tbuckley/cabot-search huggingface dataset:
TMOD-14. CREATION OF A GENETICALLY ENGINEERED MOUSE MODEL OF ANAPLASTIC ASTROCYTOMA DRIVEN BY THE IDH1-R132H ONCOGENE
Authors: Diana Shi, Adam Wang, Wenhua Gao, Januka Khanal, Michael Levitt, Rebecca Jennings, Dennis Bonal, Sabina Signoretti, Quang-De Nguyen, Daniel Cahill, Kalil Abdullah, Keith Ligon, William Kaelin, Samuel McBrayer
Journal: Neuro-Oncology (2020)

Abstract Despite the high prevalence of IDH1-R132H mutations in lower grade gliomas, the ability to study this mutation in vivo has been hampered by a lack of faithful mouse models. Therefore, we used a CRISPR/Cas9- and AAV-based strategy to create a genetically engineered mouse model (GEMM) of astrocytoma driven by IDH1-R132H that recreates the genetic landscape of human IDH1 mutant astrocytoma. IDH1 mutations in astrocytomas often co-occur with mutations in TP53, ATRX, and either PIK3R1 or PIK3CA. Using human astrocytes immortalized via expression of telomerase (which phenocopies ATRX loss) and HPV E6 and E7 oncoproteins (which phenocopy p53 and pRb loss, respectively), we found that PIK3R1 and IDH1 oncogenes cooperate to promote anchorage-independent cell growth in vitro and orthotopic brain tumor formation in vivo. These data identified a combination of clinically relevant mutations that we hypothesized could be leveraged to cause spontaneous astrocytoma formation in mice. To simultaneously engineer Idh1, Pik3ca, Tp53, and Atrx mutations in mouse brain tissue, we intracranially injected adeno-associated virus (AAV) expressing Cre recombinase and sgRNAs targeting murine Atrx and Tp53 genes into four mouse strains with the following conditional alleles: 1) LSL-Cas9; 2) LSL-Cas9; LSL-Pik3caH1047R, 3) LSL-Cas9; LSL-Idh1R132H, and 4) LSL-Cas9; LSL-Idh1R132H; LSL-Pik3caH1047R. Grade III anaplastic astrocytomas preferentially formed 9-14 months after injecting the mice carrying both the Idh1 and Pik3ca conditional alleles. These astrocytomas harbored all intended mutations, expressed astrocytoma lineage markers, and displayed elevated (R)-2-hydroxyglutarate, the oncometabolite produced by mutant Idh1. To create an additional model with shorter tumor latency, we transplanted glioma stem-like cells derived from our GEMM into recipient mice to produce Idh1 mutant astrocytoma allografts. These allografts provide a tractable platform for preclinical therapeutic studies. Taken together, our findings show that IDH1 and PI3K oncoproteins cooperate to promote gliomagenesis and unveil new genetically faithful mouse models of mutant IDH1-driven astrocytoma.
GCT-36. TREATMENT RESULTS AND RADIATION-INDUCED TUMORS IN CASES OF CENTRAL NERVOUS SYSTEM GERM CELL TUMOR: A LONG-TERM FOLLOW-UP STUDY IN KUMAMOTO PREFECTURE
Authors: Takahiro Yamamoto, Keishi Makino, Hideo Nakamura, Jun-ichiro Kuroda, Takashi Itoyama, Tatsuya Takezaki, Kazutaka Ota, Naoki Shinojima, Akitake Mukasa
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Central nervous system germ cell tumor (GCT) is one of the pediatric brain tumors. Although there have been epidemiological studies in the past, long-term prognosis and the late effects remained unclear. In this study, we examined GCT over the past 41 years in Kumamoto prefecture. METHODS Epidemiological features and complications with radiation-induced tumors were searched in patients diagnosed with GCT in the 41-year period from 1977 to 2018. RESULTS There were 93 patients diagnosed with GCT. These cases were divided into 14-year periods before and after incorporation of chemotherapy into the treatment, and the results for germinomas were compared. An improvement in the 10-year survival rate from 12 of 23 cases (52.2%) between 1977 and 1991 to 19 of 28 cases (67.9%) between 1992 and 2006 was observed. The 10-year survival rate for germinoma cases that received medical treatment during a more recent 5-year period between 2004 and 2009 increased to over 90%. However, 10.3% of all long-term survivors of GCT developed radiation-induced glioblastoma. The examination results showed that regardless of the tumor type, patients who received a high dose of radiation during their initial treatment developed the complication of radiation-induced glioblastoma within 10 to 25 years after their initial treatment. CONCLUSION This study suggests that the long-term survival rates for GCT are improving but the rate of radiation-induced glioblastoma in these cases are too high to be ignored. Long-term follow-up of at least 10 years is essential to effectively evaluate the details of treatment for pediatric brain tumors.
SURG-05. AN AWAKE SURGERY FOR A CHILD SUFFERING FROM EPILEPSY DUE TO DYSEMBRYPLASTIC NEUROEPITHELIAL TUMOR LOCATED IN THE LEFT PARIETAL LOBE
Authors: Juri Kiyokawa, Shinji Yamamoto, Yasuhiro Murota, Mariko Ishikawa, Hiroto Yamaoka, Satoshi Kaneko, Masataka Yoshimura, Shin Hirota, Motoki Inaji, Taketoshi Maehara
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND An awake surgery is a useful measure to remove tumors located close to eloquent areas of the brain to reduce surgical complications and maximize the resection. However, it has some disadvantages compared to surgeries under general anesthesia. Generally speaking, applying it to a child under 15 years-old (y/o) is hesitating because of anxiety, poor tolerance, failure to cooperate in tasks and so forth. Here, we present a case of a 13y/o girl who underwent an awake surgery due to dysembryplastic neuroepithelial tumor (DNT) located in the left parietal lobe. CASE PRESENTATION: She consulted our hospital for epileptic seizures. MRI showed a multilocular mass lesion in the left parietal lobe. The tumor was located in or close to eloquent areas. The epilepsy was refractory even with multiple antiepileptic drugs (AEDs). A Wada examination revealed that her speech area is on the left hemisphere. The operations were performed in two stages. Prior to the operations, we had several thought-out simulations in the operating room and ICU with her, her parents, and our staff including nurses and lab technicians. The first operation was to perform tumor biopsy and place intracranial electrodes. The histological diagnosis was DNT. Video electroencephalogram showed that the epileptogenic lesion was around the tumor. The second operation resulted in total tumor resection and reduction of paroxysmal epileptic spikes without major complications. She is seizure free for more than three years with two AEDs. CONCLUSION Careful preparations may enable an awake surgery even for a child under 15y/o.
Abstract 15678: In Patients Treated With Immune Checkpoint Inhibitors, Myocarditis is Infrequent Compared With Other Cardiovascular Events
Authors: Judith A Hsia, Jessica Thurston, Lavanya Kondapalli, Ronni Miller, Rita Dale, Marc P Bonaca
Journal: Circulation (2020)

Introduction: Cardiotoxicity with immune checkpoint inhibitor (ICI) treatment has predominantly focused on myocarditis, which has been estimated to affect ~1% of treated patients. To contextualize myocarditis risk in relation to other cardiovascular (CV) events, we explored reporting of myocarditis, heart failure, arterial and venous thrombotic events in ICI-treated cancer patients. Methods: Data from adults treated with ICI between January 2011 and April 2019 were extracted by the University of Colorado enterprise health data warehouse which draws from electronic medical records and claims data. Medical conditions were determined by International Classification of Diseases (ICD) code; analyses was descriptive. Results: Among 1813 ICI-treated patients, mean age (SD) was 62.5 (13.5 years), 41% were women, 90% were white, 6% Hispanic, 2% black, 1% Asian, &lt;1% American Indian/Alaskan native or native Hawaiian/Pacific islander and 1% multiple race. Prior to ICI initiation, 48% had hypertension, 16% diabetes, 11% were current smokers, 46% former smokers, 11% had estimated glomerular filtration rate &lt;60 ml/min/1.73m 2 and 17% reported prior coronary revascularization. The most commonly treated malignancies were melanoma (40%) and lung cancer (31%). 47% of patients received pembrolizumab and 42% received nivolumab, the most often administered ICIs during this time period. Both before and after ICI administration, venous thromboembolism (VTE) and heart failure were the most frequently reported CV events (Figure). After initiation of ICI, myocardial infarction (MI) and stroke were reported for 54 (3.0%) and 73 (4.0%) patients, respectively. Myocarditis was more common after ICI than before ICI initiation (1 vs 9 patients [0.1%vs 0.5%]) but was infrequent compared with other CV events. Conclusions: Arterial and venous thrombotic events and heart failure were much more common than myocarditis in patients treated with ICI.
TAMI-07. THE IMMUNE MICROENVIRONMENT IN LOWER GRADE GLIOMAS
Authors: Anupam Kumar, Katharine Chen, Claudia Petritsch, Theodore Nicolaides, Mariarita Santi-Vicini, Arie Perry, Andrew Bollen, David Solomon, Annette M Molinaro, Joanna Phillips
Journal: Neuro-Oncology (2020)

Abstract The determinants of the tumor-associated immune response in brain tumors are poorly understood. Using tumor samples from two molecularly distinct subtypes of lower grade glioma, MAPK-driven glioma with biallelic inactivation of CDKN2A (n=30) and IDH-mutant, 1p/19q-intact astrocytoma (n=29), we demonstrate qualitative and quantitative differences in the tumor-associated immune response and we investigate the molecular mechanisms involved. Histologically the MAPK-driven gliomas were comprised of pleomorphic xanthoastrocytoma (PXA) (n=11) and anaplastic PXA (n=19). Seven patients had paired samples from two sequential surgeries. Immune cell populations and their activity were determined by quantitative multiplex immunostaining and Digital Spatial Profiling and gene expression was analyzed by Nanostring. Functional studies were performed using established cell lines and two new patient-derived lines from MAPK-driven LGGs. MAPK-driven tumors exhibited an increased number of CD8+ T cells and tumor-associated microglial/macrophage (TAMs), including CD163+ TAMs, as compared to IDH-mutant astrocytoma. In contrast, IDH-mutant tumors had increased FOXP3+ immunosuppressive T regulatory cells. Transcriptional and protein level analyses in MAPK-driven tumors suggested an active cytotoxic T cell response with robust expression of granzyme B, present on 27% of CD8+ T cells, increased MHC class I expression, and altered cytokine profiles. Interestingly, MAPK-driven tumors also had increased expression of immunosuppressive molecules, including CXCR4, PD-L1, and VEGFA. Expression differences for cell surface and secreted proteins were confirmed in patient-derived tumor lines and functional relationships between altered chemokine expression and immune cell infiltration was investigated. Our data provide novel insights into the immune contexture of MAPK driven LGGs and suggest MAPK driven gliomas with biallelic inactivation of CDKN2A may be particularly vulnerable to immunotherapeutic modulation
QOL-23. ASSESSING THE IMPACT OF METHYLPHENIDATE ON LATE COGNITIVE EFFECTS IN PAEDIATRIC BRAIN TUMOUR SURVIVORS: A SERVICE-BASED EVALUATION
Authors: Sarah Verity, Rebecca Hill, Gail Halliday, Jade Ryles, Simon Bailey
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE One of the most disabling side effects of treatment in survivors of brain tumours is the resultant reduction in level of processing speed and attention. This study aimed to evaluate intellectual and psychological benefit of short-acting methylphenidate to survivors of brain tumour. METHODS Paediatric BT patients attending a UK specialist treatment centre received assessment of cognitive performance. All patients identified with attentional difficulties were screened for contraindications to methylphenidate. Participants (N=23), mean age 11.09 years, completed a 6-month trial of methylphenidate. Measures of attention (Test of Everyday Attention for Children 2; SNAP-IV), side-effects (Stimulant Side-Effects Rating Scale), Health-Related Quality of Life (PEDS-QL), and experience of methylphenidate questionnaire (purpose-developed semi-structured questionnaire) were administered prior to medication and after six months. RESULTS Participants showed improvement in selective attention (t(18)=-5.4, p=&amp;lt;.001, d=.93) and processing speed (t(16)=-3.0, p=.01) at follow up. Family ratings of attention were significant (t(17)=14.46, p&amp;lt;.001, d=-1.19). Change in subjective measures of Health-Related Quality of Life (HRQoL) was also statistically significant as reported by children (t(16)=3.91, p=.001, d=-.99), and on a parental-report measure of child HRQoL (t(15)=-8.19, p&amp;lt;.001, d=-1.09). HRQoL measures show improvement to physical, academic, and emotional domains as reported by participants. CONCLUSIONS Paediatric BT survivors showed benefit from provision of methylphenidate in terms of reduced attentional and processing deficit, and in terms of emotional wellbeing. Treatment was well tolerated. Continued follow-up of the current participants in a longitudinal study aims to evidence longer-term benefit to participants.
NCOG-54. SAFETY OF TRANSSPHENOIDAL SURGERY FOR NONFUNCTIONING PITUITARY ADENOMA IN ELDERLY PATIENTS
Authors: Matheus Pereira, Taemin Oh, Rushikesh Joshi, Alexander Haddad, Kaitlyn Pereira, Robert Osorio, Kevin Donohue, Zain Peeran, Sweta Sudhir, Saket Jain, Angad Beniwal, José Gurrola, Ivan El-Sayed, Lewis Blevins, Philip Theodosopoulos, Sandeep Kunwar, Manish Aghi
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Life expectancy has increased over the past century, shifting the demographic distribution towards older age groups. Elderly patients comprise up to 14% of patients with pituitary tumors, with most lesions being nonfunctioning adenomas (NFPAs). Here, we compare clinical and surgical outcomes and post-operative complications between non-elderly adult (age ≥ 18 years and ≤ 65 years) and elderly (age &amp;gt; 65 years) NFPA patients. METHODS Retrospective review of 908 patients undergoing transsphenoidal surgery for NFPA at a single institution from 2007-2019. RESULTS Elderly patients represented 32.4% of patients. Both groups were similar in gender (57.3% vs 60.5% male;P=0.4), tumor size (2.56 vs 2.46 cm;P=0.2), and cavernous sinus invasion (35.8% vs 33.7%;P=0.6). Regarding post-operative outcomes, length of stay (1 vs 2 days; P=0.5), extent of resection (59.8% vs 64.8% GTR;P=0.2), CSF leak requiring surgical revision (4.3% vs 1.4%;P=0.06), 30-day readmission (8.1% vs 7.3%;P=0.7), infection (3.1% vs 2.0%;P=0.5), and new hypopituitarism (13.9% vs 12.0%;P=0.3) were similar between both groups. Elderly patients were less likely to have adjuvant radiation (8.7% vs 16.3%;P=0.009), future re-operation (3.8% vs 9.5%;P=0.003), and post-operative diabetes insipidus (DI) (3.7% vs 9.4%;P=0.002), and more likely to have post-operative hyponatremia (26.7% vs 16.4%;P&amp;lt; 0.001) and new cranial nerve deficit (1.9% vs 0.0%;P=0.01). Elderly patients’ post-operative sodium peaked and troughed on POD3 (mean=138.7 mEq/L) and POD9 (mean=130.8 mEq/L), respectively, compared to non-elderly patients (peak POD2 mean=139.9 mEq/L, trough POD8 mean=131.3 mEq/L). CONCLUSION Our analysis revealed that elderly patients experienced more post-operative hyponatremia, while non-elderly patients experienced more post-operative DI. Elderly patients also experience later peak and trough in serum sodium, suggesting age-related differences in stalk-related morbidities of NFPA resection. Overall, our results show that transsphenoidal surgery for NFPA in elderly patients is safe with low complication rates. We hope our results will guide discussions with elderly patients regarding possible risks and outcomes.
Ophthalmic Disease Prevalence and Incidence among People Living with Human Immunodeficiency Virus in the AFRICOS Study
Authors: Morgan M. Harvey, Nicole Dear, Allahna Esber, Michael Iroezindu, Emmanuel Bahemana, Hannah Kibuuka, Jonah Maswai, John Owuoth, Trevor A. Crowell, Christina S. Polyak, Brian K. Agan, Julie A. Ake, Grant A. Justin
Journal: Ophthalmology (2020)
Transcriptome-wide profiles of circular RNA and RNA-binding protein interactions reveal effects on circular RNA biogenesis and cancer pathway expression
Authors: Trine Line Hauge Okholm, Shashank Sathe, Samuel S. Park, Andreas Bjerregaard Kamstrup, Asta Mannstaedt Rasmussen, Archana Shankar, Zong Ming Chua, Niels Fristrup, Morten Muhlig Nielsen, Søren Vang, Lars Dyrskjøt, Stefan Aigner, Christian Kroun Damgaard, Gene W. Yeo, Jakob Skou Pedersen
Journal: Genome Medicine (2020)

Circular RNAs (circRNAs) are stable, often highly expressed RNA transcripts with potential to modulate other regulatory RNAs. A few circRNAs have been shown to bind RNA-binding proteins (RBPs); however, little is known about the prevalence and distribution of these interactions in different biological contexts.We conduct an extensive screen of circRNA-RBP interactions in the ENCODE cell lines HepG2 and K562. We profile circRNAs in deep-sequenced total RNA samples and analyze circRNA-RBP interactions using a large set of eCLIP data with binding sites of 150 RBPs. We validate interactions for select circRNAs and RBPs by performing RNA immunoprecipitation and functionally characterize our most interesting candidates by conducting knockdown studies followed by RNA-Seq.We generate a comprehensive catalog of circRNA-RBP interactions in HepG2 and K562 cells. We show that KHSRP binding sites are enriched in flanking introns of circRNAs and that KHSRP depletion affects circRNA biogenesis. We identify circRNAs that are highly covered by RBP binding sites and experimentally validate individual circRNA-RBP interactions. We show that circCDYL, a highly expressed circRNA with clinical and functional implications in bladder cancer, is almost completely covered with GRWD1 binding sites in HepG2 cells, and that circCDYL depletion counteracts the effect of GRWD1 depletion. Furthermore, we confirm interactions between circCDYL and RBPs in bladder cancer cells and demonstrate that circCDYL depletion affects hallmarks of cancer and perturbs the expression of key cancer genes, e.g., TP53. Finally, we show that elevated levels of circCDYL are associated with overall survival of bladder cancer patients.Our study demonstrates transcriptome-wide and cell-type-specific circRNA-RBP interactions that could play important regulatory roles in tumorigenesis.
STEM-22. TARGETING KIF11 TO RADIOSENSITIZE GLIOBLASTOMA
Authors: Abigail Zalenski, Monica Venere
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) is the most common primary brain tumor, and is incredibly lethal, with less than 10% of patients surviving more than 5 years after diagnosis. These tumors are routinely treated with radiotherapy, although we and others have shown that there is a subpopulation of GBM cells, called cancer stem-like cells (CSCs), that are radio-resistant, and do not respond to this standard therapy. We aim to overcome the radio-resistance of GBM CSCs by using radiotherapy in combination with a KIF11 inhibitor. We previously reported that the mitotic kinesin KIF11, required for bipolar spindle formation during mitosis, is elevated in GBM and portends poor prognosis. We also demonstrated that invasiveness and self-renewal of CSCs could be targeted with ispinesib, a small molecule inhibitor to KIF11. Furthermore, survival of mice bearing orthotopic glioblastoma was prolonged with KIF11 inhibition, although tumor burden increased with cessation of treatment. To combat tumor recurrence after treatment cessation, we proposed to use a KIF11 inhibitor with radiotherapy. KIF11 inhibitors will arrest cells in G2/M, where they are most sensitive to radiotherapy. By enriching CSCs in G2/M, we hypothesized that we would overcome CSC radio-resistance to decrease CSC viability and improve survival. We first tested the efficacy of combining a KIF11 inhibitor and irradiation in vitro. We found that using combination therapy to treat CSCs significantly decreased CSC survival over vehicle or either treatment used as a monotherapy. We then investigated the effects of combination therapy in vivo. Using a KIF11 inhibitor combined with irradiation increased survival of mice bearing orthotopic glioblastoma. Our results suggest that targeting KIF11 in combination with radiotherapy is a promising technique to overcome the radio-resistance of CSCs, and holds potential to significantly improve treatment outcomes and extend survival of patients with GBM.
SAT0064 Treatment with etoricoxib (mk-0663), a cox-2 selective inhibitor, resulted in clinical improvement in knee osteoarthritis (oa) over 52 weeks
Authors: SP Curtis, C Fisher, S Kafka, B Bockow, A Ko, A Compton, B Pramanik, BJ Gertz
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Prostanoid synthesis is catalysed by two distinct cyclooxygenase (COX) isoforms; COX-1 (constitutive) and COX-2 (inducible). NSAIDs such as aspirin and ibuprofen inhibit both COX isoforms. Etoricoxib has been characterised as a COX-2 selective inhibitor with doses up to 150 mg QD (~100-fold selective in human whole blood assay). <h3>Objectives</h3> Evaluate long-term efficacy following dose range finding of etoricoxib in knee OA. <h3>Methods</h3> Double-blind, randomised, placebo-controlled, multicenter study conducted in 617 knee OA patients. Patients with increased pain after NSAID withdrawal were allocated to qd oral etoricoxib 5 mg (N = 117), 10 mg (N = 114), 30 mg (N = 102), 60 mg (N = 112), 90 mg (N = 112) or placebo (N = 60). Following Part I (6 weeks), patients continued in double-blind continuation studies (total treatment 52 weeks). Patients receiving placebo, etoricoxib 5 and 10 mg in Part I were reallocated to etoricoxib 30-, 60-, 90 mg, or diclofenac 150 mg in the continuation studies. Etoricoxib 30-, 60-, and 90 mg remained constant over 52 weeks. <h3>Results</h3> In Part I, etoricoxib 5-, 10-, 30-, 60-, and 90 mg demonstrated significantly greater efficacy than placebo for the primary endpoints (p &lt; 0.05), with effect sizes exhibiting a strong, dose-related trend. For the subset of patients remaining in the etoricoxib 30-, 60-, 90 mg groups over 52 weeks, the treatment effect was generally maintained. Similar to the results in Part I, the 60- and 90-mg treatments were shown to be more effective than the 30-mg dose with respect to each of the 3 primary efficacy endpoints (WOMAC VA 3.0 pain subscale, patient and investigator global assessment of disease status). Etoricoxib was generally well tolerated over 52-weeks. In Part I, the incidence of patient discontinuation due to adverse events (AEs) was not significantly different between MK-663 and placebo. There were no clinically significant dose-related trends across treatments with &gt; = 1 AEs, drug-related AEs, serious AEs, or drug-related serious AEs. The safety results through 52 weeks were consistent with those in Part I, with no evidence of new types of AEs arising. <h3>Conclusion</h3> Etoricoxib was generally well tolerated in doses up to 90 mg in patients with OA for up to 52 weeks, and resulted in sustained clinical efficacy.
Diabetes and Heart Failure: The Role of Thiazolidinediones in Managing These Partners in Crime⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Carl V. Leier, Garrie J. Haas
Journal: Journal of the American College of Cardiology (2007)