tbuckley/cabot-search huggingface dataset:
EPCO-32. IDENTIFICATION OF PROGNOSTIC CHORDOMA SUBGROUPS USING DNA METHYLATION SIGNATURES IN TISSUE AND PLASMA
Authors: Jeffrey Zuccato, Vikas Patil, Sheila Mansouri, Jeffrey Liu, Farshad Nassiri, Yasin Mamatjan, Ankur Chakravarthy, Shirin Karimi, Joao Paulo Almeida, Anne-Laure Bernat, Mohammed Hasen, Shahbaz Khan, Thomas Kislinger, Namita Sinha, Sébastien Froelich, Homa Adle-Biassette, Kenneth Aldape, Daniel De Carvalho, Gelareh Zadeh
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Chordomas are malignant bone cancers arising from the skull-base and spine that are rare but cause devastating central nervous system morbidities. Survival is highly variable despite surgery and radiotherapy as 10% live under 1 year and 30-35% survive over 20 years. There are currently no reliable prognostic factors and this limits our ability to tailor patient treatment to their risk. Accordingly, this work identifies epigenetic prognostic chordoma subgroups that are detectable non-invasively through plasma methylomes to guide treatment. METHODS A total of 68 chordoma surgical specimens resected between 1996-2018 across three international centres underwent DNA methylation profiling. Cell-free methylated tumor DNA immunoprecipitation and high-throughput sequencing was performed on available matched plasma samples. RESULTS Two stable tumor clusters were identified through consensus clustering of tissue methylation data. Clusters had statistically significantly different disease-specific survivals (log-rank p=0.0062) independent of clinical factors in a multivariable Cox analysis (HR=16.5, 95%CI: 2.8-96, p=0.0018). The poorer-performing “Immune-infiltrated” cluster had genes hypomethylated at promoters, typically resulting in transcription, within immune-related pathways and higher immune cell abundance within tumors. The better-performing “Cellular” cluster showed higher tumor cellularity plus cell-to-cell interaction and extracellular matrix pathway hypomethylation. Fifty chordoma-versus-other binomial generalized linear models built using plasma methylome data distinguished chordomas from meningiomas and spinal metastases, as representative clinical differential diagnoses, in random left-out 20% testing sets (mean AUROC=0.84, 95%CI: 0.52-1.00). Plasma-based methylation signatures were highly correlated with tissue-based signals within both poor-performing (median r=0.69, 95%CI: 0.66-0.72) and better-performing cluster tumors (median r=0.67, 95%CI: 0.62-0.72). CONCLUSIONS The first identification of two distinct prognostic epigenetic chordoma subgroups is shown here with “Immune-infiltrated” tumors having a poorer prognosis than “Cellular” tumors. Plasma methylomes can be utilized for non-invasive chordoma diagnosis and subtyping. This work may transform chordoma treatment decision-making by guiding surgical planning in advance to match resection aggressiveness with patient prognosis.
Abstract 12830: Cardiac POCUS: Another Tool in the Armory
Authors: Rhythm Vasudeva, Abhiram Challa, Nourhan Chaaban, Hamna Shah, Elisha J Brumfield, Brent Duran, Mohinder Vindhyal
Journal: Circulation (2021)

Introduction: Cardiac Point-Of-Care-Ultrasound (POCUS) is a valuable bedside tool that has been shown to provide better-quality patient care. Few studies have examined residents’ interest and the educational impact of a hybrid Cardiac POCUS training model in a community-based academic setting. Material and Methods: Internal Medicine and Medicine/Pediatrics residents across all post-graduate years (PGY) undertook a structured hybrid (online and hands-on teaching) model of POCUS training. Anonymous surveys with Likert-type scale responses were conducted before and after the curriculum. Questions were categorized into domains to assess the residents’ interest in learning POCUS, their understanding of fundamental cardiac ultrasound (US) concepts, and their confidence in its application. Direct comparisons were made using Fisher’s exact and t-test as appropriate. Odds ratios were estimated to further gauge the impact of the training. Results: A total of 27 and 26 residents completed the pre-and post-training anonymous surveys, respectively. A median of 1 previous cardiac US was reported, with the distribution showing a positive skew. Responses inquiring about residents’ interest in learning POCUS were similar post-training compared to the pre-training survey (OR 3.66 [CI 0.86 - 15.59], p = 0.07), a finding consistent amongst sub-groups female gender, and PGY levels 2 &amp; 3. The training did reveal a significant increase in both, the understanding of cardiac POCUS principles (OR 8.25 [CI 1.61 - 42.28], p = 0.005), and the residents’ confidence in its application (OR 13.53 [CI 1.58 - 116.04, p=0.005]. The mean score on confidence level, though higher post-training, was not significant amongst PGY 1 residents. Conclusions: Understanding fundamental cardiac ultrasound concepts and the confidence level in its application were significantly greater amongst residents after implementing a structured hybrid teaching model for Cardiac POCUS. This may be most impactful if designed for PGY levels 2 &amp; 3. Future studies with a comprehensive teaching curriculum and more objective assessment tools are needed to gauge its clinical impact, its adoption rate in clinical practice, and a recommendation for incorporation into the residency curriculum.
Abstract 14266: Outcomes of Chest Pain Patients Following Application of a Validated High Sensitivity Troponin Algorithm: Comparison of 30 Day Death/ MI of Algorithm Concordant vs Discordant Discharges
Authors: Ayesha Khan, Muhammad Sabih S Saleem, Keith Willner, Luke Sullivan, Martin E Matsumura
Journal: Circulation (2021)

Introduction: High sensitivity troponin (hsTn) assays effectively risk stratify patients with chest pain when a validated serial algorithm is utilized. Most of these algorithms require multiple draws for initial values in an intermediate range below a cutoff considered unequivocally consistent with MI. Little is known regarding outcomes of patients who are discharged following deviation from these algorithms. Hypothesis: Minor deviation from a validated hsTn algorithm may yield unacceptable outcomes in chest pain patients. Methods: Retrospective review of outcomes in patients presenting with chest pain to Geisinger Health System emergency departments and discharged based on application of a validated 0/1/3 hour hsTroponinT (hsTnT) algorithm over a 2-year period. We compared 30-day death/MI in patients who had hsTnT results that were consistent with “ruling out” (algorithm concordant) vs those who were discharged despite either equivocal hsTnT results or incomplete application of the algorithm (algorithm discordant). Patients who were admitted or met criteria for MI based on a peak hsTnT &gt; 52ng/L were excluded. Results: Out of 10,342 patients discharged after hsTnT algorithm, 1,166 (11.3%) were algorithm-discordant. Thirty-day death/MI occurred in 13 (0.14%) of patients managed protocol concordant and 16 (1.37%)of patients managed protocol discordant (p&lt;0.001). The 16 discordant pts with death/MI were algorithm-discordant due to either having only a single hsTnT draw (12) or a 0-1hr delta &gt; 5ng/L (4). Comparing all patients with vs without 30day death/MI, univariate predictors included median age (66 vs 50yr, p&lt;0.0001), prior CAD history (41.4 vs 17.5%, p=0.002), hyperlipidemia (44.8 vs 21.8%, p=0.006) and hsTnT algorithm discordance (55.2 vs 11.1%, p&lt;0.001). A multivariable logistic regression model found that among univariate predictors only algorithm discordance was an independent predictor of 30-day death/MI (OR 6.42, p&lt;0.001). Conclusions: Deviation from an hsTnT algorithm was associated significantly with increased 30 day cardiac events. This study highlights the importance of maintaining concordance with algorithm details when using hsTnT assays to triage chest pain patients.
TAMI-44. ASSOCIATION OF CIRCADIAN CLOCK GENE EXPRESSION WITH GLIOMA TUMOR MICROENVIRONMENT AND PATIENT SURVIVAL
Authors: Julianie De La Cruz Minyety, Dorela Shuboni-Mulligan, Nicole Briceno, Demarrius Young Jr., Mark Gilbert, Orieta Celiku, Terri Armstrong
Journal: Neuro-Oncology (2021)

Abstract Circadian clock genes have been linked to differences in clinical outcomes in cancer, including gliomas. However, these studies have not accounted for established prognostic markers, including mutations in Isocitrate Dehydrogenase (IDH). To study the connection between circadian clock genes and glioma outcomes while accounting for IDH mutational status, we analyzed multiple publicly available gene expression datasets. Unsupervised clustering of 13 clock gene transcriptomic signatures from The Cancer Genome Atlas resulted in four distinct transcriptomic clusters, two clusters were enriched for IDH mutant (Circadian 1-2) and the others for IDH wild-type gliomas (Circadian 3-4). Within these clusters we observed differential prognosis of the patients by Kaplan–Meier analysis (Circadian 1-2, p=0.0001; Circadian 3-4, p=0.0002) suggesting that these transcriptomic circadian subtypes might reflect different disease states. Further analyses using Cox Proportional Hazards Regression showed that lower Period (PER) gene expression was associated with worse prognosis (increasing PER expression HR=0.655, p=0.007) independent of IDH wild-type status (HR=5.312, p&amp;lt; 0.001) and increasing age (HR = 1.04, p&amp;lt; 0.001). Lower PER expression was associated with enrichment of a number of immune signaling pathways. These findings prompted the exploration of the relationship between microenvironment and clock genes using the Ivy GAP dataset to explore tumor location-specific differences and single cell RNA sequencing data from Darmanis (accession: GSE84465) to explore cell-specific differences. Circadian clock genes were found to be differentially expressed across anatomical tumor locations and cell types, including microglia. In ongoing studies we are examining the role of the microenvironment and PER2 expression on tumor growth by disrupting PER2 expression in tumor cells and microglia using IDH mutant and wild-type in vitro models. Clock gene expression is a potential prognostic biomarker in glioma and further studies to elucidate the importance of circadian rhythms in other cell types beyond the tumor are warranted.
HIV seroprevalence in five key populations in Europe: a systematic literature review, 2009 to 2019
Authors: Annemarie Rinder Stengaard, Lauren Combs, Virginie Supervie, Sara Croxford, Sarika Desai, Ann K Sullivan, Stine Finne Jakobsen, Quenia Santos, Daniel Simões, Jordi Casabona, Jeffrey V Lazarus, John B F de Wit, Frank M Amort, Anastasia Pharris, Lina Nerlander, Dorthe Raben
Journal: Eurosurveillance (2021)

Background In Europe, HIV disproportionately affects men who have sex with men (MSM), people who inject drugs (PWID), prisoners, sex workers, and transgender people. Epidemiological data are primarily available from national HIV case surveillance systems that rarely capture information on sex work, gender identity or imprisonment. Surveillance of HIV prevalence in key populations often occurs as independent studies with no established mechanism for collating such information at the European level. Aim We assessed HIV prevalence in MSM, PWID, prisoners, sex workers, and transgender people in the 30 European Union/European Economic Area countries and the United Kingdom. Methods We conducted a systematic literature review of peer-reviewed studies published during 2009–19, by searching PubMed, Embase and the Cochrane Library. Data are presented in forest plots by country, as simple prevalence or pooled across multiple studies. Results Eighty-seven country- and population-specific studies were identified from 23 countries. The highest number of studies, and the largest variation in HIV prevalence, were identified for MSM, ranging from 2.4–29.0% (19 countries) and PWID, from 0.0–59.5% (13 countries). Prevalence ranged from 0.0–15.6% in prisoners (nine countries), 1.1–8.5% in sex workers (five countries) and was 10.9% in transgender people (one country). Individuals belonging to several key population groups had higher prevalence. Conclusion This review demonstrates that HIV prevalence is highly diverse across population groups and countries. People belonging to multiple key population groups are particularly vulnerable; however, more studies are needed, particularly for sex workers, transgender people and people with multiple risks.
Abstract P459: Mavacamten And Danicamtiv Reverse Respective Contractile Abnormalities In Engineered Heart Tissue Models Of Hypertrophic And Dilated Cardiomyopathy
Authors: Saiti S Halder, Lorenzo R Sewanan, Michael J Rynkiewicz, Jeffrey R Moore, William J Lehman, Stuart G Campbell
Journal: Circulation Research (2021)

Missense mutations in alpha-tropomyosin (TPM1) can lead to development of hypertrophic (HCM) or dilated cardiomyopathy (DCM). HCM mutation E62Q and DCM mutation E54K have previously been studied extensively in experimental systems ranging from in vitro biochemical assays to animal models, although some conflicting results have been found. We undertook a detailed multi-scale assessment of these mutants that included atomistic simulations, regulated in vitro motility (IVM) assays, and finally physiologically relevant human engineered heart tissues. In IVM assays, E62Q previously has shown increased Calcium sensitivity. New molecular dynamics data shows mutation-induced changes to tropomyosin dynamics and interactions with actin and troponin. Human engineered heart tissues (EHT) were generated by seeding iPSC-derived cardiomyocytes engineered using CRISPR/CAS9 to express either E62Q or E54K cardiomyopathy mutations. After two weeks in culture, E62Q EHTs showed a drastically hypercontractile twitch force and significantly increased stiffness while displaying little difference in twitch kinetics compared to wild-type isogenic control EHTs. On the other hand, E54K EHTs displayed hypocontractile isometric twitch force with faster kinetics, impaired length-dependent activation and lowered stiffness. Given these contractile abnormalities, we hypothesized that small molecule myosin modulators to appropriately activate or inhibit myosin activity would restore E54K or E62Q EHTs to normal behavior. Accordingly, E62Q EHTs were treated with 0.5μM mavacamten (to remedy hypercontractility) and E54K EHTs with 0.5 μM danicamtiv (to remedy hypocontractility) for 4 days, followed by a 1 day washout period. Upon contractility testing, it was observed that the drugs were able to reverse contractile phenotypes observed in mutant EHTs and restore contractile properties to levels resembling those of the untreated wild type group. The computational, IVM and EHT studies provide clear evidence in support of the hyper- vs. hypo-contractility paradigm as a common axis that distinguishes HCM and DCM TPM1 mutations. Myosin modulators that directly compensate for underlying myofilament aberrations show promising efficacy in human in vitro systems.
Abstract 11510: Associations of Cardiovascular Health in Young Adulthood with Long-Term Blood Pressure Trajectories: Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: James W Guo, Hongyan Ning, Norrina Allen, Kiang Liu, Orna Reges, Don Lloyd-jones
Journal: Circulation (2021)

Introduction: Cardiovascular health (CVH) in young adulthood (YA) has been associated with cardiovascular outcomes in older age. However, little is known about the relationship between YA CVH and mid-life BP trajectories. Methods: CVH (defined by 6 of AHA’s 7 metrics, excluding BP) was measured twice in YA and defined as poor, intermediate, and ideal for each metric, scored as 0, 1, or 2 points respectively, then summed as a composite CVH score (range 0 to 12). Categorical CVH status was defined as ≥10 points = high, 6-9 = moderate, 0-5 = low. Latent-class modeling (SAS Proc Traj) was used to identify trajectories of mid-BP (mean of SBP and DBP) from ages 35 to 55 years. Multinomial logistic regression was used to estimate the association of YA CVH status with mid-life BP trajectory group membership. Results: There were 3,358 CARDIA participants (56% female, 46% Black; mean age 25 years) in YA with follow-up data for BP trajectories. We observed 3 BP trajectory groups, labeled as low, middle, and higher (Figure). A 1-point higher CVH score in YA was associated with adjusted odds ratios (aORs) of 0.84 (95% CI, 0.80-0.89) for being in the middle and 0.73 (0.67-0.79) for being in the higher mid-life BP trajectory groups. Compared with high CVH status at baseline, those with low and moderate CVH were significantly more likely to be in the middle and higher BP trajectory groups (Table). Among the CVH metrics, only BMI was significantly associated with BP trajectory group. Conclusions: Moderate or low CVH status in YA is associated with elevated mid-life BP trajectory. These data suggest that early life CVH status, and particularly BMI, may be important to manage for primordial prevention of hypertension.
BIOM-07. QUANTITATIVE MGMT PROMOTER METHYLATION INDEX INDICATES A NON-LINEAR PROGNOSTIC EFFECT IN GLIOBLASTOMA, SUGGESTING THAT USE OF OPTIMAL CUTOFF POINTS MAY BE CLINICALLY DISADVANTAGEOUS
Authors: David Gibson, Akshay Ravi, Eduardo Rodriguez Almaraz, Susan Chang, Nancy Ann Oberheim-Bush, Jennie Taylor, Jennifer Clarke, David Solomon, Aaron Scheffler, John Witte, Hannah Lambing, Mitchel Berger, Hideho Okada, Farid Chehab, Nicholas Butowski
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Epigenetic inhibition of the O6-methylguanine-DNA-methyltransferase (MGMT) gene has emerged as a clinically relevant prognostic marker in glioblastoma (GBM). Methylation of the MGMT promoter has been shown to increase chemotherapy efficacy. While traditionally reported as a binary marker, recent methodological advancements have led to quantitative approaches that measure methylation, providing clearer insights into methylation’s functional relationship with survival. METHODS A CLIA assay and bisulfite sequencing was utilized to develop a quantitative, 17-point MGMT promoter methylation index derived from the number of methylated CpG sites. Retrospective review of 240 newly diagnosed GBM patients was performed in order to discern how risk for mortality transforms as promoter methylation increases. Non-linearities were captured by fitting splines to Cox proportional hazard models, plotting smoothed residuals, and creating survival plots. Covariates included age, KPS, IDH1 mutation, and extent of resection. RESULTS Median follow-up time and progression free survival were 16 and 9 months, respectively. 176 subjects experienced death. A one-unit increase in CpG methylation on a scale of 1-17 resulted in a 4% reduction in hazard (95% CI 0.93–0.99, P&amp;lt; 0.005). Moreover, GBM patients with low-levels of methylation (1-6 CpG sites) fared markedly worse (HR=1.62, 95% CI 1.03-2.54, P&amp;lt; 0.036) than individuals who were unmethylated (reference group). Subjects with medium-levels of methylation (7-12 CpG sites) had the greatest reduction in hazard (HR=0.48, 95% CI 0.29-0.80, P&amp;lt; 0.004), followed by individuals in the highest methylation tertile (HR=0.62, 95% CI 0.40-0.97, P&amp;lt; 0.035). CONCLUSION This novel approach offers greater bisulfite conversion efficiency when compared to alternative methods, reducing the likelihood of false positives. Analysis of the resulting methylation index scores demonstrates a non-linear relationship between MGMT methylation and survival, suggesting conformation of the marker’s protective effect. These findings challenge the current understanding of MGMT’s functional form and underline why implementing an “optimal cutoff point” may be disadvantageous.
EXTH-03. COMBINED TOP1 AND PARP INHIBITION ENFORCES GENOMIC INSTABILITY AND CELL DEATH IN PTEN-DEFICIENT GLIOBLASTOMA
Authors: Olga Kim, Madison Butler, Ying Pang, Guangyang Yu, Mythili Merchant, Alice Ranjan, Mark Gilbert, Yves Pommier, Jing Wu
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Glioblastoma is an aggressive brain tumor with high mortality. The development of new therapies is critical for improving patient outcomes. LMP400, a novel topoisomerase I (TOP1) inhibitor, traps TOP1 cleavage complexes, thereby generating DNA damage. Poly(ADP-ribose) polymerase (PARP) is involved in DNA repair responses triggered by TOP1 inhibition. Niraparib is a potent PARP inhibitor that can cross the blood-brain barrier. Loss of phosphatase and tensin homolog (PTEN) occurs in 40% of GBM patients and is known to promote DNA damage repair deficiency. Here, we hypothesize that PTEN loss presents a vulnerability to a combined induction of DNA damage and inhibition of repair mechanisms. METHODS Human glioblastoma cells (U251, SNB-75, SF-295, LN18) and patient-derived glioblastoma stem cells (GSC923 and GSC827) were treated with LMP400 and/or Niraparib. Cell viability and apoptosis were examined using Celigo image cytometer and Annexin V/PI assay at 72h after treatment. Single clones after PTEN knockdown using shRNA were isolated after puromycin selection. For planned studies of PTEN knockout, sgRNA plasmids targeting PTEN will be transiently transfected and GFP-positive single KO clones will be isolated. PTEN will be restored in PTEN-null cells using lentiviral transduction. RESULTS CRISPR-Cas9 KO screening in GSC923 cells suggests that LMP400 is unlikely a substrate for ABC transporters. LMP400 and Niraparib synergistically induced cytotoxic effects in U251, SF-295, GSC923, GSC827 cells lacking PTEN expression. Combined LMP400/Niraparib led to increased expression of gamma-H2AX, cleaved caspase 3 and PARP, indicative of enhanced DNA damage and cell death. CONCLUSION LMP400 and Niraparib act synergistically to target PTEN-deficient glioblastoma by inducing DNA damage and cell death. These results will be further verified in isogenic cells in vitro as well as in vivo in a mouse model driven by PTEN deletion which would strongly support a novel therapeutic strategy in a subset of glioblastoma with PTEN loss.
Efficacy and Safety of Ferric Derisomaltose/Iron Isomaltoside in Patients with Inflammatory Bowel Disease: A Systematic Review
Authors: Keren Sam, Atif Irfan Khan, Anam Khan, Sobia Aamir, Fatima Sajid, Yusra Minahil Nasir, Muhammad Arslan, Muhammad Asad, Faiz Anwer
Journal: Blood (2021)
ITVT-03. Use of Functional MRI and DTI for Surgical Planning of Maximal Extent of Resection of CNS Tumors - A Single Neurosurgical Center’s Experience
Authors: Fred Lam, Hanan Algethami, Kasper Ekkehard
Journal: Neuro-Oncology (2021)

Abstract Use of functional neuroimaging capabilities such as fMRI, DTI, MRP, MRS, AS-PET-CT, SPECT, and TMS as noninvasive tools to visualize intrinsic brain and spine morphology in relation to function have developed over the past 30 years. Amongst these imaging modalities, functional magnetic resonance imaging (fMRI) is of particular interest since it follows the physiological coupling between neuronal electrical activity and metabolic structural (cellular) activity as it relates to tissue vascularity and perfusion states. As an adjunct to this modality, MRI-based diffusion tensor imaging (DTI) allows further detailed radiographic assessment of fiber tracts in the brain in relationship to the surgical lesion of interest. In addition, combination of other imaging modalities including MR perfusion and intraoperative tools such as neuronavigation and direct cortical stimulation can help guide the extent of maximal safe resection. Herein we present a case series from our neurosurgical institution of primary intra-axial, extra-axial, supratentorial, and brainstem tumors resected using fMRI and DTI for presurgical planning allowing for maximal safe extent of resection and outcomes.
A Randomised Evaluation of Low-Dose Ara-C Plus BCT-100 Versus Low Dose Ara-C in Older Patients with Acute Myeloid Leukaemia: Results from the LI-1 Trial
Authors: Francis J. Mussai, Ian Thomas, Cono Ariti, Laura Upton, Mia Sydenham, Alan K. Burnett, Steve Knapper, Priyanka Mehta, Mary Frances McMullin, Mhairi Copland, Nigel H. Russell, Robert Hills
Journal: Blood (2021)