tbuckley/cabot-search huggingface dataset:
PATH-24. RECURRENT UNUSUAL PATTERNS IN CLINICAL MOLECULAR PROFILING OF ADULT DIFFUSE GLIOMAS
Authors: Cristiane Ida, Cinthya Zepeda Mendoza, Corinne Praska, Jessica Balcom, Kirsten Swanson, Emily Barr Fritcher, Joseph Parisi, Mark Jentoft, Katherine Geiersbach, Aditya Raghunathan, Caterina Giannini, Benjamin Kipp, Robert Jenkins
Journal: Neuro-Oncology (2018)

Adult diffuse gliomas (ADG) are stratified in clinically relevant groups based on 1p/19q co-deletion status, and IDH and TERT promoter (TERTp) mutational status. Using a clinical NGS assay targeting 50 ADG-associated genes, 419 ADG (at least 18 years; 59 grade II, 131 grade III, 229 grade IV) were profiled within a 15-month period. In a subset of cases, chromosomal microarray (n=132) or 1p/19q FISH (n=19) was performed. There were 89 IDH-mutant (33 WHO “Oligodendroglioma, IDH-mutant and 1p/19q co-deleted”, 3 “Astrocytoma, IDH-mutant” with TERTp mutation and 53 “Astrocytoma, IDH-mutant”) and 330 IDH wild-type (254 TERTp-mutant and 76 TERTp wild-type) cases. Mutation pattern analysis was performed using heatmap2 hierarchical clustering. ADG arising within the midline were predominantly “Astrocytoma, IDH-wildtype” (11 TERTp-mutant and 10 TERTp wild-type cases), with one “Astrocytoma, IDH-mutant” and two “Diffuse midline glioma, H3 K27M-mutant” cases. Unusual recurrent patterns were noteworthy. “Astrocytoma, IDH-mutant” with TERTp mutation were 1p/19q-intact lower-grade gliomas that lacked ATRX mutations and recurrently showed TP53 mutations, chromosome 7 gain and CDKN2A/B copy-neutral loss-of-heterozygosity. “Astrocytoma, IDH-wildtype” with TERTp and BRAF mutations had BRAF V600E (n=4) and non-V600E (n=3) mutations, and were high-grade tumors with recurrent PTEN mutations. A subset of “Astrocytoma, IDH-wildtype” had a single gene mutation (n= 29). Only 9 tumors (2%) were negative for mutations within the 50 interrogated genes. Chromosomal microarray of 6 of these mutation-negative cases revealed genomic abnormalities, including gain/amplification involving TERT in addition to copy number changes usually observed in “Astrocytoma, IDH-wildtype”. This suggests that such tumors were likely driven mainly by chromosomal instability/copy number abnormalities and that TERT copy number changes may represent an alternative telomere maintenance mechanism in ADG. Clinical molecular profiling shows recurrent unusual patterns in ADG and underscores the challenges and the need for large scale initiatives to provide guidance on how to clinically interpret such patterns.
PATH-03. PROGNOSTIC IMPORTANCE OF TUMOR GRADE IN THE POST-GENOMIC ERA
Authors: Rushikesh Joshi, Ali Alattar, Kate Carroll, Clark Chen
Journal: Neuro-Oncology (2018)

In the post-genomic era of glioma biology, an emerging paradigm is that the molecular and genomic features of gliomas may be more important than tumor grade in determining prognosis. Here, we analyze The Cancer Genome Atlas (TCGA) to assess whether isocitrate dehydrogenase mutation (IDHm) and mutated methylguanine methyltransferase (mMGMT) are better prognostic indicators than tumor grade. We identified 1,115 astrocytic gliomas of all grades. We assessed survival using univariate and multivariate Cox proportional hazards models. Multivariate models were adjusted for tumor grade, age, Karnofsky’s Performance Score (KPS), mMGMT, and IDHm. Pearson’s correlation analysis indicated significant pairwise associations between mMGMT and age (r = -0.22), KPS (r = 0.14), and tumor grade (r = -0.32) (all p< 0.05). Similarly, there were significant pairwise associations between IDHm and age (r = -0.60), KPS (r = 0.34), and tumor grade (r = -0.70) (all p< 0.05). Multivariate analysis showed that age, KPS, tumor grade, mMGMT, and IDHm independently contributed to survival prognosis. For mMGMT tumors, the median survival for grade II, III, and IV tumors was 17.10, 12.70, and 8.55 months; and for MGMT unmethylated tumors, was 13.25, 13.75, and 9.30 months, respectively. For IDHm tumors, two distinct survival distributions were observed for each tumor grade. The first distribution with survival < 60 months, exhibited median survival for grades II, III, and IV patients of 14.3, 12.5, and 16.6 months, while patients surviving >= 60 months demonstrated median survivals of 88.10, 75.15, and 91.10 months, respectively. These survival distributions in IDHm survival did not significantly differ. Wild type IDH tumors fell into a single distribution, with median survival of 7.40, 10.40, and 9.70 months for grade II, III, and IV tumors, respectively. Similar survival patterns were observed in the CGGA. Survival prognostication requires synthesis of molecular features of tumors with patient characteristics and tumor grade. For IDHm gliomas, however, tumor grade is a pertinent prognostic factor.
Abstract 16138: Chest and Cardiac Compression on CT/MRI and on TEE Predicts Improvement in Right Heart Chamber Size and Right Ventricular Deformation Post Pectus Excavatum Repair Surgery
Authors: Chieh-Ju Chao, Michael B Gotway, Dawn E Jaroszewski, Steven Lester, Samuel Unzek, Susan Wilansky, Hari P Chaliki, Christopher P Appleton, Farouk Mookadam, Tasneem Z Naqvi
Journal: Circulation (2015)

Background: Pectus excavatum (PE) deformity involves posterior depression of the sternum and adjacent costal cartilages. The relationship of CT/MRI chest cardiac compression indices used as indications for surgical repair of PE with echocardiographic findings and with improvement in cardiac chamber compression and function post PE repair is unknown. Methods: We evaluated right atrial (RA) size, tricuspid annulus (TA size, right ventricular (RV) outflow tract size as well as RV 2D strain on intra-operative trans-esophageal echocardiography (TEE) immediately pre and post surgical PE repair. Inspiratory and expiratory Haller Index (HI) and cardiac compression indices (CCI) were measured on pre op CT/MR scans (Figure). Offline measurement of chamber dimensions on TEE images was performed and Speckle tracking strain measurements were made using Syngo US Workplace software (Siemens). P&lt;0.05 was considered significant. Results: 60 patients, 73% male, 27% female, age 33.6±10.3 yrs underwent PE repair following CT/MRI from 2010-2014 (Figure). There was a strong correlation between expiratory CT/MRI chest AP diameter and pre-op RA size (panel A). Pre op RA and TA compression on TEE inversely correlated with pre op RV global longitudinal strain rate(RVGLSR) (panels B &amp; C). CCI predicted improvement in RA size post PE repair (panels D &amp; E). In addition pre op RA size on TEE correlated with improvement in RVGLSR post PE repair surgery (panel F). Conclusion: In patients with PE deformity, pre surgical CCI correlated with right-sided cardiac chamber compression on pre op TEE. Severity of chest and cardiac compression also predicted magnitude of improvement in right-sided chamber size and RV longitudinal deformation post PE repair. Our findings provide insight regarding the beneficial effects of PE surgery on right heart chamber compression and improvement in RV function and the important role of intraoperative TEE for patients undergoing PE repair surgery.
IMMU-44. OPTICAL BARCODING TO INVESTIGATE CLONAL DYNAMICS OF GBM HIGHLIGHTS THE INTRINSIC CAPACITY OF GBM TO RE-ACTIVATE DEVELOPMENTAL GENES AND ESCAPE IMMUNE SURVEILLANCE
Authors: Cecile Maire, Malte Mohme, Kristoffer Riecken, Antonio-Virgilio Failla, Daniela Boernigen, Krystian Fita, Katharina Kolbe, Boris Fehse, Manfred Westphal, Katrin Lamszus
Journal: Neuro-Oncology (2018)

The dynamic interplay of the heterogeneous nature of GBM within the microenvironment remains one of the biggest challenges and inhibits effective treatment strategies. It is still unknown how the brain microenvironment and in particular the immune cells are shaping tumor cell clonal heterogeneity and contribute to drug resistance. To model the growth dynamic of clonal GBM populations in vivo, we used patient derived cells lines (PDX, n = 10) as well as a syngeneic mouse line, labelled with an RGB combination of colors, allowing us to directly visualize thousands of clones. Brains were analyzed by confocal microscopy and flow cytometry, and an algorithm was developed to quantify and plot clonal heterogeneity as 3D graphs. The results demonstrated different degrees of clonal constriction and selection, depending on cell type and microenvironment. We next investigated the GBM clonal development by tracking clones applying a unique approach called optical barcoding (OBC). We were able to re-isolate subpopulations grown out from single cells in immunocompetent vs immunodeficient mice by cell sorting and to analyze specific clones by RNAseq. In the absence of immune cells, clonal constriction appears to be more random and less stringent while the recruitment of T cells, macrophages and NK cells during the early phase of tumor growth shapes tumor heterogeneity, favoring some specific clones fit to escape the immune cells. Moreover, we discovered in our PDX models that the comparison of bulk tumor expression profiles to only the fittest clones that contribute to tumor growth highlighted the specific expression of genes involved in neurogenesis and neural stem cell specification. These results indicate that clonal GBM cell expansion is not only determined by genomic alterations but also by their capacity to re-activate developmental gene expression programs.
AB0744 A “lost-to-follow-up” autoantibody for the diagnosis of autoimmune disease: prevalence and clinical characteristics of anti-nor90/hubf positive patients
Authors: C. Koutsianas, K. Levasseur, M. Rutter, C. Webber, M. Bhole, C. Bell, K. Douglas
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Anti-nuclear antibody (ANA) patterns in indirect immunofluorescence testing (IIF) have been valuable in the diagnosis of autoimmune diseases. A pattern of speckling with fluorescent mitotic dots is considered to represent autoantibodies against nucleolar organising regions (NORs). Anti-NOR90 antibodies target the human upstream binding factor (hUBF) which activates RNA polymerase I-activated ribosomal RNA transcription. They have been anecdotally associated with systemic sclerosis (SSc), Sjögren's Syndrome (pSS) and rheumatoid arthritis (RA). <h3>Objectives</h3> To analyse the prevalence and clinical characteristics of patients found to be anti-NOR90 positive by immunology at The Dudley Group NHS FT (DGH) which also serves Worcestershire Acute Hospitals NHS Trust (WAH). <h3>Methods</h3> Clinical letters and electronic patient records of anti-NOR90 positive patients identified in the DGH immunology laboratory between July 2016 and October 2017 were reviewed. Advice was sought regarding ethical approval and consent; this was deemed unnecessary for this clinical survey. Anonymized patient data was collected on Excel. Anti-NOR90 was tested for when the characteristic ANA pattern was observed and as part of an extended SSc blot (EUROLINE SSc (Nucleoli) profile (IgG) – EUROIMMUN). <h3>Results</h3> We identified 11 anti-NOR90 positive patients among 8000 positive ANA results (estimated prevalence 0.0137%). Patient demographics, diagnoses and immunology are illustrated in table 1. Patients were in their vast majority female (10/11, 91%) and had a median age of 63 (IQR:53–74) years. The median anti-NOR90 titer was 111 (IQR:14–139) intensity units. 6/11 (54.5%) had a confirmed diagnosis of rheumatic disease. The most common clinical features were Raynaud's phenomenon (63.6%), sicca symptomatology (36.4%) and polyarthritis (36.4%). Interstitial lung disease (ILD) and oesophageal dysmotility (OD) were predominant clinical features in two cases (SSc, pSS). In general, patients lacked skin involvement (scleroderma, telangiectasias, calcinosis). <h3>Conclusions</h3> Literature regarding anti-NOR90 auto-antibodies has been scarce and in the age of automated IIF ANA testing, it is plausible that their specific nucleolar pattern is frequently missed. In our survey, they were observed in the context of several rheumatic diseases and linked to Raynaud's, sicca symptoms and polyarthritis. Studies in larger relevant patient cohorts are needed to further clarify their clinical value. <h3>Disclosure of Interest</h3> None declared
TMOD-06. HIGH INCIDENCE OF TUMORS AFTER TREATMENT WITH A DNA-ALKYLATING AGENT IN MOUSE STRAINS COMMONLY USED IN PRE-CLINICAL STUDIES
Authors: Susan Irtenkauf, Laura Hasselbach, Andrea Transou, Laila Poisson, Houtan Noushmehr, Igor Rybkin, Ana deCarvalho
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is commonly treated with the DNA-alkylating agent temozolomide (TMZ). Silencing O6-methylguanine-DNA methyltransferase (MGMT) by promoter hypermethylation predicts response to TMZ. Oral TMZ administration also affects tissues with low MGMT expression, such as bone marrow, resulting in high incidence of leukopenia and secondary leukemia in humans. Here we assessed the anti-tumor effect of TMZ in a panel of orthotopic GBM patient-derived xenografts (GBM-PDXs), and looked for evidence of secondary malignancy in the GBM-PDX lines with extended survival post-TMZ treatment, and also examined TMZ-treated naïve mice from two immunocompromised strains. First, a panel of 12 orthotopic GBM-PDX in athymic nude mice (NCRNU-F) were treated with 2-cycles of TMZ (40mg/kg/day for 5 days in a 21-day cycle) or with vehicle control gavage (n=10/treatment group). Treatment response was measured by log-rank test comparison of Kaplan-Meier survival curves. The untreated controls and TMZ-resistant PDXs succumbed to brain tumor burden immediately after treatment completion. TMZ-responsive GBM-PDX lines and GBM-naïve nude mice developed respiratory dysfunction 3–5 months after TMZ treatment. Histopathological analysis of lung tissue at autopsy revealed multiple foci of papillary adenocarcinoma (negative for human markers) in both lungs, at an incidence of 95% at 280 days in TMZ-treated nude mice, with no evidence of tumors in other organs. GBM-naïve untreated nude mice in the control group did not develop tumors after 1 year. TMZ treatment of severe combined immunodeficiency (SCID) mice resulted in 77% tumor incidence in the thymus and/or lungs in a GBM-PDX line, 3–4 months post-treatment, with a similar incidence for GBM-naïve treated mice, and no tumors observed in control mice after 9 months. These results present additional evidence of the tumorigenic potential of TMZ, particularly in the background of immunodeficiency. The development of lung/thymus tumors in TMZ-responsive GBM-PDX lines is an undesirable confounding factor not previously reported.
ANGI-17. INTERLEUKIN 1 SIGNALING REGULATES BLOOD-BRAIN BARRIER INTEGRITY IN GLIOBLASTOMA
Authors: Cameron Herting, Dmitry Shayakhmetov, Dolores Hambardzumyan
Journal: Neuro-Oncology (2018)

Glioblastoma is the most common and aggressive primary brain tumor characterized by a dismal prognosis despite aggressive treatment regimens. A hallmark of glioblastoma is aberrant angiogenesis that results in disruption of the blood-brain barrier. This drives glioblastoma-associated cerebral edema caused by leakage of serum from the blood into the brain. Typically, edema is managed by the corticosteroid dexamethasone which is known to normalize the blood brain barrier. Various groups have also demonstrated beneficial effects following normalization of the blood-brain barrier with anti-angiogenic therapies such as cediranib and bevacizumab. Interleukin 1 (IL-1) signaling inhibition, however, has not been investigated in this context despite evidence that it modulates blood-brain barrier integrity in other neuroinflammatory conditions. In this work, we demonstrate that IL-1 signaling does not impact the production of VEGF by bone marrow-derived macrophages and microglia in vitro. Moreover, we demonstrate no effect of dexamethasone treatment on VEGF levels in murine PDGFB-driven glioblastoma generated with RCAS/tv-a technology in vivo. This suggests that the restoration of blood-brain barrier integrity by dexamethasone is VEGF-independent. Dexamethasone is shown here, however, to downregulate both IL-1α and IL-1β expression in vivo and in vitro. Genetic ablation of IL-1β and subsequent MRI analysis is shown to reduce formation of edema in vivo, allowing mice to survive with larger tumors than wildtype controls. Serial sectioning of the tumor, and histological reconstruction of the total volume post-euthanasia confirms these results. Genetic ablation of IL-1R1 in vivo is shown to reduce blood-brain barrier permeability in a Hoechst dye-based vessel leakage assay. Future experiments will elucidate if these effects can be attributed to altered angiogenesis or regulation of endothelial cell junction molecules. Regardless, this work outlines IL-1 signaling as a promising therapeutic target to modulate blood-brain barrier integrity and serve as an alternative to dexamethasone for the treatment of glioblastoma-associated cerebral edema.
IMMU-34. A BALANCED TRYPTOPHAN DIET LEADS TO MAXIMAL IMMUNOTHERAPEUTIC EFFICACY IN GLIOBLASTOMA MODELS
Authors: Erik Ladomersky, Lijie Zhai, Alicia Lenzen, Kristen Lauing, Sebastian Otto-Meyer, Rohan Savoor, Rimas Lukas, Derek Wainwright
Journal: Neuro-Oncology (2018)

Immunotherapy has failed to improve glioblastoma (GBM) patient survival in all Phase III clinical trials to-date. A potential mechanism contributing to treatment failure, is based on our recent work showing that, GBM-infiltrating T cells directly increase the intratumoral expression of indoleamine 2,3 dioxygenase 1 (IDO1) (Zhai et al., 2017; CCR): an immunosuppressive enzyme that metabolizes tryptophan (Trp); an essential amino acid only provided to the body by dietary intake. Coincidently, we recently discovered that a substantial proportion of syngeneic mice with intracranial GL261, experience long-term survival when administered radiotherapy (RT) with concurrent PD-1 and IDO1 enzyme inhibitors (Ladomersky et al., 2018; CCR). Since the duration and penetration of pharmacologic IDO1 inhibition is variable, we questioned whether dietary Trp supplementation would influence efficacy of immunotherapy against GBM. Mice were placed on ad libitum dietary formulations containing 0%, 25%, 100%, 200%, and 500% normal daily Trp, three days prior to the intracranial-injection (ic.) of 2 × 105 GL261. At fourteen days post-ic., animal subjects enrolled on each diet were treated with: (i) IgG control Ab; or (ii) the simultaneous combination of 2Gy whole brain radiotherapy for five days, four doses of PD-1 mAb (J43) every three days, and 100mg/kg IDO1 enzyme inhibitor (BGB-5777), BID, for four weeks (n=10/group). Mice receiving normal (100%) dietary Trp achieve a long-term survival benefit (3/10; P<0.001). In contrast and unexpectedly, both the depletion and saturation of dietary Trp, has negative effects on immunotherapeutic efficacy. Strikingly, although withholding dietary Trp decreases serological Trp levels (P<0.05), CNS parenchyma Trp concentrations remain stable, regardless of low-absent dietary Trp and peripherally-circulating levels. These data support that, IDO1-mediated immunosuppression is not overcome by supplementing or depleting the diet of Trp. Moreover, it suggests that a balanced diet, with normal Trp intake, provides maximal efficacy for supporting immunotherapy against malignant glioma.
PATH-51. DNA COPY NUMBER PROFILING ACROSS GLIOBLASTOMA POPULATIONS HAS IMPLICATIONS FOR CLINICAL TRIAL DESIGN
Authors: Patrick Cimino, Lisa McFerrin, Hans-Georg Wirsching, Sonali Arora, Hamid Bolouri, Raul Rabadan, Michael Weller, Eric Holland
Journal: Neuro-Oncology (2018)

Copy number alterations form prognostic molecular subtypes of glioblastoma with clear differences in median overall survival. In this study, we leverage molecular data from several glioblastoma cohorts to define the distribution of copy number subtypes across random cohorts as well as cohorts with selection biases for patients with inherently better outcome. Copy number subtype frequency was established for four glioblastoma patient cohorts. Two randomly selected cohorts include The Cancer Genome Atlas (TCGA) and German Glioma Network (GGN). Two more selective cohorts include the phase II trial ARTE in elderly patients with newly diagnosed glioblastoma and a multi-institutional cohort focused on paired resected initial/recurrence glioblastoma. The paired initial/recurrence cohort also had exome data available, which allowed for evaluation of multidimensional scaling analysis. Smaller selective glioblastoma cohorts are enriched for copy number subtypes that are associated with better survival, reflecting the selection of patients who do well enough to enter a clinical trial or who are deemed well enough to undergo resection at recurrence. Adding exome data to copy number data provides additional data reflective of outcome. CONCLUSIONS: The overall outcome for diffuse glioma patients is predicted by DNA structure at initial tumor resection. Molecular signature shifts across glioblastoma populations reflect the inherent bias of patient selection towards longer survival in clinical trials. Therefore it may be important to include molecular profiling, including copy number, when enrolling patients for clinical trials in order to balance arms and extrapolate relevance to the general glioblastoma population.
MNGI-18. RISK FACTORS FOR PRE- AND POSTOPERATIVE SEIZURES IN MENINGIOMA PATIENTS IDENTIFIED BY LOGISTIC REGRESSION ANALYSIS
Authors: Lukas Goertz, Christina Hamisch, Nora Erdner, Hannah Muders, Niklas von Spreckelsen, Pantelis Stavrinou, Roland Goldbrunner, Boris Krischek
Journal: Neuro-Oncology (2018)

To identify independent risk factors of pre- and postoperative seizures in meningioma patients. This is a retrospective single-center analysis of consecutive patients that underwent resection of intracranial meningioma between 2004 and 2017. The impact of patient and tumor characteristics on pre- and postoperative seizures was assessed by univariate and binary logistic regression analysis. Among 729 included patients, pre- and postoperative seizures occurred in 18.9% and 10.0%, respectively. In the univariate analysis, female gender (p = 0.013), preoperative motor deficits (p < 0.001) and peritumoral edema (p < 0.001) were associated with preoperative seizures. Headache (p < 0.001), preoperative sensoric symptoms (p < 0001) and occipital tumor location (p = 0.024) were negatively correlated with preoperative seizures. In the multivariate analysis, preoperative motor deficits (p < 0.001, OR: 3.9, 95% CI: 2.6 5.9) and peritumoral edema (p < 0.001, OR: 3.5, 95% CI: 1.8 6.7) were independent risk factors of preoperative seizures. In the univariate analysis postoperative seizures were significantly associated with parietal tumor location (p= 0.021), WHO grades 2 and 3 (p < 0.001), presence of multiple meningiomas (p = 0.034), incomplete tumor resection (Simpson grade > 2, p = 0.007) and recurrent meningioma (p = 0.001). Incomplete resection (p = 0.04, OR: 2.6, 95% CI: 1.1 6.6) and recurrent meningioma (p = 0.037, OR: 2.6, 95% CI = 1.1 6.2) remained as independent risk factors for postoperative seizures in the multivariate analysis. Preoperative motor deficits and peritumoral edema are independent risk factors for preoperative seizures, while incomplete tumor resection and recurrent meningioma are independently associated with postoperative seizures.