tbuckley/cabot-search huggingface dataset:
SURG-05. NAVIGATED INTRA-OPERATIVE 2-D ULTRASOUND VS STANDARD NEURONAVIGATION IN HIGH GRADE GLIOMA SURGERY
Authors: Alessandro Moiraghi, Francesco Prada, Alberto Delaidelli, Cristina Goga, Ramona Guatta, Adrien May, Andrea Bartoli, Marco Saini, Thomas Waelchli, Philippe Bijlenga, Karl Schaller, Francesco DiMeco
Journal: Neuro-Oncology (2018)

Maximizing extent of resection (EOR) and reducing residual tumor volume (RTV) while preserving neurological functions is the main goal in the surgical treatment of gliomas. Navigated Intra-operative ultrasound (N-ioUS) is a real-time imaging technique which, combining the advantages of ultrasound and conventional neuronavigation (NN), allows for overcoming the limitations of the latter. We evaluate the impact of real-time NN combining ioUS and pre-operative magnetic resonance imaging (MRI) on maximizing EOR in glioma surgery compared to standard NN. We retrospectively reviewed a series of 60 cases operated on for supratentorial gliomas, 31 operated under the guidance of N-ioUS and 29 resected with standard NN. Age, location of the tumor, pre- and post-operative Karnofsky Performance Status (KPS), EOR and, if any, post-operative complications were evaluated. Volumetric pre-operative and 48hours post-operative MRI was used to determine EOR. The rate of gross total resection (GTR) in NN group was 44.8% and EOR≤90% 10.3%, whereas in N-ioUS group a 61.2% GTR rate was obtained with a 6.4% rate of EOR≤90%. The rate of RTV> 1cc for GBMs was significantly lower for the N-ioUS group (p=0.01) compared to the NN. In 13/31 (42%) RTV was detected at the end of surgery with N-ioUS. In 8 of 13 cases (25.8% of the cohort) surgeons continued with the operation until complete resection. Specificity was greater in N-ioUS (42% vs 31%) and positive predictive value (73% vs 54%). At discharge the difference between pre and post-operative KPS was significantly higher for the N-ioUS (p=0.0008). Using N-ioUS-based real-time guidance in glioma surgery we obtained superior results in terms of both EOR and neurological outcome, in comparison to standard NN. N-ioUS has proven usefulness in detecting RTV> 1cc. In tumors located nearby eloquent areas the technique was successfully combined with cortical and subcortical mapping techniques.
FRI0183 Clinical peripheral enthesitis in the desir prospective longitudinal axial spondyloarthritis cohort
Authors: V. Nadon, A. Moltó, A. Etcheto, L. Bessette, L. Michou, M.-A. D’Agostino, P. Claudepierre, D. Wendling, M. Dougados
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Objectives</h3> 1) To describe the prevalence and characteristics of peripheral enthesitis in recent onset axial spondyloarthritis; 2) to estimate the incidence of peripheral enthesitis over time; 3) to determine the factors associated with the presence of peripheral enthesitis. <h3>Methods</h3> <i>Patients</i>: 708 patients with recent onset axial spondyloarthritis enrolled in the DESIR cohort (prospective multi-centre, longitudinal). <i>Data collected</i>: patients and spondyloarthritis characteristics at baseline with a specific focus on enthesitis and occurrence of peripheral enthesitis, during the five of years follow-up <h3>Results</h3> At inclusion, 395 patients (55.8%) reported peripheral enthesitis. The locations were mainly the plantar fascia (53.7%) and the Achilles tendon (38.5%). During the 5 year follow-up period, 109 additional patients developed peripheral enthesitis resulting in an estimated (Kaplan Meier technic) percentage of 71% (95% CI: 68–75). Variables associated with peripheral enthesitis in the univariate analysis were: older age, male gender, absence of HLA B27, MRI sacroiliitis and fulfilled Modified NY criteria, presence of anterior chest wall pain, peripheral arthritis, dactylitis, psoriasis, high BASDAI, BASFI, mean score ASAS-and the use of NSAID. Only the history of anterior chest wall pain and of peripheral arthritis were retained in the multivariate analysis (Odds Ratio (OR)=1.6 [95% Confidence interval (1.6 [1.1–2.3], and OR=2.1 [1.4–3.0], respectively). <h3>Conclusions</h3> This study highlights the high prevalence of peripheral enthesitis in recent onset axial spondyloarthritis, and suggests that in combination with peripheral arthritis, enthesitis might have an impact on the burden of the disease. <h3>Acknowledgements</h3> The DESIR cohort is financially supported via an unrestricted grant from PFIZER Ltd. France. Valérie NADON has received a research grant from JANSSEN Ltd Canada. <h3>Disclosure of Interest</h3> None declared
Abstract 12368: Cardiac Cellular Reprogramming With "Triplet" Polycistronic Vectors Encoding Gata 4, Mef2c and Tbx5 Enhances Post-Infarct Ventricular Functional Improvement Compared to Singlet Vectors
Authors: Megumi Mathison, Robert P Gersch, Stephen M Kaminsky, Jianchang Yang, Maria Chiuchiola, Ronald G Crystal, Todd Rosengart
Journal: Circulation (2013)

Reprogramming of cardiac fibroblasts into induced cardiomyocytes (iCMs) by in situ Gata4 (G), Mef 2c (M) and Tbx5 (T) administration has been shown to improve post-infarct ventricular function in myocardial infarction models, and scar pre-vascularization with VEGF has been shown to further enhance this intervention. However, the efficacy of this gene transfer strategy has been limited by the need for cell targets to be infected three times - once by each of the single G, M and T vectors. We hypothesized that a polycistronic vector encoding all three GMT transcription factors would enhance post-infarct ventricular function compared to use of single transgene vectors. Methods: Following in vitro validation studies, adult male Fischer 344 rats (n=6) underwent coronary ligation and intramyocardial administration 3 wks later of a polycistronic GMT “triplet” lentivirus vector construct (3x105 TU) or the same total dose of three vectors each individually encoding G, M, or T. GMT-treated animals also underwent in...
Ornithine decarboxylase (ODC) polymorphism and reduction of breast cancer risk
Authors: Yong Guo, Huixiang Li, Mantao Liu, Bin Hao, G O'Brien Thomas
Journal: Cancer Research (2008)

1931   Ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis, is regulated by Myc-Max-Mad transcription factor network. We have described the functional significance of a single nucleotide polymorphism (SNP) in the ODC promoter and found that this SNP is associated in a statistically significant manner with risk of colon adenoma recurrence. Breast cancer is the most commonly diagnosed cancer among women in China and worldwide. A case-control study (101 cases and 174 controls) was done to examine the association between this ODC genotype and breast cancer risk in Chinese women. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated to test the association between ODC genotype and breast cancer risk. The presence of the ODC A allele was significantly associated with a reduced risk of breast cancer (RR=0.42, 95% CI =0.23 to 0.76 for ODC genotype AG; RR=0.20, 95% CI=0.10 to 0.40 for genotype AA, P
The RET receptor tyrosine kinase causes activation of the β-catenin pathway
Authors: Taranjit Gujral, Douglas Richardson, Shirley Myers, Mireia Dunach, Lois Mulligan
Journal: Cancer Research (2007)

341  The RET proto-oncogene encodes a receptor tyrosine kinase required for development of the kidney and neural crest derived cell types. Gain-of-function mutations in RET have been implicated in over 50% of sporadic Medullary thyroid carcinoma (MTC) and 90% of families with Multiple Endocrine Neoplasia type 2 (MEN 2). MEN 2 is associated with MTC as well as the adrenal tumour pheochromocytoma (PC), with or without hyperparathyroidism. The biochemical mechanisms by which the potent transforming and mitogenic signals of RET are transduced are still not clear. Here, we report a novel mechanism of RET-mediated signalling, through the activation of the β-catenin pathway. We show that the oncogenic form of the RET receptor, and its wildtype form upon activation, tyrosine phosphorylate β-catenin, resulting in the altered sub-cellular localization of β-catenin. Using a kinase dead mutant for RET, we also show that β-catenin is tyrosine phosphorylated in a RET kinase dependent manner. However, we also show that the association of RET and β-catenin is constitutive and is not dependent on tyrosine phosphorylation of either RET or β-catenin. We also demonstrate that the interaction between RET and β-catenin can be direct and can be independent of cytoplasmic kinase, SRC. Our biochemical data shows that RET can phosphorylate β-catenin at Y654, which is predicted to cause it’s dissociation from the E-cadherin complex, leading to accumulation of cytosolic and nuclear localization of β-catenin. Consistently with this, we show altered cellular localization of β-catenin was associated with the activation of TCF dependent transcription activity, using a TOPFLASH reporter. Recent studies have shown the aberrant expression of E-cadherin/ s-catenin levels in thyroid tumors. Our data suggest that the RET-induced activation of the β-catenin pathway may contribute to cellular transformation and driving malignant tumour progression in thyroid cancer.
MNGI-07. THE ANAPLASTIC MENINGIOMA INTERNATIONAL CONSORTIUM (AMICo) RETROSPECTIVE STUDY OF TREATMENT AND OUTCOME OF PATIENTS WITH ANAPLASTIC MENINGIOMAS
Authors: Rina di Bonaventura, Adam Young, Rasheed Zakaria, Charles Champeaux, Aaron Foo, Jörg-Christian Tonn, Christopher McMurran, Tseng Tai Yeo, Matthias Kirsch, Fardad Afshari, Stefan Florian, Marco Rossi, Annamaria Biczok, Michaela Dedeciusová, Vladimir Benes, Jonathan Pollock, Stephen Magill, Kieren Allinson, Oliver Hanemann, Michael McDermott, Kush Bhatt, Lorenzo Bello, Michael Jenkinson, Ramez Kirollos, Mathew Guilfoyle, Thomas Santarius
Journal: Neuro-Oncology (2018)

Anaplastic meningiomas are rare, comprising only 1–2% of all meningiomas, and limited data on its natural history and response to treatment. An international retrospective study using 2016 Classification of the Tumours of the CNS was used to identify grade 3 meningiomas. Anonymised clinical and radiological data were collected in a uniform manner from 21 centres. 355 patients were identified to have an anaplastic meningioma. 57% cases arose de novo and 43% were progressed from lower grade; 20% directly from grade 1, 15% from grade 1 via grade 2 and 65% from grade 2. Female predominated among de novo and males among the progressive cases, with M/F ratios 0.8 and 1.4, respectively (p=0.02). De novo tumours were, on average, larger than progressive (51cc and 27cc, respectively; p=0.002). De novo cases predominated in sphenoid wing and ventricular locations, while progressive cases predominated in anterior fossa midline locations. The median survival of patient from the first diagnosis of anaplastic meningioma (index surgery) was 99 and 30 months for de novoand progressive cases, respectively (p<0.0001). Independent factors for survival were degree of resection (p=0.23) and administration of radiotherapy (p<0.001). Among the progressive anaplastic meningiomas, the longest survival was achieved in patients who received radiotherapy both before and after the index surgery. Those receiving radiotherapy only after lived longer than those who received radiotherapy before the index surgery. Those who received no radiotherapy had shortest survival. The difference in growth between surgery only and surgery and radiotherapy groups was significant (17.6%/month versus 5.3%/month; p = 0.038). Here in we present the largest cohort of patients with anaplastic meningiomas allowing detailed analysis of natural history and response to treatment in de novo and progressive anaplastic meningiomas.
GENE-10. IDENTIFICATION OF MXRA5 AND DSP AS RELEVANT TARGETS IN INFILTRATING ASTROCYTOMAS: A WHOLE EXOME ANALYSIS AT A SINGLE INSTITUTION
Authors: David Pisapia, Samaneh Motanagh, Andrea Sobner, Kenneth Eng, Michael Kluk, Juan Miguel Mosquera, Olivier Elemento, Rohan Ramakrishna
Journal: Neuro-Oncology (2018)

Infiltrating astrocytomas (IA) comprise the most common primary brain tumors in adults. Herein we summarize our findings in an adult IA cohort enrolled as part of a precision medicine-based clinical trial at a single institution. We interrogated 85 IA samples over 81 distinct adults. Whole exome sequencing was performed and matched with peripheral blood samples for germline analysis. We present a summary of our findings and a comparison to commercially available approaches available in 68 (80%) of cases, in order to assess distinct approaches to the molecular characterization of IA. The most frequently altered genes detected by both WES and commercial platforms include EGFR, CDKN2A/B, TP53, PTEN, NF1, IDH1, ATRX, and PIK3CA. Certain alterations such as TERTpromoter mutations, which were present in the majority of IDH-wildtype IA’s as detected by commercial platforms, were not assessed by WES. Several mutations in cancer related genes were revealed to be germline alterations in the WES pipeline alone, including in ARID1A, BRCA1, NF1, and WT1. In addition, several genes were noted to be recurrent at lower frequencies including CD209, DCHS2, DROSHA, FBN2, HECW2, MTUS2, OBSCN, PCLO, QRICH2, RBP3, SPTB, TENM3, VWF, MXRA5 and DSP. Notably, both MXRA5 and DSP were found to be associated with significantly differential survival when applied to the TCGA dataset for Low and High Grade Gliomas. The majority of the most common recurrent genetic alterations in the spectrum of IA are reliably detected by WES and at comparable rates to more targeted panels such as commercially available platforms; however exome sequencing pipelines require refinement to cover promoters such as TERT. Germline assessment is important to understand the implications of mutations in cancer related genes which are not currently reported by commercial platforms. Finally, mutations in DSP and MXRA5 may be potential therapeutic targets deserving of further study.
CADD-50. AN OLD STORY (MGMT) IN AN EXPANDED CONTEXT (NATIONAL CANCER DATABASE)
Authors: Santhi Konduri, Maharaj Singh, Richard Rovin, George Bobustuc, Amin Kassam
Journal: Neuro-Oncology (2018)

O6-methylguanine-DNA methyltransferase (MGMT), a DNA repair protein, which is expressed in majority of cancers including glioblastoma multiforme (GBM), a predictive biomarker in the alkylator based treatment of gliomas. The objective of this study is to confirm the MGMT’s role as a predictive biomarker and to re-evaluate the potential MGMT, patient subset specific, prognostic role using the National Cancer Database (NCDB). METHOD: We used the NCDB to identify GBM patients with MGMT (N=5934) registered from 2010 through 2014 in which MGMT status was detected. Hyper methylation was detected in 40.65% patients while the remaining 59.35% were unmethylated (low methylation scores). The mean, and SD age of the patients was 60.8 ± 12.7 years. The patient population included 90.6% white, 4.95% black, 4.42% of other races (Hispanic and Asians), out of these, males 57.7% and females 43.3 %. The incidence of GBM was 11.5% in 2010 and 34.29% in 2014. Overall survival (OS) among GBM patients was higher among methylated patients regardless of therapeutic intervention (p <0.001). Unadjusted mortality risk was higher in unmethylated patients (HR=1.22; 1.09–1.34). However adjusted for other demographic and therapeutic factors the hazard ratio was further increased to 1.5 (95% CI; 1.43–1.61). The other predictors of mortality were male (HR=1.10; 1.04–1.17), white (HR=1.31; 1.12–1.52), and black vs others (HR=1.22; 1.00–1.52), 5-year increase in age (HR=1.17; 1.15–1.19), no surgical resection (HR=2.00; 1.81–2.20) and no radiation treatment (HR=2.16; 2.01–2.32). Mean survival for the methylated group was 24.22 months, whereas mean survival for the unmethylated group was 17.55 months. These results confirm that MGMT promoter methylation is the single most important factor affecting survival among GBM patients and MGMT promoter methylation was an independent indicator of better prognosis for GBM patients. The presence of a methylated MGMT promoter is a predictive biomarker for response to alkylator based therapies.
Abstract 16988: Fatty Liver Index is Reduced With Ezetimibe in an Analysis of 15,095 Patients Randomized to Ezetimibe vs Placebo in the Improve-it Trial
Authors: Tracey G Simon, Jeong-Gun Park, Kathleen E Corey, Raymond T Chung, Christopher P Cannon, Robert Giugliano
Journal: Circulation (2015)

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the US, and is associated with early atherogenesis and increased risk of cardiovascular (CV) death. Although no pharmacologic therapy has proven benefit in NAFLD, recent clinical studies suggest that ezetimibe may reduce histologic evidence of liver inflammation and improve serum markers of NAFLD. In this post hoc analysis of the IMPROVE-IT trial, we assessed the impact of ezetimibe in patients with presumed NAFLD, using the Fatty Liver Index (FLI), a validated prediction score for hepatic steatosis. Methods: Of the 18,144 IMPROVE-IT patients randomized to ezetimibe/simvastatin (E/S) or placebo/simvastatin (P/S), 15,095 had both baseline ALT 2x ULN and sufficient data with which to calculate FLI, a calculated score composed of triglycerides (TG), gamma-glutamyltransferase (GGT), body mass index (BMI), and waist circumference. FLI ≥ 60 has been strongly correlated with NAFLD, while values &lt;30 indicate low probability of NAFLD. Differences in FLI between treatment arms over time were tested with non-parametric Wilcoxon rank-sum tests. Results: Baseline FLI was ≥ 60 in 6798 (45%) patients and &lt;30 in 3438 (23%). E/S reduced median absolute FLI from 55.0 to 51.2 over 72 months, a reduction of 6.9%, which was significantly greater than that observed in P/S group (all p&lt;0.001 at each time-point, Fig). Of those with initial FLI ≥ 60 treated with E/S, 26.3% had 48-month FLI score &lt; 60 (compared to 21.6% in P/S group, p&lt;0.001). E/S significantly reduced both TG and GGT compared to P/S (both p&lt;0.001 at 72 months). E/S significantly reduced FLI regardless of baseline ALT (normal vs. 1-2x ULN) ( p =0.002; interaction p =0.53). Conclusion: Ezetimibe significantly reduced surrogate markers of NAFLD, suggesting that it may offer protection against progression of non-alcoholic fatty liver disease, metabolic syndrome, and atherogenic risk.
RTHP-11. REIRRADIATION OF RECURRENT HIGH GRADE GLIOMAS: OUTCOMES AND PROGNOSTIC FACTORS
Authors: Christopher Chapman, Jared Hara, Jennifer Clarke, Nicholas Butowski, Susan Chang, Shannon Fogh, Penny Sneed, Jean Nakamura, David Raleigh, Steve Braunstein
Journal: Neuro-Oncology (2018)

PURPOSE/OBJECTIVE(S): Identify prognostic factors for progression-free survival (PFS) and overall survival (OS) after reirradiation (re-RT) for recurrent high grade glioma (HGG). MATERIALS/ Patients with HGG received re-RT from 2010 to present. PFS and OS prognostic variables were examined using Cox models. Receiver operative curve (ROC) analysis identified predictive thresholds for continuous variables. 58 patients received surgery and adjuvant radiation for HGG (51 grade IV, 7 grade III). The median time to first progression after initial radiation was 11 months. 36% received single fraction stereotactic re-RT (SRS) (median 18 Gy) and 64% received fractionated re-RT (median 35 Gy in 10 fractions). The median planning target volume (PTV) was 16.8 mL. The median biologically effective dose (BED10) of re-RT was 47 Gy (range 15–72). 50% received chemotherapy and 36% received bevacizumab concurrent to re-RT. Toxicity ≥ grade 3 was 7%. The median PFS after re-RT was 4.7 months and the median OS was 11 months. Lower PFS was significantly associated with shorter time to first progression, lower KPS, and lower re-RT dose. Lower OS was associated with shorter time to first progression, lower KPS, and larger PTV. Other factors were not significantly associated with PFS or OS. ROC analysis of time to first progression and re-RT dose showed best predictive thresholds at time > 12 months and BED10 > 42 Gy. CONCLUSIONS: Reirradiation was tolerated with infrequent high grade toxicity. PFS and OS after re-RT were both predicted by time to progression after initial radiation. Published prognostic scores have used total time from first to second radiation courses; however in our series the period from initial progression to re-RT did not add prognostic information. There was evidence for a dose threshold irrespective of radiotherapy technique. Use of chemotherapy and bevacizumab with re-RT were not associated with improved outcomes.
GENE-26. MOLECULAR CHARACTERIZATION OF BENIGN AND MALIGNANT PERIPHERAL NERVE SHEATH TUMORS THAT OCCUR IN SPORADIC AND SYNDROMIC SETTINGS
Authors: Suganth Suppiah, Shirin Karimi, Sheila Mansouri, Yasin Mamatjan, Jeff Liu, Kenneth Aldape, Gelareh Zadeh
Journal: Neuro-Oncology (2018)

Neurofibromas, a peripheral nerve sheath tumor commonly associated with Neurofibromatosis Type 1, are broadly categorized as cutaneous or peripheral nerve neurofibromas (localized or plexiform lesions). More recently, atypical neurofibromatous neoplasm of unknown biological potential (ANNUBP) has been described and believed to be a premalignant tumor, although the oncogenic drivers of malignant transformation are poorly understood. In this study, we establish the spectrum of genomic drivers of neuronal tumors, benign and malignant, in sporadic and syndromic settings. We performed multiplatform genomic analysis of a total of 110 cutaneous neurofibromas, peripheral nerve neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). We performed methylation profiling and RNA sequencing on these tumors. Genomic data was bioinformatically analyzed to identify biologically relevant subgroups. Correlation and validation of key drivers were carried out using a series of IHC and in-vitro studies. Consensus clustering of methylation data reliably distinguished between cutaneous and peripheral nerve tumors that supports the theory that cutaneous neurofibromas have a distinct cell of origin. Copy number analysis (CNA) identified a loss of 9p in 35% of peripheral nerve neurofibromas. Consensus clustering of peripheral nerve neurofibromas alone identified 3 subgroups, with group 1 tumors having no CNAs and groups 2&3 enriched for tumors with CDKN2A loss (p < 0.05). In addition, ANNUBP were associated with the loss of CDKN2A (p < 0.05). Neurofibromas with loss of CDKN2A had gene sets associated with H3K27me3 and sarcomas upregulated, while genes associated with neuronal and Schwann cell signature downregulated. The genomic and epigenomic landscape of neurofibromas is poorly understood. We identified that atypical neurofibromas have loss of CDKN2A, suggesting that it is lost early in malignant transformation. The loss of CDKN2A may lead to dysregulation of H3K27me3, and further work is needed to identify the molecular alterations and pathways involved in malignant transformation.