tbuckley/cabot-search huggingface dataset:
QOLP-09. ASSOCIATION BETWEEN BODY IMAGE INVESTMENT AND ALTERATION IN PATIENTS WITH PRIMARY BRAIN TUMORS
Authors: Peter Mathen, Terri Armstrong, Elizabeth Vera, Alvina Acquaye, Sonja Crandon, María Fletcher Ruiz, Orwa Aboud, Lisa Boris, Miranda Brown, Nancy Garren, Ming Ji, Jason Levine, Megan Mackey, Carlos Romo, Jennifer Reyes, Christine Siegel, DeeDee Smart, Jing Wu, Mark Gilbert, Kevin Camphausen, Tito Mendoza, Lindsay Rowe
Journal: Neuro-Oncology (2018)

Body image is an important psychosocial issue in cancer patients, including those with primary brain tumors (PBT). Investment in physical appearance is associated with depression and quality-of-life (QoL) outcomes in non-CNS malignancies. Therefore, examination of body image investment is warranted to better understand factors involved in body image disturbance in the PBT population. A cross-sectional survey of 100 PBT patients was conducted as part of an IRB approved prospective protocol. Participants completed the 10-item Body Image Scale (BIS), and the 20-item Appearance Schemas Inventory-Revised (ASI-R) which includes self-evaluative and motivational salience subscales. Potential BIS and ASI-R scores ranged from 0–30 and 1–5 respectively. Cronbach’s alpha assessed reliability. Pearson’s correlation coefficients assessed relationships between questionnaires. Significance level was p< 0.05. Patients were mostly male (56%) with a median age of 48 (range 23–74). Glioblastoma was the most common diagnosis (32%). Median time from initial diagnosis was 5 years (range 0–22), and 64% of patients had a KPS≥ 90. Median BIS score was 5 (range 0–27), ASI-R composite score was 2.9 (range 1.5–4.7), self-evaluative subscale score was 2.6 (range 1.2–4.5), and motivational subscale score was 3.4 (range 1.9–5.0). BIS was significantly correlated with ASI-R composite (r=0.53, 95%CI: 0.37 to 0.65), ASI-R self-evaluative (r=0.65, 95%CI: .52 to .75), but not ASI-R motivational (r=0.14, 95%CI: -0.06 to 0.33, p=0.17) scores. Increased severity of altered body image was correlated to increased negativity of the patient’s belief about their appearance. Cronbach’s alpha for the ASI-R composite, self-evaluative and motivational subscales were 0.87, 0.85, and 0.81 respectively. CONCLUSIONS: Body image and investment are important QoL issues for PBT patients. The ASI-R demonstrated good internal consistency in this population. While there was significant correlation between BIS and ASI-R composite and self-evaluative scores, this was not true with the motivational score.
ACTR-19. A MULTICENTER PILOT PHASE II STUDY OF CONTINUING TMZ WITH THE ADDITION OF DISULFIRAM AND COPPER FOR REFRACTORY GLIOBLASTOMA
Authors: Jiayi Huang, Rehka Chaudhary, Adam Cohen, Karen Fink, Samuel Godlust, John Boockvar, Prakash Chinnaiyan, Stephen Marcus, Jian Campian
Journal: Neuro-Oncology (2018)

Preclinical studies have suggested promising activity for the combination of disulfiram and copper (DSF/Cu) against glioblastoma (GBM) including re-sensitization to temozolomide (TMZ). A previous phase I study demonstrated the safety of combining DSF/Cu with adjuvant TMZ for newly diagnosed GBM. This pilot phase II study aimed to estimate the potential effectiveness of DSF/Cu to re-sensitize recurrent GBM to TMZ. METHOD: This open-label, single-arm phase II study treated recurrent TMZ-refractory GBM patients with TMZ 150mg/m2 on days 1–5 of every 28-day cycle with concurrent daily DSF 80mg TID and Cu 1.5mg TID. Eligible patients must have progressed after standard chemoradiotherapy and within 3 months of the last dose of TMZ. Known IDH-mutant or secondary GBMs were excluded. The primary endpoint was objective response rate (ORR), and the secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit (stable disease for at least 6 months), and safety. Evaluable patients must have received at least 28 days of DSF/Cu unless stopped due to progression, toxicity, or death. From March 2017 to January 2018, 23 TMZ-refractory GBM patients were enrolled across seven centers in the United States, and 22 patients were evaluable. The median DSF/Cu duration was 48 days (range: 12–246 days). After a median follow-up of 4.4 months, there were no objective responses, with 6-month PFS of 14% and 6-month OS of 55%. Among 17 patients who had at least 28 days of DSF/Cu, 3 patients (18%) had clinical benefit. Grade 3 toxicities that were possibly related to DFS/Cu included fatigue, headache, anxiety, and elevated alanine transaminase (5% for each). CONCLUSION: Addition of DSF/Cu to TMZ for TMZ-refractory GBM yielded minimal ORR but demonstrated clinical benefit for a subset of patients. DSF/Cu may have modest TMZ re-sensitization or single-agent activity for recurrent GBM.
PDCT-05. FEASIBILITY OF PROSPECTIVE WHOLE-EXOME SEQUENCING (WES) IN PEDIATRIC MEDULLOBLASTOMA PATIENTS ON THE HEAD START 4 PROTOCOL
Authors: Richard Graham, Erica Hlavin Bell, Amy Webb, Asha Jacob Jannu, Cynthia Timmers, Joseph McElroy, Aline Becker, Yingshi Guo, Girish Dhall, Jonathan Finlay, Arnab Chakravarti
Journal: Neuro-Oncology (2018)

Medulloblastoma is the most common brain tumor in early childhood. Molecular profiling of medulloblastomas has resulted in a classification system including at least 4 major subtypes of disease, defining prognosis in patients treated largely on traditional chemotherapy and irradiation-based protocols. The Head Start Consortium has developed treatment protocols designed to avoid irradiation and its debilitating long-term side effects. The first three Head Start trials showed promising results; however, prospective genetic data are still lacking to evaluate whether molecular alterations can predict patient response to irradiation-avoiding treatment strategies. The Head Start 4 Protocol is a multi-national trial that incorporates non-mandatory, prospective tumor and blood collection for analysis in an attempt to address this question. Currently, 100% of patients enrolled to date have submitted samples for WES. Paired blood and tumor samples (FFPE) from the first 10 medulloblastoma patients had WES (SureSelect Human All Exon V6+COSMIC) performed utilizing an Illumina Hiseq 4000. Data were processed using varscan v2.4.1 somatic command on tumor/normal pairs and annotated using Variant Effect Predictor from ensembl. Results were filtered at a threshold of 20 read depth or 40% variant allele frequency. Low-impact mutations were removed. Mutation profiles were compared with pediatric medulloblastoma gene mutation data from the PedcBioPortal and PeCan databases. A total of 903 mutation events were identified across 10 patients with each patient demonstrating mutations in one or more genes previously reported to be mutated in medulloblastoma. Two samples harbored SUFU mutations similar to those reported previously. CONCLUSIONS: These data show the feasibility of prospective high-dimensional mutational analysis using non-mandatory tissue submissions for pediatric medulloblastoma patients enrolled on the Head Start 4 Protocol. Copy-number and methylation analysis is ongoing. FUNDING: Thrasher Research Fund (JF, AC). R01CA108633, R01CA169368, RC2CA148190, U10CA180850-01 (NCI), Brain Tumor Funders Collaborative Grant, and OSUCCC (AC).
CMET-03. PHASE 1 TRIAL OF OSIMERTINIB WITH STEREOTACTIC RADIOSURGERY IN EGFR MUTANT LUNG CANCER BRAIN METASTASIS
Authors: Bicky Thapa, Samuel Chao, Nathan Pennell, David Peereboom, Manmeet Ahluwalia
Journal: Neuro-Oncology (2018)

Brain metastases (BM) occurs in 25–40% of patients with non-small cell lung cancer (NSCLC). Traditionally patients with brain metastases were treated with whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS) and surgical resection. Historically, BM is associated with dismal prognosis. Recent advances in the targeted therapy have improved BM outcomes. In patients with epidermal growth factor receptor (EGFR) positive NSCLC with 1–10 BM, we hypothesize to control the macro BM with SRS and osimertinib. Osimertinib use will help control the micro metastases. This approach would avoid WBRT that can potentially lead to significant congnitive decline. This is single arm, phase I multicenter study of Osimertinib with SRS. Primary endpoint is to determine the safety of Osimertinib in combination with SRS EGFR positive NSCLC with BM. Secondary end points include 6-month intracranial and extracranial progression free survival (PFS-6), overall survival (OS) in EGFR positive NSCLC BM. To compare results of this clinical trial to historical controls of EGFR positive NSCLC BM treated with SRS alone. To assess the intracranial and extracranial overall response rate as measured by RECIST 1.1. Eligibility criteria includes age >18 years, historically confirmed EGFR mutation positive NSCLC with newly diagnosed BM, 1–10 BM, ECOG status of 0–2. Key exclusion criteria include leptomeningeal disease, BM within 5 mm of optic chiasma or optic nerve, metastases in brain stem, history significant cardiovascular and other comorbidities, known HIV or chronic hepatitis infection and those receiving other investigational cancer therapy. Statistical analysis: The study will employ a 3 + 3 design with an expansion cohort at the maximum tolerated dose (MTD) and up-to 40 patients will be enrolled to determine safety and preliminary efficacy with the combination. The study (CASE 3517) is ongoing and enrolling patient with EGFR mutant NSCLC.
MNGI-19. SURGICAL RESECTION OF SPHENO-ORBITAL MENINGIOMAS AND ORBITAL RECONSTRUCTION USING PATIENT SPECIFIC CAD/CAM IMPLANTS
Authors: Boris Krischek, Lukas Goertz, Marco Timmer, Roland Goldbrunner, Pantelis Stavrinou
Journal: Neuro-Oncology (2018)

Computer-aided design and manufacturing (CAD/CAM) implants are fabricated based on volumetric analysis of computed tomography (CT) scans and are routinely used for the reconstruction of orbital fractures. We present three cases of patients with spheno-orbital meningiomas that underwent tumor resection, orbital decompression and orbital reconstruction with patient specific porous titanium or acrylic implants in a single procedure. The extent of bone resection of the spheno-orbital meningiomas was planned in a virtual three-dimensional (3D) environment using preoperative thin-layer CT data. The anatomy of the orbital wall in the resection area was reconstructed by superimposing the contralateral unaffected orbit and by using the information of the neighboring bony structures. The customized implants were designed in the desired size and shape using computer-aided manufacturing. Furthermore, a corresponding craniotomy template in the form of a frame was produced for precise craniotomy. All patients presented with a spheno-orbital meningioma and an exophthalmus. After osteoclastic craniotomy with the drilling template orbital decompression was performed. The cranioplasty implant fitted tightly in all three cases and could be easily fixated with mini-plates and screws, although in one case a reoperation was necessary for additional resection, as well as drilling and repositioning of the implant. The postoperative CT scans showed an accurate reconstruction of the orbital wall. After surgery, exophthalmos was substantially reduced and a satisfying cosmetic result was achieved in all patients. The concept of preoperative 3D virtual treatment planning and single-step orbital reconstruction with CAD/CAM-implants after tumor resection involving the orbit is well feasible and can lead to good cosmetic results.
TCF-1 and HEB cooperate to establish the epigenetic and transcription profiles of CD4+CD8+ thymocytes
Authors: Akinola Olumide Emmanuel, Stephen Arnovitz, Leila Haghi, Priya S. Mathur, Soumi Mondal, Jasmin Quandt, Michael K. Okoreeh, Mark Maienschein-Cline, Khashayarsha Khazaie, Marei Dose, Fotini Gounari
Journal: Nature Immunology (2018)
RARE-07. THE EFFECT OF SELUMETINIB ON SPINAL NEUROFIBROMAS IN PATIENTS WITH NF1
Authors: Sadhana Jackson, Eva Baker, Andrea Gross, Trish Whitcomb, Andrea Baldwin, Joni Mills, Marielle Holmblad, Joanne Derdak, Brigitte Widemann, Eva Dombi
Journal: Neuro-Oncology (2018)

Spinal neurofibromas (SNF) in neurofibromatosis type 1 (NF1) can cause progressive cord compression with associated morbidity. A phase 1 study of the MEK inhibitor Selumetinib in patients with plexiform neurofibromas (PN) demonstrated PN shrinkage and improvement clinical symptoms. Here we describe the effect of selumetinib on SNF burden. Participants of the ongoing phase 2 pediatric (NCT01362803) and adult (NCT02407405) selumetinib studies for NF1 PN, who underwent serial spine MRI exams were examined. The effect of selumetinib on the size of SNF, shape of the spinal canal, spinal cord, and cerebrospinal fluid (CSF) space were evaluated at baseline and during treatment by linear measurements. Nineteen patients (14 male), median age 15.5 years (range, 6–60) had documented SNF and were included in the analysis. Six patients had prior spinal decompression surgery and all had SNF extending into the central canal at one or more levels (14 cervical, 2 thoracic, 12 lumbosacral). Deformation of the spinal cord cross-section was observed in 17 patients. Sixteen patients completed at least 12 cycles of treatment, and 3 received 8 cycles. Tumors remained stable in 5 patients, improvement was observed in 14 patients (9 children, 5 adults) and no SNFs exhibited progression during treatment. Most improvements were observed after 4 cycles and were maintained. The most notable change was expansion of the CSF space (due to tumor shrinkage), with CSF signal becoming circumferential. Analysis of clinical correlations is ongoing. CONCLUSIONS: This is the first study assessing selumetinib effect on SNF. In 14 of 19 patients with SNF, we observed prolonged improvement in SNF attributes. Our findings indicate selumetinib may prevent worsening of cord compression, and reduce surgical interventions. The role of MEK inhibitor therapy for the treatment of SNF needs to be prospectively evaluated along with functional measures and patient reported outcomes.
CSIG-13. COMPUTATIONAL MODELING OF GLIOBLASTOMA STEM CELL SIGNALING NETWORKS
Authors: Emilee Holtzapple, Natasa Miskov-Zivanov, Kenneth Jahan, Yahan Zhang, Steven Young, Brent Cochran
Journal: Neuro-Oncology (2018)

Despite a tremendous increase in knowledge about glioblastoma in recent years, it has proven difficult to devise new effective therapies. It is likely that a major reason for the failure of new therapies is due to the molecular heterogeneity of GBM between tumors. We have found from RNAi screens that there is significant diversity in essential genes between the tumor stem cells of different patients with only about 50% of all inhibitory kinases being in common between any 2 stem cell lines. Thus, it is likely that a personalized therapeutic approach will be needed for effective treatment of brain tumors. We are building causal computer models of signaling pathways and networks in these tumor stem cells in order to predict the drug responsiveness of individual GBM stem cell lines. To do this, we are using a framework that assembles and tests element rule-based models in an automated manner, assuming a discrete modeling approach, capable of capturing causal relationships between model elements. The use of causal relationships (positive and negative regulation), in addition to mechanistic relationships (e.g., phosphorylation, binding), allows for capturing not only direct but also indirect interactions between elements. By including these indirect interactions on pathways, when there is no information available about exact mechanisms, we are able to account for known element relationships, and capture larger network motifs (e.g., intertwined feedback and feedforward loops), which are often critical in network response to interventions. Our current model with 141 elements and 298 edges can successfully model responses to CDK6 and GSK3-beta inhibition after initialization with RNA-Seq data. With our automated framework, we are now extending the model using text mining with human supervision, and we will test the extended model against chemical inhibitor and RNAi data from multiple GBM stem cell lines.
INNV-12. A QUALITY IMPROVEMENT PROGRAM FOR GLIOBLASTOMA PATIENT CARE QUALITY IN TWO ACADEMIC TERTIARY U.S. NEURO-ONCOLOGY CENTERS
Authors: Manmeet Ahluwalia, Wendi Evanoff, Bicky Thapa, Jeffrey Carter, Tariqa Ackbarali, Laurence Greene, Tamar Sapir, Sandy Leong, Michelle Lin, Gabriel Zada
Journal: Neuro-Oncology (2018)

To address needs for quality improvement (QI) initiatives in glioblastoma (GBM) patient care, we are conducting a QI program in 2 major U.S. neuro-oncology centers. At baseline, we retrospectively reviewed EMRs for 100 GBM patients (50 in each center), assessing physicians performance of quality-based and NCCN guideline-directed biomarker testing and diagnostic procedures, time from diagnosis to tests/treatments, tumor board reviews, clinical trial enrollment, GBM treatments, and patient-centered measures. Multidisciplinary GBM teams in each center are participating in QI interventions including feedback on baseline EMR results and developing action plans for improvement. Post-intervention EMRs will be retrospectively reviewed for 50 GBM patients in each center. At baseline, for 100 GBM patients diagnosed between 2012–17, median age was 63 years (26–89), median KPS was 80 (40–90), 22% were female, 82% were Caucasian, 72% were referred from community settings, and 17% were treated at a county hospital with chemotherapy or radiation. Percentages of biomarker tests included: MGMT, 61%; IDH1/2, 80%; 1p19q codeletion, 63%; EGFR, 65%; and TERT, 5%. Mean number of days from diagnosis to tests/treatments were: Postoperative MRI, 2.2; pathology report, 8.6; molecular test report, 8.1; initiation of chemotherapy, 27.7; and radiotherapy, 29.3. Tumor board reviews and clinical trial discussions were performed in 55% and 84% of patients, respectively. Percentages of patient-centered care practices included: interdisciplinary care coordination, 92%; discussion of prognosis, 79%; and timely hospice involvement for patients without treatment options, 40%. Higher incidence of selected biomarker tests performed was significantly associated with male sex, Caucasian race, higher KPS grade, and clinical trial discussion. The methods and findings from this QI program on GBM are relevant to designing scalable initiatives across community-based and academic neuro-oncology centers. Our presentation, which will include post-intervention results, will address practical applications for improving quality-based and guideline-directed practices for patients with GBM.
GENE-13. PEDIATRIC MENINGIOMAS ARE CHARACTERIZED BY DISTINCT METHYLATION PROFILES DIFFERENT FROM ADULT MENINGIOMAS
Authors: Elmar Kirches, Felix Sahm, Christina Blücher, Svenja Boeckhoff, Ulrich Schüller, Jens Schittenhelm, Matija Snuderl, Matthias Karajannis, Arie Perry, Torsten Pietsch, Hermann Müller, David Capper, Katja Beck, Matthias Schlesner, Siegfried Kropf, Priscilla Brastianos, Andrey Korshunov, Stefan Pfister, Christian Mawrin
Journal: Neuro-Oncology (2019)

In contrast to adulthood, meningiomas are rare among children and adolescents. However, the molecular relations between both groups have not been elucidated in detail. We have analyzed 41 tumor samples from 37 pediatric meningioma patients (female: 17, male: 20; age range: 1–21 years). Atypical meningioma WHO grade II was the most frequent histological subtype (N=14, 38%). Most tumors were located at the convexity (N=18) or the skull base (N=15). Lack of SMO, AKT, KLF4/TRAF7 mutation in Sanger sequencing (n=22) prompted whole genome sequencing of a subset (n=7). All cases exhibited bi-allelic mutation of NF2 (combined large deletion and germline (5/7) or somatic (2/7) base exchanges/frameshifts). Subsequently, representative samples of all 37 patients were subjected to 450K DNA methylation profiling and remaining DNA to sequencing of a brain tumor specific gene panel. Loss of chromosome 22 was frequently detected (N=28, 76%), followed by loss of chromosome 1 (N=12, 32%) and chromosome 18 (N=7, 19%). Moreover, a separation into three groups was evident: One group covering all clear-cell meningiomas with enrichment for SMARCE1 mutations, a second group dominated by atypical meningiomas, and a third group covering benign WHO grade I meningiomas, as well as rare subtypes such as rhabdoid meningiomas. Compared to adult tumors, the majority of pediatric meningiomas clustered in a separate group both by unsupervised hierarchical and clustering and t-stochastic nearest neighbor embedding. Analysis of four tumor recurrences did not reveal changes compared to the primary tumor. These data suggest that pediatric meningiomas are fundamentally different from adult counterparts.
PDTM-06. ALK AMPLIFICATION AND REARRANGEMENTS ARE RECURRENT TARGETABLE EVENTS IN GLIOBLASTOMA
Authors: Anne-Florence Blandin, Maya Graham, Shakti Ramkissoon, Lori Ramkissoon, Kristine Pelton, Mélanie Pages, Robert Jones, Sarah Becker, Fiona Watkinson, Kathleen Schoolcraft, Veerle Haemels, Liliana Goumnerova, Susan Chi, Karen Wright, Mark Kieran, Arnault Tauziede-espariat, Pascale Varlet, Sanda Alexandrescu, David Reardon, Benjamin Carcamo, Al Charest, Frederik De Smet, Rameen Beroukhim, Adrian Dubuc, Ralf Kittler, Patrick Wen, Brian Alexander, Pratiti Bandopadhayay, Robert Bachoo, Keith Ligon
Journal: Neuro-Oncology (2018)

Anaplastic Lymphoma Kinase (ALK) expression, rearrangements, and single nucleotide variants have been reported in several brain tumor types, but the significance and function of each aberration in adults and children have not been clearly established. To determine the degree to which ALK represents a relevant therapeutic target in gliomas, we first examined ALK expression using immunohistochemistry (IHC) in a panel of 148 adult GBM and 49 pediatric GBM/high grade gliomas. We identified high ALK expression was most frequent in pediatric gliomas (32%, 16/49, IHC score 2+ or 3+). Copy arrays/sequencing and FISH for the ALK locus revealed high level ALK amplification in 31% of ALK-expressing cases (5/16) but was a rare event in gliomas overall. Whole-genome sequencing and RNA sequencing identified novel and recurrent PPP1CB-ALK fusions in 43% of ALK-expressing pediatric GBM (7/16), suggesting IHC may be an efficient means of screening for ALK aberrations as in the identification of EML4-ALK lung cancer. All ALK- amplified cases harbored PPP1CB-ALK fusion but 2 PPP1CB-ALK cases were copy neutral. The phosphatase PPP1CB was fused in-frame to ALK at exon 20 with preservation of the ALK kinase domain and predicted to activate via the same mechanism as other ALK rearranged cancers. ALK fusion proteins promoted cell proliferation and constitutive kinase activity and upregulated STAT and AKT signaling pathways. However, expression of novel ALK missense mutations in NSCs did not promote proliferation. Administration of ALK inhibitor Crizotinib reduced tumor growth in a PDX GBM from a patient with a novel ALK fusion. This work validates amplification and rearrangement of ALK as a highly recurrent driver event and therapeutic target in GBM, particularly in young children where it may be the sole driver event.
The Medalist Trial: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Luspatercept to Treat Anemia in Patients with Very Low-, Low-, or Intermediate-Risk Myelodysplastic Syndromes (MDS) with Ring Sideroblasts (RS) Who Require Red Blood Cell (RBC) Transfusions
Authors: Pierre Fenaux, Uwe Platzbecker, Ghulam J. Mufti, Guillermo Garcia-Manero, Rena Buckstein, Valeria Santini, María Díez-Campelo, Carlo Finelli, Mario Cazzola, Osman Ilhan, Mikkael A. Sekeres, José F. Falantes, Beatriz Arrizabalaga, Flavia Salvi, Valentina Giai, Paresh Vyas, David Bowen, Dominik Selleslag, Amy E. DeZern, Joseph G. Jurcic, Ulrich Germing, Katharina S. Götze, Bruno Quesnel, Odile Beyne-Rauzy, Thomas Cluzeau, Maria Teresa Voso, Dominiek Mazure, Edo Vellenga, Peter L Greenberg, Eva Hellström-Lindberg, Amer M. Zeidan, Abderrahmane Laadem, Aziz Benzohra, Jennie Zhang, Anita Rampersad, Peter G. Linde, Matthew L. Sherman, Rami S. Komrokji, Alan F. List
Journal: Blood (2018)