tbuckley/cabot-search huggingface dataset:
Survivorship care planning and implementation in neuro-oncology
Authors: Heather Leeper, Kathrin Milbury
Journal: Neuro-Oncology (2018)

Survivorship has become a significant topic within oncologic care. The tools and means by which the provision of survivorship care can be implemented and delivered are in development and are the focus of significant research oncology-wide. These tools and methods include innovations of survivorship care delivery, survivorship care plans, and improving communication among all stakeholders in an individual patient's care as the means to elevate health-related quality of life. The merits of these survivorship care provisions in the field of neuro-oncology and its patients' exigent need for more patient-centric care focused on living with their illness are discussed. Since 2014 there has been a mandate within the United States for adult cancer patients treated with curative intent to receive survivorship care plans, comprising a treatment summary and a follow-up plan, intended to facilitate patients' care after initial diagnosis and upfront treatment. Several cancer-specific survivorship care plans have been developed and endorsed by health care professional organizations and patient advocacy groups. A survivorship care plan specific for neuro-oncology has been collaboratively developed by a multidisciplinary and interprofessional committee; it is endorsed by the Society for Neuro-Oncology Guidelines Committee. It is available as open access for download from the Society for Neuro-Oncology website under "Resources": https://www.soc-neuro-onc.org/SNO/Resources/Survivorship_Care_Plan.aspx. Survivorship care offers an opportunity to begin directly addressing the range of issues patients navigate throughout their illness trajectory, an oncology initiative to which neuro-oncology patients both need and deserve equitable access.
PDTM-46. POLIOVIRUS RECEPTOR (CD155) EXPRESSION IN PEDIATRIC BRAIN TUMORS MEDIATES ONCOLYSIS OF MEDULLOBLASTOMA AND PLEOMORPHIC XANTHOASTROCYTOMA
Authors: Eric Thompson, Michael Brown, Elena Dobrikova, Vijay Ramaswamy, Michael Taylor, Roger McLendon, Vidya Chandramohan, Darell Bigner, Matthias Gromeier
Journal: Neuro-Oncology (2018)

Poliovirus oncolytic viral immunotherapy is a putatively novel approach to treat both low grade and malignant pediatric brain tumors. However, the expression of the poliovirus receptor (PVR), CD155, on a variety of pediatric brain tumors and its ability to infect, propagate, and lyse pediatric brain tumor cells is unknown. CD155 expression in a variety of pediatric tumor specimens including pleomorphic xanthoastrocytoma (PXA), medulloblastoma, atypical teratoid rhabdoid tumor, embryonal tumor, and anaplastic ependymoma was assessed using a validated rabbit monoclonal antibody. The ability of poliovirus:rhinovirus genetic recombinant, PVSRIPO, to infect PXA (645 [BRAF V600E mutation] and 2363) and medulloblastoma (D283, D341) cell lines was determined by measurement of viral propagation and cell killing. Gene expression data from a medulloblastoma patient cohort of 763 patients was used to determine differential PVR mRNA expression and compared using analysis of variance. CD155 expression was present in 53 of 57 patient specimens analyzed in all PXA and medulloblastoma cell lines. One-step growth curves of PVSRIPO at a multiplicity of infection of 10 demonstrated productive infection and peak plaque formation units at 5–10 hours. PVSRIPO infection of all four cell lines demonstrated decreased proliferation in 2363, 645, and D341 cell lines at 48 hours (p<0.001) and resulted in cell death. PVR expression was significantly highest in Group 3γ, WNTα, and WNT (subgroups with c-myc overexpression) compared to the other medulloblastoma subtypes (p<0.001). CONCLUSIONS: Poliovirus receptor, CD155, is widely expressed in a variety of brain tumor specimens. This proof-of-concept in vitro study demonstrated that PVSRIPO was capable of infecting, propagating, and prohibiting cell proliferation in PXA with and without BRAF V300E mutations and Group 3 medulloblastoma. Future studies will evaluate PVSRIPO to treat pediatric brain tumors and the possible link between c-myc and PVR expression.
TMOD-13. A NOVEL 3D HIGH-RESOLUTION HISTOPATHOLOGICAL IMAGE RECONSTRUCTION METHOD VERSUS COMMON 2D AND 3D IMAGING METHODOLOGIES FOR APPLICATION IN CANCER SPHEROID RESEARCH: WHICH IS BETTER?
Authors: James Samarasekara, Filomena Esteves, Alistair Curd, Michael Hale, Derek Magee, Darren Treanor, Susan Short, Anke Brüning-Richardson
Journal: Neuro-Oncology (2018)

Three-dimensional tumour spheroid models are increasingly used in cancer research. However, imaging for quantification analysis of spheroids in drug testing has remained primarily based on 2D methodologies. Imaging 3D structures in 2D can cause discrepancies and introduce interpretive bias. We previously described a novel method to create high-resolution 3D spheroid images using histopathological sectioning. We compare for the first time 3D histopathological images and data analysis of glioma spheroid models in drug studies to commonly used imaging techniques, highlighting the advantages of 3D imaging over 2D methodologies. U251 glioma spheroids embedded in collagen were untreated or treated with inhibitors 6-Bromoindirubin-3’-oxime (BIO) or MI-192. Spheroids were imaged at 24-hour time points over 72 hours using light-microscopy and confocal laser-microscopy and then subsequently embedded in paraffin and sectioned at 5µm. Slides were H&E stained and serially scanned at 20x magnification. Custom software was used to digitally reconstruct the spheroid in 3D. For details at the single cellular level, 70µm spheroids were also imaged at 72 hours at high-magnification using an Instant Structured illumination microscope (iSIM). Superior detail of core cellular components and migratory single cells was achieved by 3D histopathological reconstruction compared to all other methods. Migration indices were similar to 3D confocal-generated reconstructions demonstrating promoted migration with MI-192 and reduced migration with BIO. Detailed morphological analysis of migratory cells was achieved at 40x optical magnification using our 3D histology method. However, greater morphological detail was obtained using high-magnification iSIM. Failure to capture migratory cells in the z-plane using 2D techniques lead to considerable differences between 3D and 2D imaging data. We have shown that 3D histopathological image reconstruction is a preferable method for cell migration and morphological analyses of 3D cancer spheroid models. This method can be used for high-resolution analysis of both core and migratory cells.
Donor Telomere Length and Outcomes after Allogeneic Unrelated Hematopoietic Cell Transplant in Patients with Acute Leukemia
Authors: Shahinaz M. Gadalla, Tao Wang, David Loftus, Lyssa Friedman, Casey Dagnall, Michael D Haagenson, Stephen R. Spellman, Ljubomir Buturovic, Marsha Blauwkamp, Jason Shelton, Katharina Fleischhauer, Katharine C. Hsu, Michael R. Verneris, Belynda Hicks, Kristine Jones, Stephanie J. Lee, Sharon A Savage
Journal: Blood (2016)
RBTT-03. A PHASE 1, MULTICENTER, RANDOMIZED, OPEN-LABEL, PERIOPERATIVE STUDY OF AG-120 (IVOSIDENIB) AND AG-881 IN PATIENTS WITH RECURRENT, NONENHANCING, IDH1-MUTANT, LOW-GRADE GLIOMA
Authors: Ingo Mellinghoff, Elizabeth Maher, Patrick Wen, Timothy Cloughesy, Katherine Peters, Changho Choi, Benjamin Ellingson, Alexander Lin, Yan Li, Brian Soher, Robert Young, Lori Steelman, Kha Le, Feng Yin, Bin Wu, Min Lu, Yanwei Zhang, Brandon Nicolay, Steven Schoenfeld, Katharine Yen, Shuchi Pandya, Jennifer Clarke
Journal: Neuro-Oncology (2018)

Mutations in isocitrate dehydrogenase (mIDH) are common in lower-grade glioma (LGG; mIDH1, 80%; mIDH2, 4%) and lead to epigenetic and genetic changes that promote oncogenesis via production of the oncometabolite 2-hydroxyglutarate (2-HG). AG-120 (ivosidenib) is a first-in-class oral mIDH1 inhibitor associated with a favorable safety profile in an ongoing phase 1 study in 66 glioma patients. AG-881 is a brain-penetrant oral mIDH1/2 inhibitor with an acceptable safety profile at dose levels <100 mg in an ongoing phase 1 study in 52 glioma patients. In an orthotopic mIDH1-R132H glioma model, ivosidenib and AG-881 suppressed 2-HG by 85% and 98%, respectively. This multicenter, open-label, phase 1 study is designed to measure brain tumor 2-HG concentration and drug exposure at two dose levels each of ivosidenib or AG-881 in patients with mIDH1 LGG undergoing craniotomy (NCT03343197). The study will enroll ~45 adults with recurrent WHO 2016-classified Grade 2 or 3 mIDH1 oligodendroglioma/astrocytoma eligible for resection. Key eligibility criteria include: nonenhancing disease by T2 FLAIR MRI, mIDH1-R132H, and Karnofsky Performance Score 60. Cohort 1 patients will be randomized 2:2:1 to 500 mg QD ivosidenib (n=10), 50 mg QD AG-881 (n=10), or no treatment (n=5). Based on the safety, 2-HG, and pharmacokinetic data from cohort 1, cohort 2 may enroll an additional 20 patients randomized 1:1 to 250 mg BID ivosidenib or 10 mg QD AG-881. Patients randomized to either drug will receive treatment for 4 weeks preoperatively and may continue treatment after surgery. Untreated patients can opt to be randomized to either drug postoperatively. The primary endpoint is 2-HG concentration in surgically resected tumors. Secondary endpoints include safety, tumor and plasma pharmacokinetics, and RANO LGG response. Exploratory endpoints include 2-HG and pharmacokinetics in cerebrospinal fluid, and 2-HG magnetic resonance spectroscopy. This study is currently enrolling in the USA.
OC-084 Feasibility of endogel(tm) simulation training for per-oral endoscopic myotomy (poem): first united kingdom experience
Authors: S Gulati, A Emmanuel, H Inoue, K Mizuno, H Sato, S Terai, A Haji, B Hayee
Journal: Gut (2017)

Introduction  Simulation-based training is an established method of basic endoscopic training, however this is limited in advanced endoscopic techniques due to challenges in creating realistic environments. Uptake of advanced endoscopic techniques in the West has also been slower compared to the East due to lack of structured training programmes. Porcine model training is limited in availability and subject to local ethical approval emphasising the need of an alternative simulation medium. Here we evaluate the feasibility of UK’s first EndogelTM (Sunarrow Ltd, Japan) simulation course for POEM with video demonstration of technique.  Method  Eight delegates undergoing a single POEM training course were included. All delegates received a didactic lecture including video demonstration of POEM. This was followed by a live demonstration of POEM technique using EndogelTM. Orientation of EndogelTM was as per manufacturers guidance for POEM training. Prospective data on baseline POEM experience were collected. Assessment of EndogelTM for realism, feasibility and usefulness in POEM simulation training was recorded using a 5-point Likert scale (5 being the “best” score) and analysed using median and range values.  Results  All course delegates were UK practitioners (6 gastroenterologists, 2 surgeons, 1 senior trainee and 7 consultants) and received prior lecture based training. 3 had completed previous a hands-on course including 2 with previous POEM simulation training. 3 delegates had fellowship(n=2)/observership (n=1) experience. 2 delegates had some primary operator experience (5–10 and >10 POEM). Median score was 4 for realism of EndoGelTM orientation (3-5), mucosal lift (4-5), mucosal incision (3-5), submucosal expansion (3-5) and myotomy (3-5). Realism of submucosal dissection scored higher at 5 (3-5). Median score was 4 for feasibility of EndoGelTM orientation (3-5), mucosal lift (4-5), mucosal incision (1-5), submucosal expansion (3-5), submucosal dissection (1-5) and myotomy (3-5). This cohort found the EndogelTM simulator useful (4, 4-5) and would use this again (4, 3-5) including monitoring skill development (4, 3-5).  Conclusion  This preliminary data supports EndogelTM as a feasible simulation model for POEM training for trainees of varied experience. Particular attractive features are the realism of submucosal dissection owing to the specifically designed liquid retaining submucosal plane of the layered polyvinyl alcohol hydrogel enabling precise dissection to be mastered. Additionally, EndogelTM is advantageous over porcine models in being reusable. EndogelTM provides a safe and efficacious environment for advanced endoscopic skill development in the West.  Disclosure of Interest  None Declared
Abstract 20020: Alterations in Aortic Flow After Valve Sparing Root Replacement With or Without Neo-sinuses Reconstruction
Authors: Francesco Sturla, Filippo Piatti, Nicola Galea, Jonathan Weinsaft, Christopher Lau, Emiliano Votta, Ilaria Chirichill, Ruggero De Paulis, Lenonard N Girardi, Alberto Redaelli, Mario Gaudino
Journal: Circulation (2017)

Introduction: Three-dimensional Phase-Contrast (4D Flow) MRI is a valid non-invasive technique to capture the temporal and complex 3D blood velocity field in the aortic root. Here, through advanced 4D Flow MRI processing, we quantified the aortic flow dynamics after valve sparing root replacement, comparing the effects of aortic grafts with or without recreation of the Valsalva sinuses on the neo-root postoperative fluid dynamics. Methods: We enrolled patients submitted to valve sparing root replacement with a straight tubular prosthesis (n=8) or with a prosthesis with Valsalva neo-sinuses (n=8), also including 6 control subjects. 4D Flow MRI acquisitions were performed on a 3.0T MR unit in oblique-sagittal orientation to encompass the entire thoracic aorta. In-house processing was exploited to segment the aortic lumen, extract the 4D Flow velocity field and quantify bulk flow variables in the ascending and descending aorta. We computed flow velocity, regional wall shear stress (peak and mean WSS, axial a...
NCOG-01. PRESERVATION OF NEUROCOGNITIVE FUNCTION (NCF) WITH HIPPOCAMPAL AVOIDANCE DURING WHOLE-BRAIN RADIOTHERAPY (WBRT) FOR BRAIN METASTASES: PRELIMINARY RESULTS OF PHASE III TRIAL NRG ONCOLOGY CC001
Authors: Vinai Gondi, Stephanie Pugh, Paul D Brown, Jeffrey Wefel, Mark Gilbert, Joseph Bovi, Cliff Robinson, Benzinger Tammie, Wolfgang Tome, Terri Armstrong, Deborah Bruner, Deepak Khuntia, David Grosshans, Andre Konski, Andre Robidoux, Vijayananda Kundapur, Kiran Devisetty, Sunjay Shah, Kenneth Usuki, Bethany Anderson, Baldassarre Stea, Harold Yoon, Jing Li, Nadia Laack, Tim Kruser, Steven Chmura, Wenyin Shi, Minesh P Mehta, Lisa Kachnic
Journal: Neuro-Oncology (2018)

PURPOSE: NRG CC001, a phase III trial of WBRT plus memantine with or without hippocampal avoidance, sought to evaluate the neuro-protective effects of avoiding the hippocampus using intensity-modulated radiotherapy. Adult patients with brain metastases were stratified by RPA class and receipt of prior radiosurgery/surgery and randomized to WBRT+memantine (WBRT+M) versus hippocampal-avoidant WBRT+memantine (HA-WBRT+M) (30Gy in 10 fractions). Standardized NCF tests were performed at baseline, 2, 4, 6, and 12 months. The primary endpoint was time to NCF failure, defined as decline on at least one of the following tests using the reliable change index: Hopkins Verbal Learning Test-Revised, Trail Making Test, or Controlled Oral Word Association. Cumulative incidence was used to estimate time to NCF failure (death without NCF failure was treated as competing risk) with between-arms differences tested using Grays test. To detect an 11% absolute reduction in 6-month NCF failure, 382 analyzable patients were required for 90% power with two-sided =0.05. Due to possible non-compliance, the sample size was increased by 25% (510 patients). From July 2016 to March 2018, 518 patients were randomized. Median age was 61.5 years. Median follow-up for alive patients was 6.1 months. Treatment arms did not differ in grade3 toxicity, overall survival, intracranial progression, or baseline NCF. Time to NCF failure was significantly longer in favor of HA-WBRT+M (p=0.012). The 6-month NCF failure rates were 69.1% (95% CI:61.8–75.3%) vs. 58.0% (95% CI:50.2–64.9%) for WBRT+M vs. HA-WBRT+M, respectively. After adjusting for stratification factors, HA-WBRT+M (hazard ratio (HR)=0.73, 95%CI:0.56–0.94, p=0.016) and age 61 years (HR=0.61, 95%CI:0.46–0.81, p=0.0006) remained significant. Preliminary analysis confirms that conformal avoidance of the neuro-regenerative hippocampal stem cell compartment during WBRT preserves neurocognitive function while achieving similar intracranial control and survival. Supported by grants UG1CA189867 (NCORP), U10CA180868 (NRG Oncology Operations), DCP from the National Cancer Institute.
DRES-15. GSK3 BETA AND hnRNPA1 (RNA BINDING PROTEIN) COOPERATES WITH cMyc TRANSCRIPTIONAL REGULATOR, ANTAGONIZES GSK3 ALPHA UNDER THERAPEUTIC STRESS
Authors: Ajay Yadav, Vidhi Vashistha
Journal: Neuro-Oncology (2018)

Oncogenic cooperation activity tends these glioma cells to acquire drug resistance. Where GSK3 beta isoform cooperates cMyc antagonizes GSK3 alpha isoform. Down regulated expression of GSK3 alpha cooperates elevated hnRNPA1 expression, evolving glioma development. Occurrence of hnRNPA1 dependent alternative oncogenic variant is one of the resistance mechanism. Inhibiting GSK3 beta isoform using specific siRNAs is one the approach rather than to inhibit GSK3 kinase activity, also downregulate hnRNPA1 which is cMyc dependent. Using Chromatin Immuniprecipitation approach we observed potential differences in between transcriprional regulators of GSK3 beta and GSK3 alpha isoform. Positive feedback mechanism of alpha and beta isorform of GSK3 to stabilize cMyc, therefore inhibiting expression of heterogenous ribonucleor protein family members. Interfering the positive feed back GSK3 beta- cMyc-GSK3 beta, is major hallmark to catch on cMyc transcriptional regulator. In another experiment inhibition of PI3 kinase/ AKT pathway using specific inhibitors elevates GSK3 beta and hnRNPA1 but not GSK3 alpha, associates with cMyc, indicating potential role of GSK3 beta isoform in glioma resistance development. Immunohistochemistry based analysis shows inverse correlation between GSK3 alpha and hnRNPA1.
Stemming retinal regeneration with pluripotent stem cells
Authors: Zi-Bing Jin, Mei-Ling Gao, Wen-Li Deng, Kun-Chao Wu, Sunao Sugita, Michiko Mandai, Masayo Takahashi
Journal: Progress in Retinal and Eye Research (2018)

Cell replacement therapy is a promising treatment for irreversible retinal cell death in diverse diseases, such as age-related macular degeneration (AMD), Stargardt's disease, retinitis pigmentosa (RP) and glaucoma. These diseases are all characterized by the degeneration of one or two retinal cell types that cannot regenerate spontaneously in humans. Aberrant retinal pigment epithelial (RPE) cells can be observed through optical coherence tomography (OCT) in AMD patients. In RP patients, the morphological and functional abnormalities of RPE and photoreceptor layers are caused by a genetic abnormality. Stargardt's disease or juvenile macular degeneration, which is characterized by the loss of the RPE and photoreceptors in the macular area, causes central vision loss at an early age. Loss of retinal ganglion cells (RGCs) can be observed in patients with glaucoma. Once the retinal cell degeneration is triggered, no treatments can reverse it. Transplantation-based approaches have been proposed as a universal therapy to target patients with various concomitant diseases. Both the replacement of dead cells and neuroprotection are strategies used to rescue visual function in animal models of retinal degeneration. Diverse retinal cell types derived from pluripotent stem cells, including RPE cells, photoreceptors, RGCs and even retinal organoids with a layered structure, provide unlimited cell sources for transplantation. In addition, mesenchymal stem cells (MSCs) are multifunctional and protect degenerating retinal cells. The aim of this review is to summarize current findings from preclinical and clinical studies. We begin with a brief introduction to retinal degenerative diseases and cell death in diverse diseases, followed by methods for retinal cell generation. Preclinical and clinical studies are discussed, and future concerns about efficacy, safety and immunorejection are also addressed.
ATIM-37. SAFETY RUN-IN RESULTS OF A PHASE I/II STUDY TO EVALUATE THE SAFETY AND CLINICAL EFFICACY OF ATEZOLIZUMAB (ATEZO; aPDL1) IN COMBINATION WITH TEMOZOLOMIDE (TMZ) AND RADIATION IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (GBM)
Authors: Shiao-Pei Weathers, Carlos Kamiya-Matsuoka, Shannon Dervin, Cindy Yun, Monica Loghin, Barbara O’Brien, Rebecca Harrison, W K Alfred Yung, Marta Penas-Prado, John de Groot
Journal: Neuro-Oncology (2018)

Immunotherapy strategies like PD-1/PD-L1 inhibition may work synergistically with radiation, which has been shown to increase antigen presentation and promote a pro-inflammatory tumor microenvironment. This trial evaluated the safety of concurrent atezo with radiation therapy and TMZ followed by adjuvant TMZ and atezo in newly diagnosed GBM patients. Eligibility criteria included patients with newly diagnosed GBM age ≥ 18 yrs who have undergone only surgery. The primary objective of the phase I safety run-in was to evaluate atezo in combination with radiation and TMZ during the concurrent stage and in combination with TMZ during the adjuvant stage. 11 patients were accrued in the concurrent safety run-in phase. 2 dose-limiting toxicities (DLT) were observed in 1 patient who developed both grade 3 hepatitis and pneumonitis related to atezo. 2 patients discontinued treatment during the concurrent stage due to medical complications deemed unrelated to study drug. In the 8 evaluable patients who completed the concurrent phase, no other grade 3 or 4 atezo-related toxicities were observed. 5 of the 8 evaluable patients completed the combination treatment without the need for dexamethasone. The remaining 3 of the 8 evaluable patients required no more than 4 mg daily of dexamethasone during combination treatment. All 8 patients had stable MRI findings following completion of the concurrent phase. 7 of the 8 evaluable patients proceeded with adjuvant treatment with atezo and TMZ with no grade 3 or 4 atezo-related toxicities observed to date (no. cycles range, 1–6). Concurrent use of atezo with radiation and TMZ was tolerable, and no new safety signals were noted. The majority of evaluable patients were able to complete the combination treatment without the need for concurrent steroid administration. The phase II component of the trial is recruiting patients (n=50) to evaluate clinical efficacy.