tbuckley/cabot-search huggingface dataset:
Corrigendum to “Time association between hepatitis C therapy and hepatocellular carcinoma emergence in cirrhosis: Relevance of non-characterized nodules” [J Hepatol (2019) 874–884]
Authors: Zoe Mariño, Anna Darnell, Sabela Lens, Victor Sapena, Alba Díaz, Ernest Belmonte, Christie Perelló, Jose Luis Calleja, Maria Varela, Manuel Rodriguez, Carlos Rodriguez de Lope, Susana Llerena, Xavier Torras, Adolfo Gallego, Margarita Sala, Rosa María Morillas, Beatriz Minguez, Jordi Llaneras, Susana Coll, José Antonio Carrion, Mercedes Iñarrairaegui, Bruno Sangro, Ramón Vilana, Manel Sole, Carmen Ayuso, José Ríos, Xavier Forns, Jordi Bruix, María Reig
Journal: Journal of Hepatology (2020)
EPID-15. THE INTERNATIONAL DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)/DIFFUSE MIDLINE GLIOMA (DMG) REGISTRY AND REPOSITORY (IDIPGR) EXPANSION
Authors: Marianne Torontali, Renee Doughman, Brooklyn Chaney, Katie Black, Anthony Asher, Andrew Rupert, Christine Fuller, James Leach, Blaise Jones, Maryam Fouladi, Mariko DeWire
Journal: Neuro-Oncology (2020)

Abstract Established in April 2012, the mission of the IDIPGR is to provide secure integrated data sets including clinical, pathologic, radiologic and molecular genomics to the research community to promote hypothesis driven research. Over 600 data points per patient are securely stored on a CCHMC constructed web resource and domain using the open-source data mart development framework Harvest (PMID:24303304) (‘Links’). Genomic data is stored in the cloud-enabled VIVA platform and accessed through cross-platform integration and standardization algorithms for comparison across datasets. Features include source identification, data wrangling, and standardization of molecular and phenotypic data (2017), a web-enabled data mart that provides phenotype-genotype query/exploration, along with raw and processed data file downloads to authorized investigators (Harvest, 2017), additional tools for filtering and analysis of genomic datasets at the level of a phenotype, sample, gene, and variant (VIVA, 2017–2018), and uploaded digitized slides (Aperio, 2019). The IDIPGR Repository stores abstracted datasets for &amp;gt;1020 patients with DIPG/DMG, of whom 366 have tumor tissue available through biopsy and/or autopsy, and centrally reviewed and digitized specimens from 124 patients. The Repository contains &amp;gt;5000 radiology studies from &amp;gt;700 patients, with &amp;gt;550 patients centrally reviewed, and genomics data from 80 patients. Currently 27 IDIPGR approved projects utilize these datasets. The DIPG/DMG Registry constructed a robust database platform and integration system that provides the infrastructure to promote highly collaborative, international, hypothesis-driven research. Broadening collaboration among investigators for hypothesis-driven research studies will lead to better classification and more effective treatment of patients with DIPG and DMG.
EPCO-23. COMPARATIVE TRANSCRIPTOMICS TO IDENTIFY TARGETED THERAPY CANDIDATES IN HIGH GRADE GLIOMA
Authors: Kelsey Hundley, Olena Vaske, Geoff Lyle, Katrina Learned, Holly Beale, Ellen Kephart, Annick De Loose, Madison Lee, J D Day, Analiz Rodriguez
Journal: Neuro-Oncology (2020)

Abstract Genomic characterization is often used for the identification of therapeutic targets in tumors. Recently, comparative transcriptomics has begun to be utilized for this purpose. In this pilot, we compare the transcriptome of a patient with recurrent high grade glioma (HGG) to our cohort to identify potential therapies. We reviewed transcriptomic profiles from patients who had resection of HGG at our institution over the past year as well as the UCSC cancer compendium. Briefly, tumor RNA was extracted from embedded tumor tissue sections with tumor cellularity higher than 20%. RNA libraries were sequenced to obtain approximately 65 million reads on an Illumina HiSeq 4000 System utilizing patterned flow cell technology. The RNA profile of a 24 male with Li-Fraumeni syndrome and recurrent HGG with leptomeningeal spread underwent comparative transcriptomics to identify targets. A Bayesian statistical framework for gene expression outlier detection was used. These comparisons allowed for the identification of genes and pathways that are significantly overexpressed. Our internal HGG cohort consisted of 44 adult patients and was evenly distributed among the 4 HGG Verhaak subtypes. Our patient of interest had druggable outlier expression in HDAC1, STAT1 and STAT2 in comparison to our internal cohort indicating vorinostat and ruxolitinib as potential therapies, respectively. We then compared our patient of interest to 12,747 patients in the cancer compendium and STAT2 expression was high but not an outlier. In comparison to 738 glioma samples, STAT1 and STAT2 were outliers but not HDAC1 again indicating ruxolitinib as a potential targeted therapy. The patient did not have outlier expression in notch transcriptional targets or immune checkpoint biomarkers when compared to all cohorts. In conclusion, comparative Transcriptomics can identify therapeutic targets in a patient with recurrent HGG even in small cohorts. In our pilot, we identified ruxolitinib as a potential candidate to treat leptomeningeal recurrence.
PATH-21. TELOMERE LENGTH ANALYSIS OF CNS TUMORS IN THE PEDIATRIC BRAIN TUMOR ATLAS
Authors: Jo Lynn Rokita, Krutika Gaonkar, Heba Ijaz, Daniel Miller, Tasso Karras, Mariarita Santi, Daniel Martinez, Mateusz Koptyra, Thomas De Raedt, Jennifer Mason, Elizabeth Appert, Jena Lilly, Yakun Zhu, Angela Waanders, Adam Resnick, Jay Storm, Kristina Cole
Journal: Neuro-Oncology (2020)

Abstract Subsets of pediatric cancers, including high grade glioma (pHGG), have high rates of uniquely long telomeres, associated with ATRX gene mutations and alternative lengthening of telomeres (ALT). Ultimately, these cancers may benefit from a therapy stratification approach. In order to identify and further characterize pediatric brain tumors with telomere lengthening (TL), we determined the intratelomeric content in silico from paired WGS of 918 tumors from CBTTC Pediatric Brain Tumor Atlas (PBTA). The results were highly concordant with experimental assays to determine ALT in a subset of 45 pHGG tumors from the set. Overall, 13% of the PBTA cohort had telomere lengthening. We confirmed the highest rate of TL (37%) in the pHGG cohort (37/100 tumors; 30/82 patients). There was no statistical difference in age, gender or survival in subset analysis. As expected, the patient pHGG tumors with telomere lengthening were enriched for ATRX mutations (60%, q= 1.76e-3). However, 6 tumors without ATRX mutation also had normal protein expression, suggesting a different mechanism of inactivation or TL. The pHGG tumors with telomere lengthening had increased mutational burden (q=8.98e-3) and included all known pHGG cases (n=6) in the cohort with replication repair deficiencies. Of interest, the second highest rate of telomere lengthening was 9 subjects (24%) in the craniopharyngioma cohort. None of the craniopharyngioma tumors had ATRX mutations or low ATRX expression, and 55% of those with TL had CTNNB1 mutations. Finally, lower rates of telomere lengthening were found in medulloblastoma (10%), ependymoma (10%), low grade astrocytoma (8%) and ganglioglioma (7/47, 15%).
EPID-11. ESTABLISHING A BASELINE TIME-FRAME FOR SYMPTOM ONSET TO DEFINITIVE DIAGNOSIS FOR CHILDREN WITH NEWLY-DIAGNOSED CNS TUMORS: AN EXPANDED, MULTI-INSTITUTIONAL COLLABORATIVE STUDY
Authors: Eamon Eccles, Yan Han, Hao Liu, David Walker, Sarah Rush, Jonathan Finlay, Scott Coven
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND We have previously documented the presence of diagnostic delays in children with central nervous system (CNS) tumors in the United States. This study serves to expand and validate the previously established baseline from symptom onset to definitive diagnosis in children with newly-diagnosed CNS tumors. DESIGN: The medical records of children with newly-diagnosed CNS tumors were retrospectively reviewed from January 2004 to December 2017 at Nationwide Children’s Hospital, Akron Children’s Hospital and Riley Hospital for Children at IU Health. Records were reviewed for age, gender, tumor type, presenting symptoms, number of healthcare visits prior to diagnosis, time interval (in months) from onset of symptoms to definitive diagnosis and any associated genetic syndromes. RESULTS Of the 768 patients with newly-diagnosed CNS tumors, the median time interval from symptom onset to definitive diagnosis was 40.5 days while the mean symptom interval was 144 days (range &amp;lt; 1 to 5,475 days). The median age of diagnosis was 7 years, with a male predominance (57%). This expanded cohort continues to reveal that pediatric brain tumor patients most often seek care at the primary care level, although many patients were seen in various multiple subspecialty clinics prior to diagnosis. CONCLUSIONS This multi-institutional cohort study updates our previously documented single state time interval and provides a consistent Midwest “benchmark” to improve awareness for children with brain tumors through the adaptation of the UK ‘HeadSmart,’ now renamed ‘BrainFirst.’ Additionally, future work could include a prospective registry to better examine potential risk factors for delays in diagnosis.
QOL-43. ENDOCRINE AND METABOLIC CHANGES IN CHILDREN TREATED FOR MEDULLOBLASTOMA
Authors: Alexey Kalinin, Natalia Strebkova, Olga Zheludkova
Journal: Neuro-Oncology (2020)

Abstract We examined 63 patients (40 males/23 females) after complex treatment of medulloblastoma. Patients had a median age (range) of 11.3 (5.5 ÷ 17.9) years. The median time after the end of treatment was 3.7 (1.5 ÷ 11.6) years. Endocrine disorders were detected with the following frequency: growth hormone deficiency - 98.41% (62 of 63 patients), thyroid hormone deficiency – 69.8% (44/63), adrenal hormone deficiency - 17.4% (11/63). Three cases (4.7%) of premature sexual development were also detected. Lipids levels, beta-cell function and insulin resistance (IR) during 2-h oral glucose tolerance test were evaluated. A mono frequent bioelectrical impedanciometer was used to measure body composition. Overweight (SDS BMI&amp;gt; 1) was observed only in 16 patients (3 girls and 13 boys), obesity (SDS BMI&amp;gt; 2) in 1 boy. Dyslipidemia was found in 34 patients (54%). All patients underwent oral glucose tolerance test. Insulin resistance (ISI Matsuda &amp;lt;2.5 and/or HOMA-IR&amp;gt; 3.2) was detected in 7 patients (11/1%), impaired glucose tolerance (120 min glucose ≥7.8 mmol / l) was observed in 2 patients with IR and in 2 patients without IR. At the same time, IR and impaired glucose tolerance were encountered in only 5 children with overweight and no one with obesity. All patients with impaired glucose tolerance had normal values of fasting glucose (4.3 ÷ 5.04 mmol / l) and HbA1c (4.8 ÷ 5.8%). A bioelectrical impedanciometer was used to measure body composition in 49 cases, the percentage of adipose tissue was increased in 14 patients (28%) with normal BMI.
Abstract 16180: Cardiovascular Adverse Events Associated With Androgen Receptor-targeted Therapy Used in the Treatment of Prostate Cancer
Authors: Bishesh Shrestha, Sugam Gouli, Asis Shrestha
Journal: Circulation (2020)

Introduction: Prostate cancer is the second most common cancer in males. Its risk increases with age. So does the risk for cardiovascular disease. Androgen receptor-targeted therapy is now recommended to be added to androgen-deprivation therapy in the treatment of prostate cancer. We present common cardiovascular adverse events seen with the use of anti-androgens medication: abiraterone, enzalutamide, apalutamide, and darolutamide. Methods: We conducted a meta-analysis of 13 multinational randomized phase III clinical trials looking for cardiovascular adverse events in groups that received abiraterone, enzalutamide, apalutamide and darolutamide for treatment of prostate cancer. We analyzed a cohort of 9867 patients in these trials. Results: In the abiraterone usage group (n= 3492), most common cardiovascular adverse event was hypertension reported in 16.03%. Atrial fibrillation was reported in 0.97% and other cardiovascular events (IHD, MI, SVT, VT, and heart failure) were seen in 9.56%. In the enzalutamide usage group (n=4094) hypertension was seen in 10.6%, IHD in 1.88%, and atrial fibrillation was seen in 0.39%. Other unspecified cardiovascular adverse events were reported in 5.98%. In the apalutamide usage group (n=1327) hypertension was seen in 22%. Other cardiovascular adverse events (atrial fibrillation, MI, cardiogenic shock) were seen in 0.96%. In the darolutamide usage group (n=954) hypertension was seen in 6.6%, coronary artery disorders (coronary artery disease, coronary artery occlusion and stenosis) in 3.24%, and heart failure in 1.88%. Conclusions: The most common cardiovascular adverse event with use of anti-androgen medication seen in this large cohort analysis was hypertension with highest incidence seen in apalutamide group. Other cardiovascular side-effects noted were atrial fibrillation, SVT, VT, ischemic heart disease, MI, heart failure, and cardiogenic shock. Abiraterone and enzalutamide are the drugs that have been used in most trials. FDA adverse reaction reporting system (FAERS) shows hypertension as the most commonly reported cardiovascular adverse event with abiraterone and enzalutamide use. More prospective studies are needed to further access cardiovascular risk with use of anti-androgen therapy.
IMMU-02. CHIMERIC ANTIGEN RECEPTOR (CAR) T CELL NEUROTOXICITY CORRELATES WITH PRETREATMENT AND ACUTE CSF NEUROFILAMENT LIGHT CHAIN (NFL) LEVELS
Authors: Juliane Gust, Ashley Wilson, Olivia Finney, Kendra Jae Hartsuyker, Prabha Narayanaswamy, Vicky Wu, Gwenn Garden, Colleen Annesley, Rebecca Gardner
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE Immunotherapy for hematologic malignancies with CD19-directed CAR T cells is complicated by neurotoxicity in approximately 40% of patients. We have previously reported evidence of glial injury in pediatric patients with CAR T neurotoxicity by elevated CSF levels of GFAP and S100b. We now hypothesize that NFL is also a useful biomarker of neuronal injury related to abnormal blood-brain-barrier and glial function. METHODS We used the Mesoscale Discovery platform to measure CSF and serum NFL levels in a consecutive cohort of 43 pediatric patients with B cell ALL who received CD19-directed CAR T cells. In addition, we will present expansion cohort measurements of NFL and GFAP (N=95). RESULTS CSF NFL levels prior to CAR T cell infusion positively correlated with the risk of subsequently developing severe neurotoxicity (no neurotoxicity, median 275pg/mL, mild 378pg/mL, severe 951pg/mL, P=0.0182 for severe vs none, P=0.0458 for severe vs mild). During neurotoxicity, mean CSF NFL levels increased to 1179pg/mL (mild neurotoxicity, P=0.0338) and 1345 pg/mL (severe neurotoxicity, P=0.0148), respectively. In serum, pretreatment NFL levels were highly abnormal in many patients (median 368pg/mL, range 10–56,321pg/mL; healthy control median 4pg/mL, range 1–7.5pg/mL). However, there was no correlation with neurotoxicity, history of CNS radiation, peripheral neuropathy, stem cell transplant, or number of prior chemotherapies. Day 7 serum NFL levels did not change significantly (median 439pg/mL, range 5–17,439pg/mL, P=0.3254). CONCLUSION We conclude that CSF NFL is promising biomarker of CAR T neurotoxicity risk and severity. The abnormal baseline serum NFL concentrations remain unexplained and require further study.
Abstract 16023: Cardiovascular Health Status and Lifetime Risk of Heart Failure Among White and Black US Adults
Authors: Sadiya S Khan, Hongyan Ning, Amanda Paluch, Victor Zhong, Norrina B Allen, Mercedes R Carnethon, John T Wilkins, Donald M Lloyd-Jones
Journal: Circulation (2019)

Introduction: Ideal cardiovascular health (CVH) is associated with lower short-term risk of HF. However, the association of CVH with lifetime risk estimates and years lived free of HF has not been ...
TAMI-14. NANOPARTICLE DELIVERY OF PD-L1 CRISPR/CAS9 PLASMID DNA FOR ANTI-GLIOBLASTOMA IMMUNOTHERAPY
Authors: Javier Fierro, An Tran, Chris Factoriza, Brandon Chin, Huanyu Dou
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma multiforme (GBM) is a devastating cancer that develops from astrocytes in the brain. GBM is fast acting and kills 90% of patients within 5 years. Several immunotherapies have been developed to treat GBM, however, major challenges still persist. For example, checkpoint proteins such as programmed cell death protein 1 (PD-1) and its ligand, programmed death ligand 1 (PD-L1), are upregulated in GBM cells to evade the immune system. Targeting PD-L1 for genetic knockdown is thus a promising avenue for the treatment of GBM. However, PD-L1 protein inhibitors have been shown to cause immune overreaction and toxicity, therefore requiring new technologies. CRISPR/Cas9 gene editing has been widely used for the study and treatment of many diseases, but has not been extensively studied for the treatment of GBM. The main challenge is developing a gene delivery platform for the delivery of CRISPR/Cas9 plasmid DNA (pDNA). Many viral vectors have been used for the delivery of pDNA, but unfortunately are associated with high toxicity. Nanotechnology is emerging as a new platform for the delivery of pDNA as it shows high transfection efficiency with low cytotoxicity. We developed a cationic core-shell nanoparticle (NP) capable of carrying CRISPR/Cas9 pDNA. This plasmid contains multiple guide RNA (gRNA) expression cassettes for the knockdown of PD-L1. PDL1gRNA-CRISPR/Cas9pDNA-NPs were taken up by U87 cells within 30 minutes, and entered into the nucleus at 2 hours. The effective delivery of PDL1gRNA-CRISPR/Cas9pDNA-NPs led to the expression of PD-L1 gRNA and Cas9 enzyme, and the knockdown of PD-L1. Regulation of immune balance was determined after PD-L1 knockdown in vitro and in vivo. Our study shows the potential of NP-based PDL1gRNA-CRISPR/Cas9 delivery as an anti-GBM immunotherapy for clinical applications.
Abstract P453: Short-term Air Pollution Exposures, Lifestyle Risk Factors, and Glucose Levels: A Family-based Study in China
Authors: Mengying Wang, Yaohua Tian, Yao Wu, Xiaowen Wang, Junhui Wu, Zijing Wang, Tao Wu, Yonghua Hu
Journal: Circulation (2020)

Introduction: Previous studies have reported the association between ambient air pollution exposures and glucose levels. However, less is known about whether usual lifestyles could modify the association. Hypothesis: We assessed the hypothesis that lifestyles may modify the association between short-term exposure to ambient air pollution and fasting blood glucose levels among Chinese populations. Methods: The analysis was based on a family-based study in Northern China. In addition, data of air pollution from 2014 to 2017 were obtained from the Beijing Municipal Environmental Monitoring Center. A generalized additive model was adopted to estimate the change in blood glucose levels with a 10 μg/m 3 increase in 2-day moving average concentrations of air pollutants (lag0-1) (considering the potential lag pattern effect of air pollution on glucose levels). Interaction analyses were conducted by including a cross-product term of PM 2.5 or PM 10 by lifestyles (smoking, alcohol consumption, BMI, and sedentary lifestyles) in the models. Results: A total of 4,151 participants (2259 females, 1892 males, 58.9±8.7 years) without antidiabetic drugs on the survey day were included in the analysis. We found a 10 μg/m 3 increase in PM 2.5 concentrations and PM 10 concentrations corresponded to 0.06 (95% CI: 0.04-0.09) and 0.06 (95% CI: 0.04-0.08) mmol/L increase in glucose levels, respectively after adjusting for sex, age, education levels, BMI (kg/m 3 ), smoking, alcohol consumption, sedentary lifestyles, family history of diabetes, use of antidiabetic drugs, temperature, and relative humidity. Besides, the results showed higher risks of PM 2.5 and PM 10 among the overweight and obese when compared with the normal weight ( P for interaction less than 0.05). However, drinking status and sedentary lifestyles did not modify the association between PM and glucose levels. Conclusions: Short-term exposures to air pollution were associated with higher blood glucose levels, which could be modified by BMI. Populations with higher BMI may be more susceptible to the adverse effects.
Basophil activation test shows high accuracy in the diagnosis of peanut and tree nut allergy: The Markers of Nut Allergy Study
Authors: Lucy Duan, Alper Celik, Jennifer A. Hoang, Klara Schmidthaler, Delvin So, Xiaojun Yin, Christina M. Ditlof, Marta Ponce, Julia E.M. Upton, Jean‐Soo Lee, Lisa Hung, Heimo Breiteneder, Chiara Palladino, Adelle R. Atkinson, Vy H.D. Kim, Alireza Berenjy, Maria Asper, David Hummel, Samantha Wong, Mara Alexanian‐Farr, Ahuva Magder, Sharon R. Chinthrajah, Kaori Mukai, Mindy Tsai, Kari Nadeau, Stephen J. Galli, Arun K. Ramani, Zsolt Szepfalusi, Thomas Eiwegger
Journal: Allergy (2020)

Abstract Background Peanut and tree nut allergies are the most important causes of anaphylaxis. Co‐reactivity to more than one nut is frequent, and co‐sensitization in the absence of clinical data is often obtained. Confirmatory oral food challenges (OFCs) are inconsistently performed. Objective To investigate the utility of the basophil activation test (BAT) in diagnosing peanut and tree nut allergies. Methods The Markers Of Nut Allergy Study (MONAS) prospectively enrolled patients aged 0.5–17 years with confirmed peanut and/or tree nut (almond, cashew, hazelnut, pistachio, walnut) allergy or sensitization from Canadian (n = 150) and Austrian (n = 50) tertiary pediatric centers. BAT using %CD63 + basophils (SSClow/CCR3pos) as outcome was performed with whole blood samples stimulated with allergen extracts of each nut (0.001‐1000 ng/mL protein). BAT results were assessed against confirmed allergic status in a blinded fashion to develop a generalizable statistical model for comparison to extract and marker allergen‐specific IgE. Results A mixed effect model integrating BAT results for 10 and 100 ng/mL of peanut and individual tree nut extracts was optimal. The area under the ROC curve (AUROC) was 0.98 for peanut, 0.97 for cashew, 0.92 for hazelnut, 0.95 for pistachio, and 0.97 for walnut. The BAT outperformed sIgE testing for peanut or hazelnut and was comparable for walnut (AUROC 0.95, 0.94, 0.92) in a sub‐analysis in sensitized patients undergoing OFC. Conclusions Basophil activation test can predict allergic clinical status to peanut and tree nuts in multi‐nut‐sensitized children and may reduce the need for high‐risk OFCs in patients.
Providing Neonatal Outcome Estimates as an Intervention
Authors: Matthew A. Rysavy, Marlyse F. Haward
Journal: JAMA Pediatrics (2020)

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