tbuckley/cabot-search huggingface dataset:
IMMU-50. THE IMMUNE LANDSCAPE OF BLOOD DENDRITIC CELLS IN GLIOBLASTOMA MULTIFORME: IMPLICATIONS FOR DC VACCINATION COMBINED WITH CHECKPOINT INHIBITION
Authors: Benjamin Kong, Julius Kim, Phillip Fromm, Kim Tam Bui, Anthony Linton, Kimberley Kaufman, Philip Beale, Michael Buckland, Georgina Clark
Journal: Neuro-Oncology (2018)

Therapeutic dendritic cell vaccination for GBM using primary blood dendritic cells (BDC) has the potential to improve response rates compared with more commonly used monocyte-derived dendritic cells due to their superior antigen-presentation and migration. Combination of vaccination with immune checkpoint inhibitors such as anti-PD-1 antibodies may remove tumour-associated immune suppression and directly enhance DC function. GBM is associated with systemic as well as local immune suppression. Therefore it is critical to understand the immune landscape and effect of current treatments on DC function and modulate this to successfully translate vaccination into patients. To that end, we firstly compared the expression of immune checkpoint molecules (PD-1, CTLA-4, TIM-3, LAG-3, ICOS, CD27 axes) on BDC (DC1, DC 2/3, DC6) and lymphocyte subsets (CD3+, CD4+, CD8+, CD56+, Treg) from newly diagnosed or currently treated GBM patients (GBM) with age-matched healthy donors (HD) using flow cytometry. This analysis revealed that the major BDC subsets were identifiable in HD and GBM but were affected by both corticosteroids and concurrent chemoradiation. Furthermore, phenotypic differences exist between HD and GBM, most notably in expression of PD-L2 by BDC. We tested the functional capacity of CD1c+ BDC from HD and GBM patients. After optimizing the maturation process of CD1c+ BDC, their ability to initiate polyclonal immune responses was determined using one-way mixed leucocyte reactions. To further augment vaccine efficacy and overcome tumour-associated immune suppression, we combined this with immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4 antibodies. BDC were loaded with the glioma antigen, CMV-pp65 protein to demonstrate the combined effect of immune checkpoint blockade on cytokine production by intracellular staining, antigen-specific T cell expansion and cytotoxicity. DC vaccination in GBM with BDC is a feasible, rational combination with immune checkpoint inhibitors which enhances cytotoxicity in an antigen-specific fashion.
NIMG-69. CHANGES IN SIGNAL INTENSITY RATIOS OF GLOBUS PALLIDUS AND DENTATE NUCLEUS ON UNENHANCED T1-WEIGHTED IMAGES AFTER MULTIPLE ADMINISTRATIONS OF MACROCYCLIC GADOLINIUM-BASED CONTRAST AGENTS IN BRAIN TUMOR PATIENTS
Authors: Shira Rozenblatt, Judith Luckman, Shlomit Yust-Katz, Tali Siegal
Journal: Neuro-Oncology (2018)

Gadolinium-based contrast agents (GBCAs) are routinely used in MRI studies performed for evaluation of brain tumors. Recent studies have demonstrated, progressively increased signal intensity in the globus pallidus (GP) and dentate nucleus (DN) on T1-weighted brain images obtained in patients undergoing repeated MR studies. Linear GBCAs result in more retention and longer time of retention than macrocyclic GBCAs. The aim of this study is to evaluate changes in signal intensity ratios of the GP and the DN on unenhanced T1-weighted images after multiple administrations of macrocyclic GBCAs in brain tumor patients. The study included 37 patients with primary brain tumors who had more than 3 MRI evaluations (range: 4–10 studies). Ten of them (27%) have not receive radiation therapy. Patients were divided into two groups: Group 1 included 24 patients who had Gadoterate meglumine (Dotarem®) enhanced MRI and group 2 included 13 patients who had Gadobutrol (Gadavist®) enhanced MRI. Median age of group 1 patients was 46 (24–69) years and of group 2 it was 56 (32–67). Two radiologists conducted a quantitative analysis of unenhanced T1-weighted images by using region of interest measurements. The difference in mean GP-to-thalamus (GP\TH) signal intensity ratio, DN-to-middle cerebellar peduncle (DN\MCP) signal intensity ratio between the first and last examinations for each patient were calculated. In both groups GP \TH Ratio difference was greater than 0 (Gadavist 0.08 ± 0.06, Dotarem 0.02 ± 0.08 [P=0.035]) following multiple MRI examinations. There was no significant change in DN\MCP ratio in both groups (Gadavist 0.02 ± 0.07, Dotarem -0.01 ± 0.08 [P=0.230]). A significant increased GP\Thal ratio is associated with multiple administrations of both macrocyclic agents, but to a greater extent with administration of Gadavist possibly reflecting the difference in elimination and stability of both contrast agents. Further studies are needed to identify clinical implications, if any, of these findings.
VHL mediates NF-κB activity through HIFα-dependent activation of an EGFR/PI3K/AKT pathway
Authors: Jiabin An, Matthew B. Rettig
Journal: Cancer Research (2005)

4315   VHL mediates NF-κB activity through HIFa-dependent activation of an EGFR/PI3K/AKT pathway. Inactivating mutations of the von Hippel-Lindau ( VHL ) tumor suppressor gene occur frequently in sporadic clear cell renal cell carcinoma (CCRCC). A principal function of the protein product of the  VHL  gene, pVHL, is related to the cellular response to hypoxia. Specifically, under normoxic conditions, pVHL targets the transcription factor, hypoxia inducible factor alpha (HIFα), for ubiquitination and proteasomal degradation. Under hypoxic conditions or when pVHL expression is lost, HIFα accumulates and induces transcription of a wide array of genes including VEGF and TGFα. Loss of VHL also results in heightened activation of NF-κB, a family of transcription factors that promotes proliferation, angiogenesis, invasion and metastasis and inhibits apoptosis. To identify the biochemical pathways associated with VHL-mediated NF-κB regulation, we used three isogenic versions of the 786-0 CCRCC cell line: 1) the parental line that lacks endogenous pVHL expression (786-0-P), 2) the parental cell engineered to stably express wild-type pVHL (786-0-VHL), and 3) 786-0-VHL that is stably transfected with an HIFα mutant that is resistant to VHL-mediated ubiquitination (786-0-VHL/HIFα M ). Using these cell lines, we have shown that increased constitutive NF-κB activity resulting from VHL loss is HIFα-dependent. That is, the significantly reduced NF-κB activity observed in 786-0-VHL cells compared to the parental counterpart is restored in 786-0-VHL/HIFα M  cells. In addition to decreased NF-κB activation, 786-0-VHL cells have reduced constitutive activation of EGFR and the PI3K/AKT pathway. When HIFa expression was reconstituted in the 786-0-VHL/HIFα M  cells, activation of EGFR, PI3K/AKT, and NF-κB was restored to that of 786-0-P cells. Exposure of 786-0-P cells to selective genetic and chemical inhibitors of EGFR, PI3K, and AKT established a causative relationship between the activation of the EGFR/PI3K/AKT pathway and heightened NF-κB activation. As further evidence of the link between the activation of the EGFR/PI3K/AKT pathway and increased NF-κB activity, we demonstrated that the heightened AKT activity observed in 786-0-P results in augmentation of IκB kinase (IKK) phosphorylation, a critical step in NF-κB activation. We postulated that heightened EGFR/PI3K/AKT activation results from HIFα-induced expression of TGFα, an important EGFR ligand that is over-expressed in 786-0-P compared to 786-0-VHL cells. Silencing of TGFα expression by RNA interference in 786-0-P cells resulted in decreased activation of the EGFR/PI3K/AKT pathway as well as reduced NF-κB activity. In summary, VHL loss results in heightened NF-κB activity through accumulation of HIFα, which induces expression of TGFα, resulting in ligand-mediated activation of EGFR with consequent activation of PI3K/AKT, and finally phosphorylation of IKK.
ACTR-35. MOLECULAR MATCHMAKING: EFFICACY OF EARLY CLINICAL TRIALS GUIDED BY NEXT-GENERATION SEQUENCING IN PATIENTS WITH GLIOBLASTOMA MULTIFORME
Authors: Jacob Leary, Michael Pearlman, Gerald Falchook
Journal: Neuro-Oncology (2018)

INTRODUCTION: Next-generation sequencing (NGS) is available for analysis of tumors in patients with glioblastoma multiforme (GBM) and can be used to match patients to clinical trials of agents that target specific alterations. We studied the relationship between molecular matching by NGS and treatment outcome in GBM patients treated on trials of targeted agents. Patients were adults with GBM who enrolled on clinical trials at our center. Patients underwent NGS with either FoundationOne (tissue) or Guardant360 (cell-free DNA) prior to enrollment on a trial. Treatment was classified as a direct match, indirect match, or non-match. Clinical benefit was defined as complete response, partial response, or at least 4 months on treatment without progressive disease by RANO criteria. 19 consecutive patients underwent NGS and were treated on 1 or more of 8 different clinical trials, including 4 patients who were treated on 2 trials, for a total of 23 cases analyzed. 10 patients were male; 9 were female. Median age was 58 years (range 26–73). Median number of prior systemic therapies was 1. Three cases were a direct match, 8 cases were an indirect match, and 12 cases were a non-match. Clinical benefit was observed in 54.5% of patients with a direct or indirect match vs. 8.3% of patients with a non-match. Mean treatment duration was 252 days for patients with a direct or indirect match vs. 57 days for patients with a non-match. CONCLUSION: GBM patients treated on clinical trials of targeted agents that were a direct match or indirect match had a trend of longer duration of treatment and higher rate of clinical benefit, compared to trials that were a non-match. These observations support the use of next-generation sequencing to identify clinical trials for patients with GBM.
Assessment and Management of Patients With Metastatic Spinal Cord Compression: A Multidisciplinary Review
Authors: Andrew J. Lawton, Kathleen A. Lee, Andrea L. Cheville, Marco L. Ferrone, Dirk Rades, Tracy A. Balboni, Janet L. Abrahm
Journal: Journal of Clinical Oncology (2018)

Purpose Metastatic spinal cord compression (MSCC) can be a catastrophic manifestation of advanced cancer that causes immobilizing pain and significant neurologic impairment. Oncologists can protect their patients by having a high index of suspicion for MSCC when patients present with new or worsening back pain before motor, sensory, bowel, or bladder deficits develop. We provide an updated, evidence-based narrative review of the presentation, diagnosis, and treatment of MSCC. Methods This narrative review was conducted by searching MEDLINE and Cochrane Database of Systematic Reviews for relevant literature on the presentation, diagnosis, and treatment of patients with MSCC. The article addresses the key elements of MSCC management germane to the medical oncologist, with special attention given to pain and symptom management, decision making with regard to surgery and radiation therapy, the importance of rehabilitative care, and the value of a multidisciplinary approach. Results Magnetic resonance imaging of the entire spine is recommended for the diagnosis of MSCC. Treatment includes glucocorticoid therapy, pain management, radiation therapy with or without surgery, and specialized rehabilitation. When formulating a treatment plan, clinicians should consider the patient’s care goals and psychosocial needs. Conclusion Prompt diagnosis and treatment of MSCC can reduce pain and prevent irreversible functional loss. Regular collaboration among multidisciplinary providers may streamline care and enhance achievement of treatment goals.
<i>HSD17B13</i> and Chronic Liver Disease in Blacks and Hispanics
Authors: Julia Kozlitina, Stefan Stender, Helen H Hobbs, Jonathan C Cohen
Journal: New England Journal of Medicine (2018)

HSD17B13, Chronic Liver Disease, and Ancestry The established association between variant HSD17B13 and protection against chronic liver disease has been replicated. A newly discovered, probably dam...
STEM-17. SPATIAL IDENTITY OF GLIOBLASTOMA CELLS DEFINES THERAPY-INDUCED CLONAL COMPETITION
Authors: Anutosh Ganguly, Hai Yu, Sadashib Ghosh, Svetlana Komarova, Yamashita Daisuke, Shinobu Yamaguchi, Do-Hyun Nam, Ichiro Nakano
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is characterized by high tumor heterogeneity. It has been hypothesized that the tumor core is enriched with tumor cells harboring mesenchymal phenotype, whereas the tumor edge retains those with proneural phenotype. Recent studies including ours have identified the mutually-distinct glioma stem cells (GSCs) are present in these two lesions. Here, in order to investigate the diversity of GSCs, we established subclones of GSCs from the edge and core region of the tumor of GBM patients. These subclones were then stably labeled by fluorescent proteins by a lentiviral transduction system. When either edge derived, or core derived subclones were mixed together, growth competition was observed between those subpopulations. In contrast, edge derived subclones were mixed with those from the core derived ones, the relative proportion of each remain unchanged. This data indicate that clonal competition could be dependent on the spatial identity of the original clones. Interestingly, a further shift in the competition was observed when these clones are exposed to temozolomide in the mixed cultures. In addition, the clonal competition was dependent on the ability of proliferation but not on the cell death. Selective apoptosis of non-competing clones was non-significant but were not ruled out. We will further determine the genetic and epigenetic signatures of the dominant and hyper-proliferative subclones in the mixed culture. Currently, in vivo validation of these studies are underway. Our study indicates that understanding spatial heterogeneity at the clonal level will be a crucial step to devise a new strategy for the future treatment.
Physical blood-brain barrier disruption induced by focused ultrasound does not overcome the transporter-mediated efflux of erlotinib
Authors: Sébastien Goutal, Matthieu Gerstenmayer, Sylvain Auvity, Fabien Caillé, Sébastien Mériaux, Irène Buvat, Benoit Larrat, Nicolas Tournier
Journal: Journal of Controlled Release (2018)
PATH-44. THE LANDSCAPE OF SOMATIC MUTATIONS AND COPY NUMBER ALTERATIONS IN PRIMARY GLIOBLASTOMA IN JAPAN
Authors: Toru Umehara, Hideyuki Arita, Yoshioka Ema, Tomoko Shofuda, Manabu Kinoshita, Yoshinori Kodama, Naoki Kagawa, Yasunori Fujimoto, Yoshiko Okita, Masahiro Nonaka, Takehiro Uda, Junya Fukai, Koji Fujita, Daisuke Sakamoto, Kanji Mori, Haruhiko Kishima, Yonehiro Kanemura
Journal: Neuro-Oncology (2018)

Some differences in the frequencies of cancer genetic alterations across the population have been reported, including EGFR mutations in lung cancer. However, little information is provided in glioblastomas. Here, we investigated the mutational landscape of primary glioblastomas of Japanese population and its trends against the Cancer Genome Atlas (TCGA) dataset. METHOD: We retrospectively analyzed somatic genetic alterations of 220 cases diagnosed as primary glioblastoma based on CNS WHO2016, which were resected in Japan between December 2006 and November 2017. Mutational status of IDH1/2, TERT, and TP53 were determined using the Sanger technique. MGMT promoter methylation status was analyzed by quantitative methylation-specific PCR. Copy number alterations of eight major genes including EGFR were evaluated by using multiplex ligation-dependent probe amplification. The frequency of each alteration was compared with that in TCGA cohort. The relationships and survival impact of each molecular marker were also investigated. Our cohort showed lower frequencies of TERT mutation (56.8%), EGFR gain (55.0%), PTEN loss (44.1%), CDK4 gain (14.1%), and MDM2 gain (9.5%) when comparing with the data of TCGA. On the other hand, the frequencies of TP53 mutation (39.1%) and loss (40.4%) were higher. TERT mutation had a significant positive correlation with EGFR gain (p < 0.001) and PTEN loss (p < 0.001). In survival analysis excluding tumors with IDH mutation, unmethylated MGMT promoter and TERT mutation were significant independent prognostic factors, while other genetic aberrations were not. DISCUSSION: The frequencies of several genetic aberrations differed between Japan and TCGA cohort. Although further studies are needed, our results suggest that the racial differences in genetic alterations may affect the interpretation of clinical trials conducted in different countries.
Role of linoleic acid in autoimmune disorders: a Mendelian randomisation study
Authors: Jie V Zhao, C Mary Schooling
Journal: Annals of the Rheumatic Diseases (2018)

Autoimmune diseases are a major challenge for global health. From an evolutionary biology perspective, reproduction, particularly androgens, trades off against immune activity.1 Correspondingly, trials suggest androgens improve rheumatoid arthritis (RA).2 3 As such, dietary factors promoting reproduction might prevent or treat autoimmune disorders. Linoleic acid (LA) is a major n−6 polyunsaturated fatty acid (PUFA) in widely used polyunsaturated vegetable oils, such as sunflower, corn, soybean and cottonseed oil. In animal experiments, LA stimulates the synthesis of testosterone.4 Observationally, endogenous LA is inversely associated with RA5 and systemic lupus erythematosus (SLE),6 but these findings have not been confirmed in randomised controlled trials. Comparing autoimmune disorders according to naturally occurring LA-related genetic variants, that is, Mendelian randomisation (MR), provides a means of obtaining unconfounded estimates of causal effects.

We obtained strong, independent genetic predictors of LA using (1) the three most significant uncorrelated single-nucleotide polymorphisms (SNPs) and (2) …
NIMG-26. RADIOMIC FEATURES OF GLIOBLASTOMA ON PRE-TREATMENT GD-T1W MRI ARE PREDICTIVE OF RESPONSE TO CHEMO-RADIATION THERAPY AND ASSOCIATED WITH AKT AND APOPTOSIS PATHWAYS
Authors: Niha Beig, Prateek Prasanna, Ruchika Verma, Virginia Hill, Vinay Varadan, Anant Madabhushi, Pallavi Tiwari
Journal: Neuro-Oncology (2018)

>40% of Glioblastoma patients do not respond to chemo-radiation (Ch-Rx) treatment and recur within 6–8 months, suggesting that they could be better candidates for experimental therapies. We seek to discover radiomic features on pre-treatment MRI that are predictive of response to Ch-Rx. Further, in an attempt to establish biological underpinning of these predictive radiomic features, we then identified radiogenomic correlations between these features with molecular pathways that are known to impact response to Ch-Rx. 49 GBM studies were obtained from publicly available IVYGap (n=29) and TCIA (n=20) databases, with pre-treatment MRI scans (Gd-T1w, T2w, FLAIR) and corresponding RNA-Seq data. Responders were defined as patients with progression-free survival (PFS) of >= 4-months, while non-responders had PFS of <4-months. A total of 1305 3D-radiomic features (Gabor, Haralick, and Laws energy) were extracted from each MRI protocol from expert annotated regions (enhancing, edema/non-enhancing, necrosis) for every study. Top 5 predictive features were obtained from a training set and validated using a support vector machine classifier. 13 signaling pathways that are known to be implicated in Ch-Rx response were curated from the MSigDB HALLMARK cohort. Gene Set Enrichment Analysis (GSEA) scores of these pathways was correlated with the top radiomic features with Bonferroni correction. Laws energy features that characterize appearance of ripples and spots from enhancing region on Gd-T1 MRI were found to best predict Ch-Rx response (sensitivity of 73.3% on validation set). These features were statistically significantly correlated with AKT and apoptosis signaling pathways (p<0.02, FDR = 5%). Activation of AKT pathway facilitates angiogenesis and develops Ch-Rx resistance. Similarly, higher expression of apoptotic proteins in GBM is associated with favorable Ch-Rx response. Our radiogenomic approach may allow for non-invasive CRT response prediction by providing biological understanding of molecular pathways implicated in Ch-Rx response, as manifested on pre-treatment Gd-T1 MRI.
NIMG-78. EVALUATION OF ISCHEMIC COMPLICATIONS IN REMOVAL OF GLIAL TUMOR
Authors: Tadashi Higuchi, Fumiio Yamaguchi, Tomoko Oomura, Shun Sato, Koji Adachi, Akio Morita
Journal: Neuro-Oncology (2018)

Recently, the use of navigation system, brain mapping, and intraoperative photo diagnosis during tumor resection becomes possible to prevent maximally neurological function and undergo surgery safety. However, postoperative ischemic complication is unpredictability, as a result, it may cause neurological deficits. We examined retrospectively how predicted ischemic complication and intraoperative important point to avoid complication. In our institute, 45 glioma patients underwent tumor resection using neuro-navigation system, brain mapping, and 5-ALA PD from 2013 to 2017. Evaluation of presence or absence of postoperative ischemic complication was measuring distance between removal cavity and ischemia lesion, referring diffusion-weighted MR image. And, evaluation of presence or absence of neurological deficits were referred to medical records. In all 45 cases, 30 cases (68%) appeared abnormal change in diffusion-weighted MR image, 7 cases (17%) of them had neurological deficits because of ischemic complication. All cases of within 5mm ischemic complication from removal cavity with MRI had not clinical neurological deficits. More than half our cases appeared ischemic complication. And it is considered necessary to undergo operation while thinking possibility of onset risk of ischemic complication. In particular, resection of brain tumor near eloquent area, we suggest one method of residual tumor 5mm from eloquent area because of prevent neurological function.