tbuckley/cabot-search huggingface dataset:
Abstract 17409: Comparison of Post-procedural Echocardiographic Valvular Performance after Transcatheter Aoritc Valve Implantation using Edwards SAPIEN valve versus Medtronic CoreValve for Severe Aortic Stenosis: a Meta-Analysis
Authors: Samit Bhatheja, Hemang B Panchal, Neil Barry, Parthavkumar Patel, Kais Albalbissi, Timir Paul
Journal: Circulation (2014)

Background: In patients with severe aortic stenosis (AS) who are at high risk for surgical aortic valve replacement, transcatheter aortic valve implantation (TAVI) is an emerged alternative procedure. TAVI can be performed using a balloon-expandable Edwards SAPIEN valve (EV) or self-expandable Medtronic CoreValve (CV). The objective of this meta-analysis is to compare post-procedural left ventricular ejection fraction and other echocardiographic valvular performance in patients who underwent TAVI using EV and CV. Methods: PubMed and the Cochrane Center Register of Controlled Trials were searched through May 2014. Eleven studies (n=1513) comparing TAVI procedures that used EV (n=774) and CV (n=739) were included. End points were left ventricular ejection fraction, aortic valve effective orifice area, and mean and peak trans-aortic pressure gradients. The mean difference (MD) with 95% confidence interval (CI) was computed and p&lt;0.05 was considered as a level of significance. Results: There was no significant difference in left ventricular ejection fraction (MD: 1.02, CI: -1.25 to 3.28, p=0.38) and aortic valve effective orifice area (MD: -0.06, CI: -0.17 to 0.06, p=0.04) between EV and CV groups. Mean and peak trans-aortic pressure gradient were significantly higher in CV group compared to EV group (MD: 1.42, CI: 0.4-2.44, p=0.007) (Figure) and (MD: 4.21, CI: 2.33-6.09, p&lt;0.0001) respectively. Conclusion: The results of our meta-analysis suggest that TAVI procedures using CV and EV provide clinically similar valvular performance with possibly clinically insignificant subtle differences in mean and peak trans-aortic pressure gradients in patients with severe aortic stenosis. Further randomized studies are needed for long term echocardiographic outcomes to evaluate valvular performance.
TMIC-46. FIBROBLAST-PRODUCED EDA FIBRONECTIN IN THE SUBVENTRICULAR ZONE DRIVES GLIOBLASTOMA PATHOGENESIS
Authors: Jonathan Rick, Alan Nguyen, Ankush Chandra, Garima Yagnik, Darryl Lau, Polly Chuntova, Angel Ordaz, Fara Dayani, Joseph Garcia, Soumya Sagar, Saman Arfaie, Cecilia Dalle Ore, Manish Aghi
Journal: Neuro-Oncology (2018)

Glioblastoma is an aggressive cancer with a dismal median survival of under two years. Recent studies have shifted the paradigm of glioblastoma from a homogenous mass of tumor cells into a complex organ containing interacting elements. We sought to determine whether cancer-associated fibroblasts (CAFs) are among these elements in glioblastoma. We collected site-directed biopsies from glioblastoma patients. Ex vivo analysis was performed using immunohistochemistry (IHC), quantitative reverse-transcription PCR (RT-qPCR), fluorescence-activated cell sorting (FACS), Matrigel invasion and CyQuant proliferation assays. FACS of site-directed biopsies determined that PDGF receptor alpha+ CAFs comprised 9% of cells in the glioblastoma subventricular zone (SVZ), a region known to harbor glioblastomas with a worse prognosis, vs. 2% of cells outside the SVZ in glioblastomas and were not present in SVZ specimens from epilepsy cases (p=0.02). CAFs were chemotactically attracted to the glioblastoma stem cells found in the SVZ. In vitro culture of EDA-FN, a molecule secreted by CAFs, with macrophages resulted in a 16-fold increase in pro-tumoral genes when compared to non-EDA expressing FN (p=0.0001). The expression level of EDA-FN was directly and significantly associated with upregulated mesenchymal genetic markers (p<0.001), which have also been associated with worse patient outcomes. IHC revealed that EDA-FN forms a scaffolding network and is spatially associated with CAFs. We defined a cascade by which tumor stem cells in the SVZ recruit CAFs, which in turn produce EDA-FN in the SVZ. EDA-FN induces M2 polarization and is associated with mesenchymal gene expression. Given the specificity of CAFs and EDA-FN to cancer, both represent viable therapeutic targets.
Abstract 17192: Counterpulsation Requires Pulsation: Acute Hemodynamic Effects of Large Capacity Intra-aortic Balloon Counterpulsation Pumps in Patients With Advanced Heart Failure
Authors: Shiva Annamalai, Lyanne Buitten, Michele Esposito, Andrew Mullin, Catalina Breton, Robert Pedicini, Carey Kimmelstiel, Michael Kiernan, David Denofrio, Richard Karas, Navin K Kapur
Journal: Circulation (2016)

Introduction: Large (50cc) intra-aortic balloon counterpulsation pumps (IABPs) are commonly used in advanced heart failure (AHF). Few studies have examined the hemodynamic efficacy of IABPs in AHF....
Glatiramer acetate persists at the injection site and draining lymph nodes via electrostatically-induced aggregation
Authors: Jimmy Y. Song, Nicholas R. Larson, Sharadvi Thati, Irma Torres-Vazquez, Noraida Martinez-Rivera, Natalia J. Subelzu, Martin A. Leon, Eduardo Rosa-Molinar, Christian Schöneich, M. Laird Forrest, C. Russell Middaugh, Cory J. Berkland
Journal: Journal of Controlled Release (2018)
CMET-36. BEVACIZUMAB WITH OR WITHOUT LOMUSTINE FOR METASTATIC ORBITAL, DURAL AND LEPTOMENINGEAL ESTHESIONEUROBLASTOMA
Authors: Richard Green, Colleen Thornton
Journal: Neuro-Oncology (2018)

Esthesioneuroblastoma is a malignant neuroectodermal tumor originating from the olfactory neuroepithelium. Bevacizumab is a specific inhibitor of the vascular endothelial growth factor ligand, preventing its interaction with receptors on endothelial cells. Lomustine is a widely used alkylating agent with good CNS penetration. We report 3 cases of metastatic dural esthesioneuroblastoma that responded to bevacizumab with or without lomustine. All patients had been treated up-front for Kadish Stage D disease with craniofacial resection, radiation therapy, and platinum-based chemotherapy with or without etoposide. One patient had been treated for recurrence with temozolomide plus sunitinib. Recurrent disease consisted of leptomeningeal, dural, orbital, and skull metastases. Patients 1 and 2 were treated with bevacizumab, 5 mg/kg every 2 weeks; patient 3 also received lomustine 110 mg/sq m every 42 days for 6 cycles. Two patients had partial responses and 1 had stable disease. Responses consisted of reduction in dural contrast enhancement, tumor cyst volumes, and perilesional edema, along with symptomatic improvement. Mean progression free survival was 388 days, and overall survival 432 days. These patients with metastatic orbital, dural and leptomeningeal esthesioneuroblastoma achieved durable responses with bevacizumab with or without CCNU. Antiangiogenic and alkylating agent strategies may play a role in salvage therapy for this tumor.
QOLP-15. SAFETY AND ADVERSE EVENT PROFILE OF TUMOR TREATING FIELDS IN ANAPLASTIC GLIOMA A POST-MARKETING SURVEILLANCE ANALYSIS
Authors: David Tran, Santosh Kesari, Daniela A Bota
Journal: Neuro-Oncology (2018)

Tumor Treating Fields (TTFields) are approved for glioblastoma (GBM) based on two randomized phase 3 trials. The Optune system non-invasively administers TTFields at 200kHz via transducer arrays placed upon a shaved scalp. Despite advancements in the molecular characterization of anaplastic gliomas (AGs), there remains a paucity of treatment options. While Optune is not FDA-approved for AGs, there are several open clinical trials. To further characterize potential safety risks in AG, post-marketing surveillance data are reported for patients with AGs treated with TTFields. A review of adverse events in patients with a diagnosis of anaplastic astrocytoma or anaplastic oligodendroglioma treated with TTFields. Post-market surveillance data were analyzed based on the MedDRA body system (system organ class) preferred terms. A total of 498 patients with AGs were treated with TTFields in the United States and Europe. Of these, 262 patients (53%) experienced at least 1 adverse event (AE). These included heat sensation in 50 (10%), electric sensation in 36 (7%), headache in 41 (8%) and fatigue in 14 (3%). Skin toxicity was the most common type of AE reported in 152 patients (31%) and included skin reaction (30%), skin ulcer (3%), hyperhidrosis (3%), and rash (<1%). These findings as well as the incidence of other reported AEs were in line with glioblastoma phase 3 trials. In this retrospective review of available post-marketing surveillance data, there were no unexpected adverse events when TTFields were used in patients with AGs. The incidence of the most common AE, skin reaction, as well as other reported AEs were comparable with rates observed in the EF-11 trial for patients with recurrent GBM, and the EF-14 trial for patients with newly diagnosed GBM. This data supports further investigation on safety and efficacy of TTFields in patients with AGs, and prospective studies are currently planned.
ACTR-23. SAFETY OF INTRA-ARTERIAL CHEMOTHERAPY WITH OSMOTIC OPENING OF THE BLOOD-BRAIN BARRIER
Authors: Ryan Priest, Prakash Ambady, Edward Neweult
Journal: Neuro-Oncology (2018)

Intra-arterial (IA) infusion of hypertonic mannitol transiently opens the blood-brain barrier (BBB) to improve drug delivery to intracerebral tumors. The aim of this study was to evaluate the safety of osmotic BBB disruption (BBBD) followed by administration of IA chemotherapy. We performed a retrospective chart review of all malignant brain tumor patients who underwent BBBD on six IRB approved treatment protocols or off protocol at Oregon Health and Science University between 1997 and 2017. Toxicities and adverse events (AEs), including death within 30 days of treatment, were assessed. A total of 4018 BBBD procedures were performed on 268 patients (mean 15 BBBD procedures per patient). The most common pathologies were primary central nervous system lymphoma (32%) and anaplastic oligodendroglioma (12%). Most AEs were chemotherapy-related. Only 5% of AEs were attributable to the BBBD procedure, and only 0.42% of these were associated with permanent neurological damage (Grade 3 or 4 SAE). Four SAEs were due to ischemia as detected on magnetic resonance imaging and had minimal impact on quality of life. Four SAEs were due to anterior cord syndrome subsequent to iatrogenic laminar flow of the chemotherapy and were partially responsive to steroids. Subsequently this toxicity was eliminated by procedures to avoid laminar flow. Focal seizures, largely responsive to medical intervention, occurred within 24 hours after 257 (6.4%) BBBD procedures. Most seizures (229, 89%) followed IA administration of methotrexate and were transient and without sequelae. Five patient deaths occurred within 30 days; 1 due to a brain stem stroke related to BBBD, 1 due to a pulmonary embolus, and 3 due to disease progression. We conclude that although the BBBD procedure is invasive, permanent toxicities or death are rare. These results show that osmotic BBBD can be performed safely in brain tumor patients.
GENE-17. TOP2B REGULATES CDK4 SPLICE VARIANTS IN GLIOMAS
Authors: Edgar Gonzalez-Buendia, Junfei Zhao, Li Chen, Eric Feldstein, Aayushi Mahajan, Raul Rabadan, C David James, Adam Sonabend
Journal: Neuro-Oncology (2018)

Topoisomerase IIB (TOP2B) is known to decoil and decatenate DNA, releasing chromatin torsional forces. Whereas TOP2B has been implicated in transcript splicing, direct evidence supporting this function, through localization of TOP2B to specific chromatin sites and in association with specific types of cancer, is modest at best. Here, we report our preliminary activities that are intended to address this knowledge gap. GSEA differential expression analysis using TCGA glioblastoma data showed that high TOP2B expression is associated with elevated expression of cell cycle-related genes (p-value= 1.67E-05). To investigate the possible association of TOP2B with specific gene sequences we used TOP2B ChIP-seq in analyzing glioma cell lines TS543 and BT142, and found TOP2B associations with the introns of especially long genes (gen length ≥ 100Kb, p-value= 0.001). Functional annotation analysis for genes with TOP2B intron binding showed a significant enrichment for genes with multiple known splice variants (p-value= 1.9E-11). To determine effects of TOP2B inhibition on splice variant expression, we treated BT142 cells with the TOP2 inhibitor ICRF-193 and examined treatment effects on splice variant expression using paired-end RNA-seq. We observed altered splicing of 319 genes following TOP2 inhibition, with increased expression of splice variant CDK4-009 being the most significant of all splice variant expression changes (p-value= 1E-54). This result corresponded well with TCGA data whose analysis showed a strong positive correlation between TOP2B and CDK4-009 expression (rho= -0.3 and p-value= 7.28E-05). Our results support TOP2B expression and activity as being influential in regulating the levels of CDK4 splice variant 009 in GBM.
Neoadjuvant (Chemo)radiotherapy With Total Mesorectal Excision Only Is Not Sufficient to Prevent Lateral Local Recurrence in Enlarged Nodes: Results of the Multicenter Lateral Node Study of Patients With Low cT3/4 Rectal Cancer
Authors: Atsushi Ogura, Tsuyoshi Konishi, Chris Cunningham, Julio Garcia-Aguilar, Henrik Iversen, Shigeo Toda, In Kyu Lee, Hong Xiang Lee, Keisuke Uehara, Peter Lee, Hein Putter, Cornelis J.H. van de Velde, Geerard L. Beets, Harm J.T. Rutten, Miranda Kusters
Journal: Journal of Clinical Oncology (2018)

Improvements in magnetic resonance imaging (MRI), total mesorectal excision (TME) surgery, and the use of (chemo)radiotherapy ([C]RT) have improved local control of rectal cancer; however, we have been unable to eradicate local recurrence (LR). Even in the face of TME and negative resection margins (R0), a significant proportion of patients with enlarged lateral lymph nodes (LLNs) suffer from lateral LR (LLR). Japanese studies suggest that the addition of an LLN dissection (LLND) could reduce LLR. This multicenter pooled analysis aims to ascertain whether LLNs actually pose a problem and whether LLND results in fewer LLRs.Data from 1,216 consecutive patients with cT3/T4 rectal cancers up to 8 cm from the anal verge who underwent surgery in a 5-year period were collected. LLND was performed in 142 patients (12%). MRIs were re-evaluated with a standardized protocol to assess LLN features.On pretreatment MRI, 703 patients (58%) had visible LLN, and 192 (16%) had a short axis of at least 7 mm. One hundred eight patients developed LR (5-year LR rate, 10.0%), of which 59 (54%) were LLRs (5-year LLR rate, 5.5%). After multivariable analyses, LLNs with a short axis of at least 7 mm resulted in a significantly higher risk of LLR (hazard ratio, 2.060; P = .045) compared with LLNs of less than 7 mm. In patients with LLNs at least 7 mm, (C)RT plus TME plus LLND resulted in a 5-year LLR of 5.7%, which was significantly lower than that in patients who underwent (C)RT plus TME (5-year LLR, 19.5%; P = .042).LLR is still a significant problem after (C)RT plus TME in LLNs with a short axis at least 7 mm on pretreatment MRI. The addition of LLND results in a significantly lower LLR rate.
PATH-50. HIGH DETECTION RATE OF MYD88MUTATIONS IN CEREBROSPINAL FLUID FROM PATIENTS WITH CENTRAL NERVOUS SYSTEM LYMPHOMAS
Authors: Jun Watanabe, Manabu Natsumeda, Masayasu Okada, Taiki Kobayashi, Yu Kanemaru, Makoto Oishi, Akiyoshi Kakita, Yukihiko Fujii
Journal: Neuro-Oncology (2018)

OBJECT: Biopsy is generally necessary for the diagnosis of primary central nervous system lymphoma PCNSL. However, surgical biopsy has problems of fatal hemorrhagic complication and false negative findings, so more safe and reliable diagnostic methods are required. The aim of this present study is to detect MYD88 mutations, an important driver mutation, in cerebrospinal fluid (CSF) taken from PCNSL patients. METHOD: Fifteen CNS lymphoma (13 PCNSL, 3 CNS relapse from systemic lymphoma) patients were studied. We obtained cell free DNA (cfDNA) from CSF by lumbar puncture. CfDNA was extracted from 1ml of CSF, and both direct sequence and droplet digital PCR (ddPCR) were performed. Furthermore, we performed direct sequence from surgical obtained formalin fixed paraffin embedded (FFPE) tissue and analyzed the relationship to clinical data. RESULT: The mean cfDNA concentration of 1 ml CSF was 188.8 ng/ml [95% CI 124.2–253.8 ng/ml]. MYD88 mutations from CSF were detected in 60.0% (9 of 15 cases), and L265P in exon5 was the most frequent mutation in 8 out of 9 (88.8%) cases, S219C in exon3 was detected in one case. In 2 patients, MYD88 mutation was confirmed by ddPCR but not direct sequence. In all 8 cases with sufficient FFPE tissue for DNA analysis, MYD88 mutation was confirmed in the FFPE tissue. In 1 patient, there was insufficient FFPE tissue for DNA analysis. MYD88 mutation was not detected in the CSF of all 6 patients without MYD88 mutation in the tumor. This pilot study provided evidence that the somatic driver mutation MYD88 can be reliably detected by direct sequence and ddPCR in the cfDNA taken from 1 ml of CSF in patients with CNS lymphomas.
TMIC-17. IMMUNE MICROENVIRONMENT OF NF2-ALTERED RADIATION-INDUCED MENINGIOMAS
Authors: Suganth Suppiah, Shirin Karimi, Yasin Mamatjan, Farshad Nassiri, Kenneth Aldape, Gelareh Zadeh
Journal: Neuro-Oncology (2018)

Radiation-induced meningiomas (RIMS) are more clinically aggressive than their sporadic counterparts, with higher rates of tumor recurrence, multiplicity and neurological impairment. Our laboratory has previously demonstrated that RIMs have a distinct genomic profile with a subset of tumors harboring NF2 inactivation through genomic rearrangements. In this study we establish the clinical characteristics and immune microenvironment between RIMs with and without the NF2 alterations. A retrospective chart review was performed on 31 RIMs. Volumetric analysis was performed using ITK-SNAP on serial preoperative imaging to estimate tumor growth rate. Immunohistochemistry staining for PD-1, PD-L1, CD-3, CD-163, and FOX-P3 were performed. Results were correlated with whole exome sequencing and RNA sequencing data previously published. Pathway analysis was performed using Gene Set Enrichment Analysis (GSEA) on RNA sequencing data using the differentially expressed genes. Clinically, NF2-altered tumors and NF2-WT (wildtype) tumors did not differ based on age at diagnosis, indication for previous radiation, WHO grade, histopathological subtype, extent of resection and tumor location. NF2-altered tumors had a significantly faster growth rate compared to NF2-WT tumors (3.8X faster, p>0.05). The difference in growth rate was independent of tumor grade. PD-L1 staining was negative on tumor cells in NF2-altered tumors and patchy positivity in 60% of NF2-WT tumors (p < 0.05). In contrast, 100% and 60% of tumors had PD-L1 positive immune cells in NF2-altered and NF2-WT tumors, respectively (p<0.05). The degree of CD3+ lymphocyte infiltration was lower in NF2-altered tumors (t=2.73, p<0.05). Our findings suggest that there is a difference in the immune microenvironment between NF2-altered and NF2-WT RIMs. NF2-altered tumors have a lower degree of CD3+ lymphocyte infiltration and higher frequency of PD-L1 positive immune cells that are indicative of an immunosuppressed microenvironment. Further work is needed to elucidate pathways that may be targeted to manipulate the immune microenvironment.
EXTH-79. BEVACIZUMAB, IRINOTECAN, TEMOZOLOMIDE, TYROSINE KINASE INHIBITION, AND MEK INHIBITION ARE EFFECTIVE AGAINST PLEOMORPHIC XANTHOASTROCYTOMA REGARDLESS OF V600E STATUS
Authors: Eric Thompson, Daniel Landi, David Ashley, Steve Keir, Darell Bigner
Journal: Neuro-Oncology (2018)

Pleomorphic xanthoastrocytoma (PXA) is a rare Grade II and III glioma. Surgical resection is the mainstay of treatment; however, adjuvant therapy is sometimes necessary. Given the rarity of PXA, chemotherapeutic efficacy data is limited. The importance of the BRAF V600E mutation in the context of MAP kinase pathway inhibition is unknown. The purpose of this study was to perform an in vivo screen of a variety to agents to determine efficacy against both V600E mutant and non-mutant PXA. The efficacy of bevacizumab, temozolomide, lomustine (CCNU), irinotecan (CPT 11), a tyrosine kinase inhibitor (sorafenib), a selective MEK1/2 inhibitor (cobimetinib), and a BRAF inhibitor (vemurafenib) were assessed in two subcutaneous xenografts: D645 PXA (V600E-mutant) and D2363 PXA (V600E-non-mutant) (n=5–10 mice). Select agents were also assessed in an intracranial model of D2363 PXA (n=6–9). Subcutaneous tumor growth and survival were the endpoints. Temozolomide, bevacizumab, CPT 11, and sorafenib significantly inhibited subcutaneous tumor growth in both V600E-mutant and V600E-non-mutant models (P<0.05). MEK inhibition (cobimetinib) but not BRAF inhibition (vemurafenib) also inhibited tumor growth regardless of V600E mutation (P<0.05). Temozolomide, CPT 11, and bevacizumab also prolonged survival in V600E-negative intracranial model (median overall survival (OS) 68.5, 62.5, and 42.5 days, respectively) in contrast to controls (31.5 days, P<0.001). These findings suggest that when adjuvant treatment is clinically indicated for PXA, temozolomide, CPT 11, sorafenib, or bevacizumab may be considered. Additionally, a trial of a MEK inhibitor could be considered for PXA regardless of V600E mutation status.
CSIG-22. RECONCILING TUMOR HETEROGENEITY IN GLIOBLASTOMA USING A PATHWAY-BASED APPROACH
Authors: Alvaro Alvarado, Riki Kawaguchi, Giovanni Coppola, Steven Goldman, Harley Kornblum
Journal: Neuro-Oncology (2018)

Despite efforts to gain a deeper understanding of its molecular architecture, glioblastoma (GBM) remains uniformly fatal. While genome-based molecular subtyping has revealed that GBMs may be parsed into several molecularly distinct categories, this insight has yielded little progress towards extending patient survival. In particular, the great phenotypic heterogeneity of GBM –both inter and intratumorally – has hindered therapeutic efforts. To this end, we interrogated tumor samples using a pathway-based approach to resolve tumoral heterogeneity. Gene set enrichment analysis (GSEA) was applied to gene expression data and used to provide an overview of each sample that can be then compared to other samples, to generate sample clusters based on their overall patterns of enrichment. The Cancer Genome Atlas (TCGA) samples were clustered using the canonical and oncogenic signatures and in both cases the clustering was distinct from the molecular subtype previously reported. Using principal component analysis (PCA) and other bioinformatics tools we extracted gene sets to further characterize the pathways contributing to each of these clusters. We generated gene lists comprised of the top common elements and Ingenuity pathway analysis exposed molecular targets that control critical pathways of each identified cluster. Similar analyses were completed in a gene expression database of patient-derived gliomasphere lines and in datasets that address intratumoral heterogeneity: 1) sorted stem cell populations compared with unsorted fractions and 2) lines derived from tumor cores, versus those derived from tumor periphery of the same patients. Validation studies are in progress, to assess whether molecules of interest may be targeted in lines from a particular cluster and to determine treatment responsiveness in terms of tumor cell cycle kinetics, proliferation, survival and self-renewal. Our studies relate inter- and intratumoral heterogeneity to critical cellular pathways dysregulated in GBM, with the ultimate goal of establishing a pipeline for patient- and tumor-specific precision medicine.