tbuckley/cabot-search huggingface dataset:
Abstract 12807: Effects of Ischemic Pain Inducing Walking Exercise vs. Pain Free Walking Exercise on Walking Velocity and Functional Performance in Peripheral Artery Disease. Results From the Lite Randomized Clinical Trial
Authors: Michael Hammond, Shujun Xu, Lu Tian, Lihui Zhao, Dongxue Zhang, Mary M McDermott
Journal: Circulation (2021)

Introduction: The LITE randomized trial recently demonstrated that home-based pain free walking exercise did not improve 6-minute walk distance, compared to home-based ischemic pain inducing walking exercise, and compared to an attention control group, among people with lower extremity peripheral artery disease (PAD). This study examined effects of home-based pain free walking exercise and home-based ischemic pain inducing walking exercise on walking velocity, and the short physical performance battery (SPPB). Methods: 305 participants with PAD were randomized to home-based pain free walking exercise, home-based ischemic pain inducing walking exercise, or an attention control group in a multi-centered randomized trial, over 12 months. Participants in the pain free walking exercise group walked at a pace that did not cause ischemic leg symptoms. Participants in the ischemic pain inducing walking exercise group walked at a pace that caused ischemic leg symptoms. The attention control group received health education talks. Usual-paced 4-meter walking velocity (4MWV), fast-paced 4MWV, and SPPB (total score range: 0-12; 12=best) were measured at baseline and 12-month follow-up. Results: Of the 305 PAD participants randomized, 246 (mean age: 69 ± 9 years; 48% women; 60% black) with baseline or 12-month data on either usual-paced 4MWV, fast-paced 4MWV, or SPPB were included. The effects of the exercise interventions on each functional measure are shown in the table. Conclusion: These data suggest that ischemic pain inducing walking exercise improves walking speed and functional performance, while walking exercise at a comfortable pace may worsen walking velocity in PAD.
DDRE-02. PATIENTS WITH LEPTOMENINGEAL METASTASES FROM NSCLC BENEFITED FROM INTRATHECAL PEMETREXED AFTER FAILURE TO TYROSINE KINASE INHIBITORS: TWO CASE REPORTS
Authors: Minting Ye, Lei Wen, Jiangfen Zhou, Linbo Cai
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND The incidence of leptomeningeal metastasis (LM) is 3%-5% in NSCLC patients; the incidence is even higher in patients with EGFR mutations or ALK gene rearrangement. The prognosis of NSCLC patients with LM is poor with an overall survival (OS) of 3 months with contemporary treatment. METHODS Here we report two cases of patients with leptomeningeal metastases from NSCLC who benefited from intrathecal pemetrexed after failure to tyrosine kinase inhibitors(TKIs). RESULTS A 53-year-old woman, diagnosed with adenocarcinoma of the lung with ALK rearrangement, suffered form right limb weakness, dysphagia after multi-line targeted therapy and radiotherapy for brain metastases. Evaluation revealed a rapidly progressing right brainstem mass and diffuse leptomeningeal enhanced. And cytological examination of CSF showed neoplastic cells, which definitely diagnosed as LM. After first intrathecal injection of 30mg pemetrexed every three weeks, the patient's symptoms improved. There were no significant treatment side effects and the quality of life was not affected during the five subsequent treatments. Another patient was a 32-year-old man, diagnosed with adenocarcinoma of the lung with EGFR E24-RAD51E4 fusion mutation with KPS score 30. LM was confirmed after multiline therapy. He suffered form blurred vision and drooping eyelid. Similarly, after first intrathecal injection of 20mg pemetrexed every week, the patient's symptoms improved and KPS score increased gradually. And level II leukopenia was detected during subsequent treatments. Combined with intrathecal pemetrexed progression-free survival (PFS) were 3 months in two NSCLC patients with LM harboring ALK/EGFR mutation . And the quality of life of patients were effectively increased. CONCLUSION Combination therapy third generation EGFR/ALK agents with intrathecal chemotherapy might be benefited in overall survival.
Abstract 9009: Management of Renin-Angiotensin-Aldosterone System Blockade in Patients Admitted in Hospital With Confirmed Coronavirus Disease (COVID-19) Infection: The McGill RAAS-COVID-19 Randomized Controlled Trial
Authors: Abhinav Sharma, Malik Elharram, Jiayi Ni, Jonathan Afilalo, Alexandria Flannery, RN, Justin Ezekowitz, Matthew P Cheng, Andrew P Ambrosy, Faiez ZANNAD, Jay Brophy, Nadia Giannetti, Amal Bessissow, Nadine Kronfli, Ariane J Marelli, Haya Aziz, Mohammad AlQahtani, Mona Aflaki, Morgan Craig, Renato D Lopes, Joao P Ferreira
Journal: Circulation (2021)

Background: More data is needed on the cardiovascular impact of discontinuing versus continuing renin-angiotensin aldosterone system inhibitors (RAASi) among patients hospitalized with a severe acute respiratory syndrome coronavirus 2 infection (COVID-19). Methods: The McGill RAAS-COVID-19 trial was a randomized, open label trial in adult patients hospitalized with COVID-19, who were previously treated with RAASi (angiotensin converting enzyme inhibitors [ACEi]/angiotensin receptor blocker [ARB]) (NCT04508985; 10/2020-03/2021). Participants were randomized 1:1 to discontinue or continue RAASi. The primary outcome was a global rank score calculated from baseline to day 7 (or discharge) incorporating clinical events and biomarker changes. Global rank scores were compared between groups using the Wilcoxon test statistic and the negative binomial test (using incident rate ratio [IRR]). All analyses were conducted using the intention-to-treat principle. Results: Overall, 21 participants were randomized to discontinue RAASi and 25 to continue. Patients’ mean age was 71.5 years and 43.5% were female. Discontinuation of RAASi, versus continuation, resulted in a similar mean global rank score (discontinuation 6 [standard deviation [SD] 6.3] vs continuation 3.8 (SD 2.5); p= 0.60), but the negative binomial analysis identified that discontinuation increased the risk of adverse outcomes (IRR 1.7 [95% CI 1.1 to 2.6]; p=0.03). Particularly, RAASi discontinuation increased brain natriuretic peptide (BNP) levels (% change from baseline: +16.7% vs. -27.5%; p= 0.02) and increased the incidence of acute heart failure (33% vs. 4.2%, p=0.03). Conclusion: Discontinuation of RAASi increased BNP levels and risk of acute heart failure in participants hospitalized with COVID-19; where possible, RAASi should be continued.
MTHFR and SLCO1B1 Gene Polymorphism and Methotrexate Induced Toxicity in Children with Acute Lymphoblastic Leukemia in the Northwest of Mexico
Authors: Samantha Fierro Sáenz, Claudia Selene Portillo Zavala, Veronica Moreno Brito, Joel Dominguez Viveros, Everardo González Rodríguez
Journal: Blood (2021)
EPCO-09. LONGITUDINAL ANALYSIS OF DIFFUSE GLIOMA REVEALS CELL STATE DYNAMICS AT RECURRENCE ASSOCIATED WITH CHANGES IN GENETICS AND THE MICROENVIRONMENT
Authors: Frederick Varn, Kevin Johnson, Taylor Wade, Tathiane Malta, Thais Sabedot, Floris Barthel, Hoon Kim, Nazia Ahmed, Indrani Datta, Jill Barnholtz-Sloan, Spyridon Bakas, Fulvio D'Angelo, Hui Gan, Luciano Garofano, Jason Huse, Mustafa Khasraw, Emre Kocakavuk, Simona Migliozzi, David Ormond, Sun Ha Paek, Erwin Van Meir, Annemiek Walenkamp, Colin Watts, Michael Weller, Tobias Weiss, Pieter Wesseling, Lucy Stead, Laila Poisson, Houtan Noushmehr, Antonio Iavarone, Roel Verhaak
Journal: Neuro-Oncology (2021)

Abstract Diffuse glioma is characterized by a poor prognosis and a universal resistance to therapy, though the evolutionary processes behind this resistance remain unclear. The Glioma Longitudinal Analysis (GLASS) Consortium has previously demonstrated that therapy-induced selective pressures shape the genetic evolution of glioma in a stochastic manner. However, single-cell studies have revealed that malignant glioma cells are highly plastic and transition their cell state in response to diverse challenges, including changes in the microenvironment and the administration of standard-of-care therapy. To interrogate the factors driving therapy resistance in diffuse glioma, we collected and analyzed RNA- and/or DNA-sequencing data from temporally separated tumor pairs of over 300 adult patients with IDH-wild-type or IDH-mutant glioma. In a subset of these tumor pairs, we complemented these data with single-nucleus RNAseq and multiplex imaging mass cytometry at each time point. Recurrent tumors exhibited diverse changes that were attributable to changes in histological features, somatic alterations, and microenvironment interactions. IDH-wild-type tumors overall were more invasive at recurrence and exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. In contrast, recurrent IDH-mutant tumors exhibited a significant increase in proliferative expression programs that correlated with discrete genetic changes. Hypermutation and acquired CDKN2A homozygous deletions associated with an increase in proliferating stem-like malignant cells at recurrence in both glioma subtypes, reflecting active tumor expansion. A transition to the mesenchymal phenotype was associated with the presence of a specific myeloid cell state defined by unique ligand-receptor interactions with malignant cells, providing opportunities to target this transition through therapy. Collectively, our results uncover recurrence-associated changes in genetics and the microenvironment that can be targeted to shape disease progression following initial diagnosis.
Abstract 8898: Biventricular Function is Impaired in RV Septal Pacing - A Prospective Study Using Myocardial Strain Imaging
Authors: Liam Toner, Janet Chen, Jay Ramchand, Piyush M Srivastava, David O'Donnell, Paul Calafiore, Elizabeth Jones
Journal: Circulation (2021)

Introduction: Left ventricular (LV) dysfunction is observed after right ventricular (RV) pacing from both apical and septal positions. Hypothesis: The primary aim of this study was to assess the impact of RV mid-septal pacing upon RV function using the novel parameter of speckle-tracking derived RV global longitudinal strain (RVGLS), as well as the conventional parameters RV fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE) and tricuspid annular systolic velocity (RV S’). Secondary aims included assessing the impact on LV function and the correlation of pacing burden with echocardiographic parameters. Methods: Thirty-two consecutive patients (mean age 75 ± 10 years) with normal baseline LV and RV function requiring permanent pacemaker insertion were prospectively recruited at a tertiary hospital in Melbourne, Australia. 3 patients were excluded due to poor image quality. Echocardiography was performed prior to implantation, at 1-day, 1-month and 1-year post-implantation, with 29 patients completing follow-up. Results: Compared to 1-day post-implantation, at 1-year a significant decline was noted in mean RV S’ (15.1 to 12.2cm/s), TAPSE (24.2 to 21.9mm), RV GLS (-24.8 to -21.8%), LVEF (66.0 to 57.9%), LV GLS (-19.9 to 17.0), all p &lt;0.01. There was no change in RV FAC (49.1 to 46.9%). Fourteen patients (44%) required a high proportion of ventricular pacing, defined as ≥10% at 1 year. These patients had a greater deterioration in RVGLS (5.0 vs 1.0%) and LVGLS (4.6 vs 0.68%), p &lt;0.05. Changes in RV S’ (3.1 vs 2.7cm/s), TAPSE (1.5 vs 3.1mm), RV FAC (1.9 vs 5.64%) and LVEF (9.5 vs 5.6%) were not significantly different from those in patients with &lt;10% ventricular pacing. Conclusions: RV and LV systolic function declined in all patients after 1 year of RV septal pacing. Further, patients with a high burden of ventricular pacing had a larger deterioration in RVGLS and LVGLS. Myocardial strain may be more useful than conventional echo parameters in detecting RV and LV dysfunction associated with RV septal pacing.
Abstract 14441: Anemia is Associated With Coronary Microvascular Dysfunction and Future Adverse Outcomes in Patients With Non-Obstructive Coronary Artery Disease
Authors: Ilke Ozcan, Ali Ahmad, Takumi Toya, Jaskanwal D Sara, Michel Corban, Nazanin Rajai, Lilach Lerman, Amir Lerman
Journal: Circulation (2021)

Introduction: Coronary microvascular dysfunction (CMD) is associated with increased morbidity and mortality. Anemia is an important predictor of outcomes in several cardiovascular diseases, such as heart failure and coronary artery disease (CAD), however its significance in patients with non-obstructive CAD is not fully elucidated. Hypothesis: We hypothesized that anemia would be associated with CMD and future adverse outcomes. Methods: We enrolled 1334 patients with signs and/or symptoms of ischemia and with non-obstructive CAD (&lt;50% angiographic stenosis) who underwent invasive CMD evaluation and had follow-up data. CMD was defined as coronary flow reserve (CFR) (hyperemic flow/baseline flow as measured by the doppler wire) of ≤2 in response to intracoronary adenosine injection. Anemia was defined as a Hgb &lt; 13.0 g/L in males and &lt;12.0 g/L in females. MACE was defined as any incidence of myocardial infarction, cardiac revascularization (PCI, CABG) and all-cause mortality. Results: Overall mean age was 51.3±12.4 years, 66% were female. Patients with anemia were more likely to be female and have diabetes mellitus. Anemics were more likely to be diagnosed with CMD (Odds Ratio 2.01, 95% Confidence Interval [1.14-3.54]; P = 0.02). This relationship remained significant even after adjusting for cardiovascular risk factors like age, sex, hypertension, diabetes mellitus and dyslipidemia (OR 1.84, 95% CI [1.03-3.29], P = 0.04). Furthermore, patients with anemia were more likely to experience MACE (OR 1.86, 95% CI [1.30-2.66], P = 0.001), independent of possible confounders (OR 1.84, 95% CI [1.27-2.69], P = 0.002). Conclusions: Anemia is an independent predictor of CMD and future adverse cardiovascular events in patients with NOCAD. Moreover, it was associated with an increased risk of future adverse events. Further studies are needed to elucidate whether treatment of anemia in this population translates into outcomes.
Accumulation of Intracellular L-Lactate and Irreversible Disruption of Mitochondrial Membrane Potential upon Dual Inhibition of Oxphos and Lactate Transporter MCT-1 Induce Synthetic Lethality in T-ALL Via Mitochondrial Exhaustion
Authors: Natalia Baran, Shraddha Patel, Alessia Lodi, Jose Enriquez Ortiz, Yogesh Dhungana, Meghan Collins, Anna Skwarska, Connie Weng, Cassandra L Ramage, Kala Hayes, Zhihong Zeng, Eric Davis, Gheath Alatrash, Joseph R Marszalek, Jiyang Yu, Pratip K Bhattacharya, Stefano Tiziani, Marina Konopleva
Journal: Blood (2021)
RADT-33. LONG-TERM OUTCOMES, TREATMENT UTILIZATION, AND PROGNOSTIC FACTORS FOR PEDIATRIC CHORDOMA: AN NCDB ANALYSIS
Authors: James Cantrell, Pawan Acharya, Sara Vesely, Michael Confer, Ozer Algan, Tyler Gunter
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Chordomas are rare tumors arising from the embryonal notochord presenting at the base of skull, spine, or sacrum. Pediatric chordomas (PC) comprise less than 5% of all chordomas and are more likely to be atypical or dedifferentiated. Evidence for management is limited to single institution series with 5-year overall survival (OS) between 60-100%. METHODS Using the NCDB Participant User File, a retrospective observational cohort study was performed. The cohort was defined using the bone-soft-tissue, brain, and central nervous system databases selecting for cases with chordoma ICD-03 codes and age ≤ 25 years. Kaplan Meier method, log-rank test, and Cox proportional hazards regression were performed. RESULTS 297 patients from 2004-2017 met inclusion criteria for descriptive analysis with 269 cases included for survival analysis. Mean age was 16.9 years, with 10% less than age 5. The cohort was 55% female, 8% Black, and 79% White. Primary sites included bones of the skull (70%), spine (22%), and pelvis (6%). Regarding treatment, 7% had no resection, 49% sub-total resection (STR), 33% gross-total resection (GTR), and 11% unspecified resection. 51% received radiation therapy with 46% of those receiving proton therapy. 7% received chemotherapy. The 1, 3, 5, and 10-year OS was 95%, 86%, 77%, and 72%. Selected prognostic factors from univariable OS model for OS analysis included: age &amp;gt; 5 (HR 0.30 (95% CI 0.16-0.57) p = 0.0002), surgical resection [GTR (HR 0.28 (95% CI 0.12-0.63) p = 0.0023) and STR (HR 0.27 (95% CI 0.12-0.59) p = 0.0011)], and radiation dose ≥ 7200cGy (HR 0.40 (95% CI 0.16-0.99) p = 0.047). CONCLUSION In the largest cohort reported for PC, 3 and 10-year OS was 86% and 72%. Age, surgery, and radiation dose are important prognostic factors. Propensity score analysis to gauge effect of treatment, tumor, and patient characteristics on OS is forthcoming.
Abstract 10608: Genome-Wide Association Study Identifies Polymorphisms Associated with Heart Failure Mortality in a Diverse Patient Population
Authors: Yimei Huang, Leanne Dumeny, Guang Yang, Christelle Lteif, Meghan J Arwood, Caitrin W McDonough, Ankit A Desai, Larisa H Cavallari, Julio D Duarte
Journal: Circulation (2021)

Introduction: Few genome-wide association studies (GWAS) of heart failure (HF) mortality have been published, with most focused on incidence or surrogate endpoints. Our aim was to identify genomic predictors of HF mortality in a racially diverse population. Hypothesis: Both ancestry-specific and trans-ancestry variants are associated with survival in HF patients. Methods: HF patients with preserved or reduced ejection fraction from the University of Illinois Chicago cardiology clinics were prospectively enrolled and followed until 11/2015. Whole blood was collected. Clinical data were retrospectively acquired through medical records. Genotyping was performed via Affymetrix Axiom Pan-African Array and imputed via TOPMed Imputation Server. Genetic ancestry (African/non-African) was assigned by principal component (PC) analysis. Within each ancestral population, associations between genetic variants and all-cause mortality were assessed by Cox regression model, adjusted for age, sex, NYHA class, HF medication regimen, and PCs. A trans-ancestry fixed-effect meta-analysis was then conducted. P &lt; 5.0 x 10 -8 was considered statistically significant. Results: The cohort included 319 HF patients (age 63 ± 13 yrs, 51% men, median follow-up 33 mos), comprised of 237 African ancestry (AA) (134 deaths) and 82 non-AA subjects (41 deaths). In the AA GWAS, 5 loci reached genome-wide significance. The top single nucleotide polymorphism (SNP), rs142008984 on chromosome 1 ( P = 5.21 x 10 -10 , HR = 8.55, 95%CI 4.34 - 16.82), resides in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene. No SNPs in the non-AA GWAS reached the defined significance level, and the AA-associated NOS1AP SNPs were not present in non-AA. Meta-analysis revealed 2 additional significant loci, among which was the top SNP on chromosome 6, rs79027708 ( P = 1.43 x 10 -9 , HR = 0.15, 95% CI 0.08 - 0.28), in the phosphodiesterase 10A ( PDE10A) gene. Conclusions: This study identified novel loci associated with all-cause mortality in a racially diverse HF population. NOS1AP and PDE10A have previously been associated with sudden cardiac death, cardiac hypertrophy, and fibrosis risk. Risk variants specific to AA were also identified, which may contribute to the lower survival in this population.
Risk of candidiasis associated with interleukin-17 inhibitors: A real-world observational study of multiple independent sources
Authors: Linda Davidson, Juul M.P.A. van den Reek, Mariolina Bruno, Florence van Hunsel, Ron M.C. Herings, Vasiliki Matzaraki, Collins K. Boahen, Vinod Kumar, Hans M.M. Groenewoud, Frank L. van de Veerdonk, Mihai G. Netea, Elke M.G.J. de Jong, Bart Jan Kullberg
Journal: The Lancet Regional Health - Europe (2021)

Biologics directed against the T-helper (Th)-17 pathway have been approved for several inflammatory diseases. Interleukin (IL)-17 is involved in anti-Candida host defense, and clinical trials suggested increased candidiasis incidence during IL-17 inhibitor therapy. We describe the worldwide epidemiology of candidiasis during Th17 inhibitor therapy, and immunological mechanisms involved in candidiasis susceptibility. A comprehensive analysis of multiple independent sources reporting Candida adverse events during biologics inhibiting the Th17 pathway was performed. Association between Th17 inhibitors and candidiasis was assessed using safety reports of (1) WHO and (2) EMA, (3) a population-based prescriptions registry, and (4) a psoriasis cohort. In a cohort of psoriasis patients experiencing candidiasis during Th17 inhibitors, Candida killing by immune cells and serum inflammatory proteome were analyzed. A strong association between IL-17 inhibitors and candidiasis (ROR 10·20) was found in the WHO database, particularly for cutaneous (ROR 12·28), oropharyngeal (ROR 19·18), and esophageal candidiasis (ROR 21·20). Risk was higher relative to TNF-α inhibitors (4–10-fold, depending on candidiasis type), confirmed by EMA reports (16–33-fold), prescriptions registry (2–42-fold), and a psoriasis cohort (3–25-fold). After start of IL-17 inhibitors, patients' risk of candidiasis requiring antifungals increased 2–16 fold. In the psoriasis cohort, 58% of IL-17 treatment episodes were associated with candidiasis. In Th17 inhibitor recipients, proteins involved in anti-Candida immunity and Candida killing by mononuclear leukocytes were impaired. IL-17 inhibitors are associated with an increased risk of oropharyngeal, esophageal, and cutaneous candidiasis, posing a significant disease burden for IL-17 inhibitor recipients. RadboudUMC.
Abstract 9729: Totum-070 Prevents Diet-induced Hyperlipidemia in High Fat High Cholesterol Fed Hamsters
Authors: Cedric Langhi, Yolanda F Otero, Florian Le Joubioux, Bruno Guigas, Sébastien PELTIER, Pascal Sirvent
Journal: Circulation (2021)

Low-density lipoprotein cholesterol (LDL-Chol) is a well-established modifiable risk factor for cardiovascular disease. TOTUM-070 (T070) is a clinical stage patented blend of biomolecules extracted from 5 plant extracts with high content of polyphenols. We tested the hypothesis that T070 administration prevents hyperlipidemia in Syrian hamsters and explored the potential mechanisms involved. Hamsters were fed either normal diet (ND) or high fat high cholesterol diet (HFHCD) with or without T070 mixed at 3.5%, 4.25% and 5% in the diet for 12 weeks (n=16 per group). During the study duration, no effect of T070 on food intake was observed. At the end of the study, no effect of T070 on the final body weight was noticed when hamsters were supplemented with T070 in comparison to the HFHCD group. HFHCD feeding led to a 5-fold increase in blood total cholesterol compared to ND (1141± 49mg/dl vs 221.4 ± 8.8 mg/dl, respectively, p&lt;0.0001), and a 13-fold increase in non-HDL Chol compared to ND (866 ± 43 mg/dl vs 65 ± 9 mg/dl, respectively, p&lt;0.0001). Compared to the HFHCD group, the 3 groups supplemented with T070 at 3.5%, 4.25% and 5% exhibited a dose-dependent decrease in total-Chol (788 ± 61 mg/dl, n.s; 678 ± 41 mg/dl, p&lt;0.01 and 667 ± 37 mg/dl, p&lt;0.01, respectively) and non-HDL Chol (542 ± 61 mg/dl, p&lt;0.05; 455 ± 37 mg/dl, p&lt;0.01 and 455 ± 33 mg/dl, p&lt;0.01, respectively). Serum triglyceride (TG) levels were increased to 1018 ± 103 mg/dl in HFHCD vs. ND (256 ± 24 mg/dl, p&lt;0.0001). T070 had a dose-dependent effect on serum TG levels reduction (709 ± 91 mg/dl T070 3.5%, p&lt;0.05; 605 ± 56 mg/dl T070 4.25%, p&lt;0.001; and 547 ± 57 mg/dl T070 5%, p&lt;0.001) in comparison to the HFHCD group. Analysis of hepatic lipid content revealed strong lipid accumulation in HFHCD (92-fold increase vs ND), while lipid content decreased by 36%, 52% and 44% in the 3.5, 4.25 and 5% supplemented groups, respectively. Lipid metabolism-related gene expression in liver and intestine was altered upon HFHCD compared to ND but tended to return to normal levels in T070 groups. Collectively, our results highlight the beneficial effect of T070 in the management of moderate cholesterol levels.