tbuckley/cabot-search huggingface dataset:
MODL-12. DEVELOPMENT OF A NOVEL IMMUNOCOMPETENT MOUSE MODEL FOR DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Maggie Seblani, Markella Zannikou, Katarzyna Pituch, Liliana Ilut, Oren Becher, Irina Balyasnikova
Journal: Neuro-Oncology (2020)

Abstract Diffuse intrinsic pontine glioma (DIPG) is a devastating brain tumor affecting young children. Immunotherapies hold promise however the lack of immunocompetent models recreating a faithful tumor microenvironment (TME) remains a challenge for development of targeted immunotherapeutics. We propose to generate an immunocompetent DIPG mouse model through induced overexpression of interleukin 13 receptor alpha 2 (IL13Rα2), a tumor-associated antigen overexpressed by glioma cells. A model with an intact TME permits comprehensive preclinical assessment of IL13Rα2-targeted immunotherapeutics. Our novel model uses the retroviral avian leucosis and sarcoma virus (RCAS) for in vivo gene delivery leading to IL13Rα2 expression in proliferating progenitor cells. Transfected cells expressing IL13Rα2 and PDGFB, a ligand for platelet derived growth factor receptor, alongside induced p53 loss via the Cre-Lox system are injected in the fourth ventricle in postnatal pups. We validated the expression of PDGFB and IL13Rα2 transgenes in vitro and in vivo and will characterize the TME through evaluation of the peripheral and tumor immunologic compartments using immunohistochemistry and flow cytometry. We confirmed expression of transgenes via flow cytometry and western blotting. Comparison of survival dynamics in mice inoculated with PDGFB alone with PDGFB+IL13Rα2 demonstrated that co-expression of IL13Rα2 did not significantly affect mice survival compared to the PDGFB model. At time of application, we initiated experiments to characterize the TME. Preliminary data demonstrate establishment of tumors within and adjacent to the brainstem and expression of target transgenes. Preclinical findings in a model recapitulating the TME may provide better insight into outcomes upon translation to clinical application.
Abstract 15341: Clinical Implication of Tissue Fibrosis and Physiological Parameters for Adverse Cardiac Events in Hypertrophic Cardiomyopathy
Authors: Yuko Wada, Takeshi Aiba, Takaaki Matsuyama, Ikutaro Nakajima, Koji Miyamoto, Yuko Yamada, Hideo Okamura, Takashi Noda, Kazuhiro Satomi, Hideaki Kanzaki, Toshihisa Anzai, Masaharu Ishihara, Satoshi Yasuda, Hisao Ogawa, Shiro Kamakura, Wataru Shimizu
Journal: Circulation (2012)
LGG-50. INTEGRATED MOLECULAR AND CLINICAL ANALYSIS OF 1,000 PEDIATRIC LOW-GRADE GLIOMAS UNCOVERS NOVEL SUBGROUPS FOR CLINICAL RISK STRATIFICATION
Authors: Uri Tabori, Scott Ryall, Michal Zapotocky, Julie Bennett, Liana Nobre, David Ellison, Mariarita Santi, Matthias Karajannis, Cynthia Hawkins
Journal: Neuro-Oncology (2020)

Abstract Pediatric low-grade gliomas (pLGG) are primarily driven by genetic alterations in the RAS/MAPK pathway, most commonly involving BRAF of NF1. Despite their molecular convergence, pLGG often show unexplained variability in their clinical outcome. To address this, we molecularly characterized a cohort of &amp;gt;1,000 clinically annotated pLGG. 84% of cases harbored a detectable driver mutation. The remaining 16% of patients nonetheless showed RAS/MAPK pathway up-regulation at the RNA level. The clinical presentation and outcome of pLGG appeared highly variable and linked to the alteration type: re-arrangement or SNV. Re-arrangement-driven tumors were diagnosed at a younger age (6.6 versus 10.9 years, p&amp;lt;0.0001), enriched for WHO grade I histology (88% versus 66%, p&amp;lt;0.0001), infrequently progressed (27% versus 46%, p&amp;lt;0.0001), and rarely resulted in death (3 versus 13%, p&amp;lt;0.0001) as compared to SNV-driven tumors. These included the rarest molecular drivers of pLGG, for which we now have the clinicopathologic features of including MYB, MYBL1, FGFR2 fusions, FGFR1-TACC1, FGFR1 SNVs, IDH1 p.R132H, and H3.3 p.K27M. Utilizing this information, we suggest novel risk categories of pLGG that effectively predicted patient outcome. Low-risk tumors progressed infrequently and rarely succumbed to their disease (10-year PFS of 71% and OS of 98%). Intermediate-risk pLGG had a 10-year PFS and OS of 35% and 90%, respectively. High risk pLGG almost invariably progressed (10-year PFS of 0%) and these patients often succumbed to their disease (10-year OS of 41%). These data highlight the biological and clinical differences between pLGG subtypes and offers molecular based risk stratification to these cancers.
Diphenhydramine may be a preventive medicine against cisplatin-induced kidney toxicity
Authors: Hirofumi Hamano, Yasumasa Ikeda, Mitsuhiro Goda, Keijo Fukushima, Seiji Kishi, Masayuki Chuma, Michiko Yamashita, Takahiro Niimura, Kenshi Takechi, Masaki Imanishi, Yoshito Zamami, Yuya Horinouchi, Yuki Izawa-Ishizawa, Licht Miyamoto, Keisuke Ishizawa, Hiromichi Fujino, Toshiaki Tamaki, Ken-ichi Aihara, Koichiro Tsuchiya
Journal: Kidney International (2020)
Updated Analysis of Complication Rates Associated With Invasive Diagnostic Procedures After Lung Cancer Screening
Authors: Hui Zhao, Ying Xu, Jinhai Huo, A. Cole Burks, David E. Ost, Ya-Chen Tina Shih
Journal: JAMA Network Open (2020)

This case-control study compares complication rates associated with invasive diagnostic procedures before and after Medicare and Medicaid coverage of lung cancer screening tests.
EPEN-53. C11orf95-RELA REPROGRAMS 3D EPIGENOME IN SUPRATENTORIAL EPENDYMOMA
Authors: Jacqueline Jufen Zhu, Nathaniel Jillette, Xiao-Nan Li, Albert Cheng, Ching Lau
Journal: Neuro-Oncology (2020)

Abstract Ependymoma is the third most common malignant brain tumor in children. However, there is no effective chemotherapy identified and treatment is limited to surgery with or without adjuvant radiation therapy currently. Thus, to develop targeted therapy based on the underlying biology is an urgent need. Since 2014, C11orf95-RELA fusion was found to be the most recurrent structural variation in approximately 70% of supratentorial ependymomas (ST-EPN), but the molecular mechanisms of oncogenesis are unclear. Here we utilized HEK293T transgene models and a ST-EPN cell line to investigate the epigenomic changes and transcriptional regulations by C11orf95-RELA fusion. By applying ChIP-seq and HiChIP approaches, we found C11orf95-RELA is a novel transcription factor that recognizes a specific DNA motif dictated by the C11orf95 component while the RELA component is required for driving the expression of ependymoma-associated genes such as CCND1 and L1CAM. Moreover, C11orf95-RELA modulates chromatin states and mediates chromatin interactions, leading to transcriptional reprogramming in ST-EPN cells. Multiple signaling pathways such as Notch signaling and G-protein signaling are identified to be involved in ST-EPN development. Our findings provide important characterization of the molecular underpinning of C11orf95-RELA fusion and shed light on potential therapeutic targets for C11orf95-RELA subtype ependymoma.
DDRE-01. ACQUIRED AND INTRINSIC RESISTANCE TO VEMURAFENIB IN BRAFV600E-DRIVEN MELANOMA BRAIN METASTASES
Authors: Mark C de Gooijer, Ping Zhang, Levi C M Buil, Stephan Freriks, Gang Li, Jos H Beijnen, Olaf van Tellingen
Journal: Neuro-Oncology (2020)

Abstract BRAF V600-mutated melanoma brain metastases (MBMs) are responsive to BRAF inhibitors, but clinical responses are less durable than those of extracranial metastases. We studied the impact of the drug efflux proteins P-glycoprotein (P-gp; ABCB1) and breast cancer resistance protein (BCRP; ABCG2) at the blood-brain barrier (BBB) on the efficacy of vemurafenib against BRAFV600E-mutated A375 MBMs. We intracranially implanted A375 tumor cells in wild-type and Abcb1a/b;Abcg2-/- mice. We characterized the tumor BBB, analyzed drug levels in plasma and brain lesions after oral vemurafenib and determined the efficacy against brain metastases and subcutaneous lesions. MRI shows that A375 MBMs disrupt BBB integrity, but vemurafenib accumulation in MBMs was still reduced by P-gp/BCRP. Vemurafenib is also less efficacious against MBMs in wild-type mice compared to Abcb1a/b;Abcg2-/- mice. Vemurafenib efficacy against subcutaneous A375 tumors was similar in both strains. Even in Abcb1a/b;Abcg2-/- mice, A375 MBMs rapidly developed resistance, which was unrelated to pharmacokinetic issues or insufficient inhibition of MAPK/PI3K pathways. Taken together, these studies demonstrate that although the BBB is disrupted in MBMs, P-gp/BCRP still limit the efficacy of vemurafenib. Moreover, the response to vemurafenib is less and of shorter duration also due to rapidly acquired resistance, most likely by resorting to non-canonical growth signaling.
CTNI-69. PRECISION NEURO-ONCOLOGY TREATMENT GUIDED BY NEXT GENERATION SEQUENCING (NGS)-BASED COMPREHENSIVE GENOMIC PROFILING: REAL WORLD EXPERIENCE IN HONG KONG
Authors: Tai-Chung Lam, Shu Jen Chen, Kien Thiam Tan, Lai Fung Li, Jenny K S Pu
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The development of next generation sequencing (NGS) based comprehensive genomic profiling (CGP) has enabled identification of druggable somatic mutations in brain tumours. This cohort reviewed the efficacy of CGP-guided precision treatment in a tertiary neuro-oncology centre. METHODOLOGY From May 2017 to May 2020, CGP were arranged for 43 patients. All patients had exhausted conventional treatments or received CGP for clinical trial screening. Targeted deep NGS was used to assess the mutational status, single nucleotide variant, small insertions and deletions and copy number variant of 440 cancer-related genes. RESULTS The diagnoses of the 43 patients were GBM (n=23), high grade glioma (n=11), brain metastases (n=4), chordoma (n=3), atypical choroid plexus papilloma (n=1) and meningioma (n=1). In most of the patients (42/43, 97.7%), CGP identified at least one druggable targets with a median of 3. Based on the CGP, 27 patients received precision treatment (62.7%). Among these, 14 were GBM and 6 were other high grade glioma. Treatment given included PARP inhibitors, immunotherapy, multi-kinase inhibitor, selective CDK4/6 inhibitor and mTOR inhibitor. Clinical benefit was achieved in 20 patients out of 27 (74%), including 2 complete response (7.4%), 9 partial response (33.3%) and 9 stable disease (33.3%). The median progression free survival (PFS) were 183 days [95% confident intervals (CI): 81–302 days]. For GBM/high grade glioma patients, median PFS was 125 days [95% CI: 52–215] and six-month PFS was 32.7%. Treatment toxicity was mild except two patients developed grade 3 complications and one grade 5 complication (fatal neutropenic fever). For the 16 patients who did not receive precision treatment, one had no druggable target identified, nine were still stable on standard therapies, 6 were too weak when CGP was available. CONCLUSION CGP guided precision treatment for selected, advanced neuro-oncological patients yielded modest clinical efficacy and satisfactory safety profile in real world setting.
HGG-24. HIGH-GRADE GLIOMA WITH A NOVEL FUSION GENE OF VCL-ALK
Authors: Shunsuke Yamamoto, Yuhki Koga, Hiroaki Ono, Hiroshi Asai, Kyutaro Ono, Ryusuke Hatae, Nobuhiro Hata, Masahiro Mizoguchi, Hidetaka Yamamoto, Satoshi O Suzuki, Toru Iwaki, Shouichi Ohga
Journal: Neuro-Oncology (2020)

Abstract A previously healthy 2-year-old boy presented with status epilepticus following intermittent vomiting. Computed tomography scan showed a 7cm mass on the left occipital lobe with midline shift, inferior cerebellar herniation, and diffuse cerebral edema. The extensive dissemination to bilateral cerebral hemispheres, brain stem, and optic nerve was also observed. He underwent brain biopsy from the lesion on his left occipital lobe. The histopathological diagnosis determined the diffuse or epithelial proliferation of astrocytic tumor cells with high mitotic rate, positive for p53 and glial fibrillary acidic protein positive staining consistent with high-grade glioma. The progressive tumor led to communicating hydrocephalus, that was favorably controlled by cerebrospinal fluid shunting. The data from the FoundationOne CDx cancer genome profile disclosed a novel VCL- anaplastic lymphoma kinase (ALK) fusion in the tumor cells of the patient. ALK rearrangement was determined to be positive for the tumor cells assessed by fluorescence in situ hybridization. Only 4 pediatric cases of glioma with ALK-rearrangement have ever been reported. All of them received subtotal or gross total resections and then survived with or without chemotherapy. This is the first case of glioma harboring VCL as a novel partner of ALK fusion gene. After the favorable response to the first-line chemotherapy, subsequent irradiation therapy has now been scheduled. The molecular classification of high-grade glioma may help to expand the targeted therapy for unresectable advanced brain tumor.
RARE-07. THE LANDSCAPE OF GENOMIC ALTERATIONS IN ADAMANTINOMATOUS CRANIOPHARYNGIOMAS
Authors: Prasidda Khadka, Eric Prince, Sophie Lu, Sandro Santagata, Keith Ligon, Peter Manley, Rameen Beroukhim, Todd Hankinson, Pratiti Bandopadhayay
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Adamantinomatous craniopharyngiomas (ACPs) are characterized by activating mutations in the CTNNB1 gene. Here we perform a comprehensive genomic analysis of 23 ACPs to define the landscape of genomic alterations in this disease. METHODS We performed whole-genome sequencing of 24 ACPs and their matched normal tissues. We used Mutect 2.0 to detect mutations and indels in these samples and MutSig2CV to identify significant mutations. Copy numbers were called using the GATK4 pipeline and GISTIC 2.0 was applied to identify significant alterations. Finally, SvABA was applied to identify genome-wide structural variants and rearrangements. RESULTS 18/24 (75%) of the sequenced ACPs harbored activating mutations in exon 3 of CTNNB1 gene with an average variant allele fraction (VAF) of 0.4±0.1. These mutations have previously been shown to activate the WNT signaling pathway in these tumors. No other significantly recurrent mutations were detected in our samples. The ACPs were quiet with regard to copy number alterations and no recurrent amplifications or deletions were detected. 528 structural variations and rearrangements were detected in total in all 24 samples with an average of 22 variants per sample. Gene-Set Enrichment Analysis (GSEA) of the RNAseq data revealed upregulation of WNT/B-catenin (FDR q-value &amp;lt;0.25) in the CTNNB1 mutant samples compared to CTNNB1 WT samples. CONCLUSION Our study identified previously described activating CTNNB1 mutations in the majority of ACPs. In addition, we identified several rearrangements and structural variations in these tumors that could play an important role in the pathogenesis of the disease.
Divergence of Cardiovascular Biomarkers of Lipids and Subclinical Myocardial Injury Among Rheumatoid Arthritis Patients With Increased Inflammation
Authors: Brittany Weber, Zeling He, Nicole Yang, Martin P. Playford, Dana Weisenfeld, Christine Iannaccone, Jonathan Coblyn, Michael Weinblatt, Nancy Shadick, Marcelo Di Carli, Nehal N. Mehta, Jorge Plutzky, Katherine P. Liao
Journal: Arthritis & Rheumatology (2020)

Patients with rheumatoid arthritis (RA) are 1.5 times more likely to develop cardiovascular disease (CVD) attributed to chronic inflammation. A decrease in inflammation in patients with RA is associated with increased low-density lipoprotein (LDL) cholesterol. This study was undertaken to prospectively evaluate the changes in lipid levels among RA patients experiencing changes in inflammation and determine the association with concomitant temporal patterns in markers of myocardial injury.A total of 196 patients were evaluated in a longitudinal RA cohort, with blood samples and high-sensitivity C-reactive protein (hsCRP) levels measured annually. Patients were stratified based on whether they experienced either a significant increase in inflammation (an increase in hsCRP of ≥10 mg/liter between any 2 time points 1 year apart; designated the increased inflammation cohort [n = 103]) or decrease in inflammation (a decrease in hsCRP of ≥10 mg/liter between any 2 time points 1 year apart; designated the decreased inflammation cohort [n = 93]). Routine and advanced lipids, markers of inflammation (interleukin-6, hsCRP, soluble tumor necrosis factor receptor II), and markers of subclinical myocardial injury (high-sensitivity cardiac troponin T [hs-cTnT], N-terminal pro-brain natriuretic peptide) were measured.Among the patients in the increased inflammation cohort, the mean age was 59 years, 81% were women, and the mean RA disease duration was 17.9 years. The average increase in hsCRP levels was 36 mg/liter, and this increase was associated with significant reductions in LDL cholesterol, triglycerides, total cholesterol, apolipoprotein (Apo B), and Apo A-I levels. In the increased inflammation cohort at baseline, 45.6% of patients (47 of 103) had detectable circulating hs-cTnT, which further increased during inflammation (P = 0.02). In the decreased inflammation cohort, hs-cTnT levels remained stable despite a reduction in inflammation over follow-up. In both cohorts, hs-cTnT levels were associated with the overall estimated risk of CVD.Among RA patients who experienced an increase in inflammation, a significant decrease in routinely measured lipids, including LDL cholesterol, and an increase in markers of subclinical myocardial injury were observed. These findings highlight the divergence in biomarkers of CVD risk and suggest a role in future studies examining the benefit of including hs-cTnT for CVD risk stratification in RA.
Women doctors paid less than men even after part time working is accounted for
Authors: Abi Rimmer, Adrian O’Dowd
Journal: BMJ (2020)

Male dominated medical specialties have larger gender pay gaps than those dominated by women, a review1 has found.

The review, led by Jane Dacre, professor of medical education at University College London (UCL), found that, on average, the pay of women doctors was between 12% and 19% less than men having accounted for any differences in hours worked.

Launched in 2018 after then health secretary Jeremy Hunt committed to eliminating the gender pay gap in medicine, the review details an analysis of the records of 86 000 trust doctors over a 10 year period, 16 000 GPs, and 4500 clinical academics.

The review team also analysed evidence from interviews conducted with clinicians at various career stages, and results of an online survey with responses from 4854 doctors. The report notes that for the past 25 years, more women than men have entered medical school and in 2017 59% of those accepted into …
GCT-52. TRANSCRIPTOME OF CENTRAL NERVOUS SYSTEM GERM CELL TUMOR REVEALS ITS PATHOGENESIS AND CONTRASTS WITH TESTICULAR COUNTERPARTS IN INTEGRATED OMICS ANALYSIS
Authors: Hirokazu Takami, Asmaa Elzawahry, Mamoru Kato, Kohei Fukuoka, Yasin Mamatjan, Tomonari Suzuki, Takaaki Yanagisawa, Yuko Matsushita, Taishi Nakamura, Kai Yamasaki, Akitake Mukasa, Nobuhito Saito, Masayuki Kanamori, Toshihiro Kumabe, Teiji Tominaga, Keiichi Kobayashi, Motoo Nagane, Toshihiko Iuchi, Kaoru Tamura, Taketoshi Maehara, Kazuhiko Sugiyama, Mitsutoshi Nakada, Yonehiro Kanemura, Masahiro Nonaka, Akio Asai, Kiyotaka Yokogami, Hideo Takeshima, Yoshitaka Narita, Soichiro Shibui, Yoichi Nakazato, Yasushi Totoki, Tatsuhiro Shibata, Ryo Nishikawa, Masao Matsutani, Koichi Ichimura
Journal: Neuro-Oncology (2020)

Abstract Germ cell tumors (GCTs) are unique neoplasms in that they arise from the migrated cells which were supposed to be directed to gonads. They occur in the central nervous system (CNS), as well as gonadal organs such as testis and ovary. Our genomic analysis revealed that they are characterized by mutations in MAPK and PI3K pathways, chromosomal instability and global hypomethylation in germinoma. However, there were plenty of cases which lacked driver alterations and their pathogenesis is yet to be fully unraveled. Here we aimed to uncover CNSGCT’s pathogenesis from a transcriptomic perspective. Genome-wide transcriptional analysis was performed for 58 CNS and 3 testicular GCTs. This demonstrated that germinoma had a transcriptional profile characteristic to primordial germ cells (PGCs) at early embryogenesis, whereas non-germinomatous germ cell tumors (NGGCTs) showed that with differentiation into various tissues. Integration of transcriptome and methylome corroborated the above finding that pluripotency/meiosis-genes were unmethylated and highly expressed in germinoma compared with NGGCT. Co-analysis with transcriptome of various developmental stages of embryonic cells revealed germinoma and NGGCT had similarities in expression to PGC and embryonic stem cells, respectively. Multi-omics analysis with testicular GCTs (n=134) from TCGA showed shared genomic backgrounds between germinoma-seminoma and NGGCT-nonseminomatous GCT (NSGCT) in mutation and methylation profiles, and contrast in the chromosomal instability, which was more highlighted in testicular GCTs. These new insights into molecular profiles of GCTs lead to a better understanding of the complex pathogenesis of GCTs, and will hopefully provide a clue to future development of new treatments.
Abstract 13315: Risk of Amputation Associated With Sodium-Glucose Co-Transporter 2 Inhibitors: A Meta-Analysis of Randomized Controlled Trials
Authors: Satoshi Miyashita, Toshiki Kuno, Hisato Takagi, Takehiro Sugiyama, Tomo Ando, Nelson Valentin, Yuichi Shimada, Masaki Kodaira, Yohei Numasawa, Yumiko Kanei, Sripal Bangalore
Journal: Circulation (2019)

Introduction: Amputation has been known to be a rare adverse event of sodium glucose co-transporter 2 (SGLT2) inhibitors. It remains unclear whether the SGLT2 inhibitor as a class and specific cate...
EPHA mutation as a predictor of immunotherapeutic efficacy in lung adenocarcinoma
Authors: Hua Bai, Jianchun Duan, Chengcheng Li, Wenzhuan Xie, Wenfeng Fang, Yu Xu, Guoqiang Wang, Rui Wan, Jing Sun, Jiachen Xu, Xin Wang, Kailun Fei, Zhengyi Zhao, Shangli Cai, Li Zhang, Jie Wang, Zhijie Wang
Journal: Journal for ImmunoTherapy of Cancer (2020)

Ephrin type-A receptors (EPHA) are members of family of receptor tyrosine kinases and are related to tumor immunogenicity and immune microenvironment, however, the association between EPHA mutation (EPHAmut ) and efficacy of immune checkpoint inhibitors (ICIs) has not been investigated in non-small cell lung cancer (NSCLC).Multiple cohorts were used to assess the immunotherapeutic predictive performance of EPHAmut , including one discovery cohort (n=79) and two public validation cohort (cohort 1: NSCLC, n=165; cohort 2: pan-cancer, n=1662). The Cancer Genome Atlas cohort was used for prognostic analysis and mechanism exploration.In the discovery cohort, patients with EPHAmut had superior disease control rate (72.2% vs 36.1%, p=0.01) and progression-free survival (PFS) (HR 0.38; 95% CI 0.21 to 0.68; p<0.001) compared with those with wide-type EPHA (EPHAwt ) in NSCLC. The association between EPHAmut and immunotherapy outcomes in NSCLC was consistently observed in the validation cohorts by multivariable models (cohort 1, PFS HR 0.59; 95% CI 0.37 to 0.96; p=0.03; cohort 2, overall survival (OS) HR 0.63; 95% CI 0.41 to 0.98; p=0.04). Further pooled estimates of the discovery and validation cohorts showed that patients with EPHAmut exhibited a significantly longer PFS and OS in lung adenocarcinoma (LUAD) while not squamous cell lung cancer (LUSC). Consistently, mechanism analysis revealed that patients with EPHAmut was associated with increased T cell signatures and downregulated transforming growth factor-β signaling compared with patients with EPHAwt in LUAD while not LUSC.Our results demonstrated that EPHAmut is an independent classifier that could stratify patients with LUAD for ICIs therapy. Further prospective studies are warranted.NCC2016JZ-03, NCC2018-092.