46 – 94%) with 17% showing volume of distribution > 100 mL. Review by the Safety Committee determined that improvements to drug distribution could be further enhanced by moving to a fixed volume of 60 mL administered via 4 catheters and allowing placement outside the peritumoral area if necessary. Treatment in the next 11 subjects showed that infusion volumes exceeding 40 mL and placement of catheters outside the enhancing tumor led to increased volumes of drug distribution (45% showed volume of distribution > 100 mL) but did not improve the target percentage coverage of the tumor (mean 60%, range 22 – 97%) and its immediate penumbra. Therefore, under the current protocol version, all subjects are receiving individualized volume of MDNA55 (according to tumor size), but not exceeding 40 mL. Further optimization is underway to ensure adequate coverage and improve drug distribution.
PDTM-32. THE NOVEL THERAPEUTIC CURCUMIN ENHANCES TARGETED BACTERIOPHAGE MEDIATED IN-VITRO CELL DEATH IN PRIMARY HUMAN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Gargi Samarth, Keittisak Suwan, Mariam Al-Bahrani, Paladd Asavarut, Amin Hajitou
Journal: Neuro-Oncology (2018)

Diffuse intrinsic pontine glioma (DIPG) is one of the most aggressive paediatric brainstem tumours, with a dismal prognosis and a 90% mortality rate within 2 years. Over the last 50 years, DIPG patients have seen no increase in survival, owing to progress being hindered by a lack of tissue available for in-vitro study, the critical anatomical location of the pons and the impermeability of the blood-brain barrier (BBB). In this in-vitro study, we describe the use of cancer gene therapy using the targeted-bacteriophage vector to deliver the therapeutic TNFα transgene to DIPG cells, in combination with the novel therapeutic, curcumin, which constitutes the spice turmeric (Curcuma longa). MATERIALS AND We evaluated the in-vitro cytotoxicity of curcumin in 2D tissue cultures of primary DIPG cells, with cell-viability measured after treatment with varying concentrations of curcumin for 72 hours. Next, we assessed the gene transduction and cell-killing efficacy of the targeted-hybrid bacteriophage, using the Luciferase and TNFα transgenes, at day 3 post-transduction. Lastly, we assessed the effect of combination therapy by adding concentrations of curcumin to DIPG cells at day 3 post-transduction by the bacteriophage, once again evaluating Luciferase expression and cell-killing. DISCUSSION: Here, we report for the first time, the in-vitro cytotoxicity of curcumin in this DIPG cell line, with significant cell death seen at as low as 37.5μM. Secondly, we show that primary DIPG cells can be successfully transduced with the targeted-modified bacteriophage vector, containing the TNFα gene, leading to TNFα-mediated cell death. Lastly, we show that the combination of curcumin with the targeted-bacteriophage vector led to enhanced DIPG cell death, due to increased bacteriophage-mediated transgene expression. We have shown that combination chemovirotherapy of curcumin and the targeted bacteriophage is efficacious in-vitro, warranting further in-vivo work to assess the safety and efficacy after systemic delivery.
MNGI-20. LARGE PERITUMORAL EDEMA RELATIVE TO TUMOR VOLUME PREDICTS SECRETORY SUBTYPE IN MENINGIOMAS
Authors: Niklas von Spreckelsen, Lukas Goertz, Boris Krischek, Roland Goldbrunner, Christian Mawrin, Pantelis Stavrinou
Journal: Neuro-Oncology (2018)

Secretory meningiomas represent a benign subtype of meningiomas (WHO I°), but show a high prevalence of serious perioperative adverse events. Preoperative identification of a secretory subtype could facilitate risk stratification, and selection of pre- and perioperative medical treatment. To evaluate the relationship of preoperative MRI features and secretory subtypes in meningioma patients. All meningioma patients with available preoperative MRI that underwent tumor resection between 2013 and 2018 were reviewed. Different imaging characteristics were collected (i.e. tumor surface, arachnoid plane, T2 intensity) as well as the volume of tumor and peritumoral edema (PTE), using a semiautomatic image-processing software. In addition, the edema index (EI) (ratio of PTE to tumor volume) was calculated and all factors were correlated with histological subtypes. Receiver operating characteristic (ROC) curve analysis was performed to identify cut-off EI values to predict histological subtypes. We identified 163 patients, whereof seven (4.3%) presented with secretory meningiomas. EI (p< .005), as well as PTE (p< .05) proved to be the only parameters significantly associated with secretory meningioma. In ROC curve analysis, EI was the most sensitive and specific parameter to predict a secretory subtype. The optimal cut-off value at > 4.39 provided a sensitivity of 85.71% and a specificity of 95.57%. EI can be used as a highly specific and sensitive parameter to predict a secretory meningioma subtype, providing a useful tool for improvement of pre- and perioperative medical management.
AB1016 Osseointegrated implants for lower limb amputees: evaluation of bone mineral density
Authors: S. Thomson, W. Lu, M. Al Muderis
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> The use of dual-energy X-ray absorptiometry (DXA) is a standard clinical procedure for the evaluation of bone mineral density (BMD). Amputee patients are known to have decreased BMD and an increased risk of osteoporosis in the affected proximal femur and hip region. The major cause of these issues in these patients is the absence adequate loading leading to bone resorption in accordance to Wolff's law. <h3>Objectives</h3> In this paper, we present a prospective study reporting changes in BMD among amputees who received osseointegrated implants to determine if the loading through the Osseointegrated implant can overcome the bone resorption issues. <h3>Methods</h3> This is a prospective study of 33 patients, consisting of 24 males and 9 females, aged 22–77 (mean=51.0±−2.0) years with one and two-year follow-up. Selection criteria included age over 18 years, unilateral amputees with socket-related problems. All patients received osseointegrated implants press-fitted into the amputated limb. BMD was assessed using DXA in the femoral neck (operative and contralateral) and lumbar spine (L2-L4) regions, and corresponding Z-scores were generated. DXA scans were taken preoperatively as well as one-year and two-years following osseointegration surgery. <h3>Results</h3> Mean BMD and Z-scores of spine, and operative and contralateral sides were generated for all patients. Dependent t-tests were used to test for significant differences (p&lt;0.05) preoperative, one-year, and two-years for mean changes in BMD and Z-Scores following surgery. Analysis of the BMD and Z-scores indicated that patients showed improvements at one-year post-surgery. <h3>Conclusions</h3> These results suggest that osseointegrated implants are effective at encouraging bone growth and restoring BMD levels for amputees within a short period of time post-surgery. Osseointegrated implants therefore have the potential to address stress distribution issues associated with socket prostheses and restore the normal bone loading regime in lower limb amputees. <h3>Disclosure of Interest</h3> None declared
PDTM-47. REAL TIME IN VIVO MONITORING OF 18F-LABELED PANOBINOSTAT PHARMAKOKINETICS FOR TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) VIA CONVECTION ENHANCED DELIVERY (CED)
Authors: Umberto Tosi, Harikrishna Kommidi, Uday Bhanu Maachani, Christopher Marnell, Hua Guo, Melanie Schweitzer, Richard Ting, Mark Souweidane
Journal: Neuro-Oncology (2018)

Diffuse intrinsic pontine glioma (DIPG) is a universally fatal tumor of childhood with median survival of one year: an initially good response to radiation therapy is invariably followed by recurrence. Recent promise comes from the use of histone deacetylase complex (HDAC) inhibitors which normalize the aberrant epigenetic environment of DIPG. Of these, the pan-HDAC inhibitor panobinostat has been rapidly translated into early phase clinical trials. The drug, however, poorly penetrates the blood-brain barrier (BBB) and thus might be better administered by convection enhanced delivery (CED). To more clearly define pharmacokinetics and therapeutic trial design, compounds with both imaging and therapeutic features (i.e. theranostics) would be advantageous. Here, we modify panobinostat to include a trifluoroborate [18F]F2B- moiety that makes it visible with positron emission tomography (PET). We demonstrated that this modified compound retains its bioactivity against glioma cell lines (IC50 of 91.49 nM and 94.94 nM against SU-DIPG-IV and SU-DIPG-XIII cell lines) and proteomics profile. This novel theranostic compound, PETobinostat, when administered via CED in the rodent brain stem demonstrates a half-life of 126 (95% CI: 109.6–146.9) minutes using decay-corrected dynamic PET scanning. The significant mouse-to-mouse variability highlights the importance of individualized patient imaging of drug delivery. Comparatively, systemic administration (intravenous or intraperitoneal) show poor cranial accumulation (39.3%, 1.5%, and 0.44% for CED, IV, and IP respectively). Both in vivo PET scanning and post mortem scintillation biodistribution elucidate routes and rates of biological PETobinostat clearance following CED. Treatment of tumor-bearing animals with both PETobinostat or the unmodified panobinostat shows significant tumor regression (2.3 fold diffrence) when compared to vehicle. Furthermore, PETobinostat allowed monitoring of tumor permeation and clearance following CED. We believe that this compound holds promise in helping us establish a CED-based panobinostat/PETobinostat clinical trial, where real-time information on pharmacokinetics and pharmacodynamics allows us to maximize therapeutic efficacy during CED.
ACTR-57. RELATIVE CEREBRAL BLOOD VOLUME (RCBV) AS RESPONSE PREDICTOR IN THE TREATMENT OF RECURRENT GLIOBLASTOMA (GB) WITH ANTIANGIOGENIC THERAPY
Authors: Michele Breda-Yepes, Enrique Gomez-Figueroa, Gerardo Arellano-Flores, Alberto Gonzalez-Aguilar
Journal: Neuro-Oncology (2018)

INTRODUCTION: Glioblastoma (GB) is the most common primary brain tumor in adults having an overall survival (OS) ranging from 12–14 months. GB is highly vascularized, partly due to excessive levels of VEGF. Recurrence is the rule in GB, the second line of treatment is antiangiogenics of which Bevacizumab(BVZ) - a humanized monoclonal antibody to the VEGF-A - is the most commonly used antiangiogenic agent in the setting of recurrent glioblastoma (rGB). rCBV has been evaluated as a predictor of response to this therapy using perfusion-weighted MR techniques. Patients with rGB according to RANO criteria treated with BVZ with an MRI perfusion with rCBV prior treatment initiation were enrolled. The correlation between rCBV and response was analyzed by correlation coefficient. A cutoff point to identify responders and non-responders to BVZ was determined by ROC curve and OS was evaluated using Kaplan Meier curve and log rank. 31 patients with GB were included. We divided the patients in non-responders (n=17) and responders (n=14), there were differences between the groups (age and KPS). The correlation between the RCBV and the Therapeutic response was r=-0.83, p0.0001 (95% CI -0.918 to -0.675). The ROC curve showed 3.7 as the cutoff value with a sensitivity of 100% and specificity of 94% to predict response to BVZ. We divided the groups into non-responders and responders, with OS of 7.7 months vs 14.4 months respectively, p 0.045 (HR 2.3, 95% CI 1.0192 to 5.6192). rCBV is a potential biomarker evaluated by MRI that predicts response to treatment in patients who will be treated with Bevacizumab. Bevacizumab treatment is highly cost-effective, and this biomarker would help identify patients that would benefit. This biomarker as predictive/prognostic has been widely used and is currently the most reliable parameter for measuring the response to antiangiogenic treatment.
MNGI-04. A PROPOSED IMAGING-BASED NOMENCLATURE SYSTEM FOR MENINGIOMAS
Authors: Javier Villanueva-Meyer, Stephen Magill, Ken Probst, Nancy Ann Oberheim Bush, David Raleigh, Philip Theodosopoulos, Manish Aghi, Michael McDermott
Journal: Neuro-Oncology (2018)

Additional criteria apply.Please refer to protocol 14379-201 for full inclusion and exclusion criteria.† Patients can participate if they had some skin cancers, superficial bladder cancer (cancer that was only on the surface of the lining of the bladder), or carcinoma in situ (cancer that had not spread) of the cervix or breast that had been cured.