tbuckley/cabot-search huggingface dataset:
Abstract 13545: Patient-Specific Computational Flow Simulation Reveals Differences in Aortic Hemodynamics Between Two versus Four Vessel Fenestrated Endovascular Aneurysm Repair
Authors: Ken Tran, Adrien Kaladji, Weiguang Yang, Alison L Marsden, Jason Lee
Journal: Circulation (2021)

Objectives: Fenestrated endovascular aneurysm repair (fEVAR) endografts with additional proximal fenestrations are the subject of upcoming pivotal trials in the United States. This study sought to use patient-specific flow simulation (CFS) to assess differences in hemodynamics associated with two (2v) versus four-vessel (4v) fEVAR after repair of complex aortic aneurysms. Methods: Patients from two institutions who underwent 2v fEVAR for juxatrenal, and 4v fEVAR for pararenal aortic aneurysms with the Cook Zenith Fenestrated platform were retrospectively selected. Device diameters were matched between 2v and 4v groups. Finite element volume meshes were created from pre- and post-operative imaging. Pulsatile flow simulations were performed using a non-compressible Navier-Stokes solver with equivalent patient-specific boundary conditions between pre- and post-operative states. Results: Patient-specific CFS was performed on 20 patients (10 2v, 10 4v fEVAR) with a total of 70 target vessels (40 renal, 10 celiac, 10 superior mesenteric (SMA) stents, and 10 SMA scallops). 4v fEVAR was associated with a decrease in SMA peak flow rate (-7.1 vs +1.1%, p=.042) compared to 2v fEVAR. 4v fEVAR was associated with decreased paravisceral aortic wall shear stress (WSS) (-31.3 vs +0.6%, p=.008), whereas SMA WSS was increased (+36.9 vs +15.5%, p=.049) compared to 2v fEVAR. No differences in celiac or renal perfusion or WSS was observed between groups (p=.14-.93). Streamline visualization revealed flow disturbances surrounding flared branch graft protrusions into the aortic lumen which may be associated with changes in SMA perfusion after 4v fEVAR ( Figure ). In conclusion, structural changes in paravisceral aortic geometry following 4v fEVAR may be associated with a decrease in SMA perfusion and large reduction in aortic wall shear stress compared to 2v fEVAR. Patient-specific CFS is useful for studying the unique hemodynamic effects of additional fenestrations.
RBIO-01. DEVELOPING THE FRAMEWORK FOR TUMOR TREATING FIELDS (TTFIELDS) TREATMENT PLANNING FOR A PATIENT WITH ASTROCYTOMA IN THE SPINAL CORD
Authors: Jennifer de Los Santos, Smadar Arvatz, Oshrit Zeevi, Shay Levi, Noa Urman, Ariel Naveh, Tal Marciano
Journal: Neuro-Oncology (2021)

Abstract The use of Tumor Treating Fields (TTFields) following resection and chemoradiation has increased survival in patients with Glioblastoma. Patient-specific planning for TTFields transducer array placement has been demonstrated to maximize TTFields dose at the tumor: providing higher TTFields intensity (≥ 1.0 V/cm) and power density (≥ 1.1 mW/cm3) which are associated with improved overall survival. Treatment planning was performed for a 48 year old patient following T10-L1 laminectomy, gross total resection, and postoperative chemoradiation for an anaplastic astrocytoma of the spinal cord. An MRI at 3 weeks following chemoradiation showed tumor recurrence. Based on the post-chemoradiation MRI, a patient-specific model was created. The model was created by modifying a realistic computational phantom of a healthy female. To mimic the laminectomy, the lamina in T10-L1 was removed, and the region assigned electric conductivity similar to that of muscle. A virtual mass was introduced into the spinal cord. Virtual transducer arrays were placed on the model at multiple positions, and delivery of TTFields simulated. The dose delivered by different transducer array layouts was calculated, and the layouts that yielded maximal dose to the tumor and spine identified. Transducer array layouts, in which the arrays were placed on the back of the patient with one array above the tumor and one array below the tumor, yielded the highest doses at the tumor site. Such layouts yielded TTFields doses of over 3.4mW/cm3 which is well above the threshold dose of 1.1 mW/cm3 reported previously [Ballo et al. Red Jour 2019]. The framework developed for TTFields dosimetry and treatment planning for this spinal tumor will have the potential to increase dose delivery to the tumor bed while optimizing placement that may enhance comfort and encourage device usage.
PATH-35. AKT1(E17K) MUTATIONS ARE FREQUENT GENOMIC EVENTS IN CERVICAL SPINAL MENINGIOMAS
Authors: Majd Alkhatib, Gabriele Schackert, Tareq Juratli
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Spinal meningiomas represent about one-third of all spine tumors. To date, little is known about the molecular profile of spinal meningiomas and their clinical impact. In this study, we correlate clinical parameters with targeted sequencing findings in a well-characterized cohort of 42 patients with spinal meningiomas. METHODS Samples from 42 spinal meningiomas (31 females and 11 males) were collected. Targeted sequencing for AKT1 E17K hot spot mutations was performed. Furthermore, clinical and imaging data were collected and correlated with the AKT1 mutation status. RESULTS Gross total resection (Simpson grade I /II) was achieved in all patients. The mean follow-up period was 60 months (6 –288 months). None of the patients demonstrated a tumor recurrence. AKT1E17K mutations were detected in 8 patients (19%), in five male and three female patients (p= 0.019). Although the majority of resected meningiomas (n= 28, 66.6%) were located in the thoracic spine, meningiomas originating in the cervical spine harbored significantly more AKT1 E17K mutations (6 out of 14, p= 0.010). Notably, all AKT1 mutated meningiomas arose ventrally or ventrolaterally to the spinal cord. The histologic examination revealed a WHO Grade 1 in 36 meningiomas (85.7%): 21 meningothelial, 8 psammomatous, 5 transitional, 2 fibrous. The remaining six meningiomas were classified as atypical WHO grade 2. Remarkably, AKT1 E17K mutations were significantly related to a meningothelial subtype (p= 0.044). CONCLUSIONS Our molecular study demonstrates that AKT1 E17K mutations are a frequent genomic event in spinal meningiomas. The majority of AKT1 mutated meningiomas occurred in male patients, originate in the cervical spine, and exhibit meningothelial histology.
Abstract 11466: Deficiency of Microrna-1 Induces Cardiac Electrical and Metabolic Remodeling of the Heart
Authors: Dandan Yang, Xiaoping Wan, Omer Cavus, Saman Firoozi, Lalita Uttarwar, Neill Schwieterman, Kenneth R Laurita, Elisa A Bradley, Loren E Wold, Peter J Mohler, Isabelle Deschenes, Jidong Fu
Journal: Circulation (2021)

Introduction: MicroRNA-1 (miR1) is an evolutionarily conserved, striated muscle-enriched microRNA and plays critical roles in regulation of the development and physiology of the heart. It has been found that miR1 was downregulated in various types of cardiac diseases. We observed that, compared to that in young mice (age 3-4 months), the expression of miR1 was significantly decreased to the level of 12.5±4.0% in the heart of aged animals (age 18 months). Hypothesis: We hypothesized that miR1 deficiency is a major etiology in diseased and/or aged hearts. In the mammalian genome, two distinct genes, miR1-1 and miR1-2 that are located on two chromosomes, generate identical mature miR1. Methods and Results: To study the hypothesis, we generated miR1-75% knockdown (75%KD) mice by crossbreeding miR1-1 knockout (KO) and miR1-2 KO animals and found that miR1-75%KD mice could survive to adult age with a relatively higher mortality, while miR1-100%-KO is postnatal lethal. The ejection fraction and fraction shortening of 75%KD hearts was significantly decreased than that of WT animals. Electrocardiogram showed that, compared to the WT group, 75%KD hearts had significantly slower heart rates with shorter PR interval and prolonged QRS interval with observed premature ventricular contractions. Optical mapping of ex vivo hearts revealed significantly slower ventricular conduction velocity in 75%KD hearts. Compared to WT cells, 75%KD ventricular cardiomyocytes had hyperpolarized RMPs with prolonged action potentials, and showed significantly decreased sarcomere shortening. Proteomic assays found that proteins of mitochondrial ATP synthesis and electron transport were significantly downregulated in 75%KD hearts. Conclusions: We conclude that the deficiency of miR1 is a major etiological factor of cardiac electrical and metabolic remodeling in the heart. Restoring the normal level of miR1 in the heart could be a critical and effective therapeutic strategy to prevent and/or treat heart diseases.
CTIM-28. MDNA55, AN INTERLEUKIN-4 RECEPTOR TARGETED IMMUNOTHERAPY, FOR RECURRENT GBM DELIVERED BY CONVECTION ENHANCED DELIVERY (CED)
Authors: John Sampson, Achal Singh Achrol, Manish K Aghi, Krystof Bankiewiecz, Martin Bexon, Steven Brem, Andrew Brenner, Chandtip Chandhasin, Sajeel Chowdhary, Melissa Coello, Benjamin Ellingson, John Floyd, Seunggu Han, Santosh Kesari, Fahar Merchant, Nina Merchant, Dina Randazzo, Michael Vogelbaum, Frank Vrionis, Miroslaw Zabek, Nicholas Butowski
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND MDNA55 is an IL4R-targeted toxin in development for treatment of recurrent glioblastoma (rGBM). MDNA55 binds to IL4R expressed by tumor cells and non-malignant cells of the tumor microenvironment. METHOD MDNA55-05 was an open-label, single-arm study of MDNA55 delivered by CED as a single treatment in patients with 1st or 2nd recurrence following de novo GBM, IDH wild type status and not indicated for resection at relapse. Dose volumes (up to 60mL) and concentration of MDNA55 (1.5 to 9.0 μg/mL) were studied. RESULTS MDNA55 showed an acceptable safety profile at all doses tested. Median OS (mOS) amongst all subjects was 11.9 months, OS-24 was 20%, and PFS-12 was 27%. Among subjects expressing high levels of IL4R (irrespective of MDNA55 dose) and low levels of IL4R expression administered high dose (≥ 180μg) of MDNA55 (IL4Rhi + IL4Rlo/hd), mOS further improved to 14.0 months with OS-24 of 20%. Unmethylated MGMT promoter status did not affect MDNA55 treatment outcomes. In the IL4Rhi + IL4Rlo/hd population (N=17), mOS was 14.9 months with OS-24 of 22%. Following treatment with high concentrations of MDNA55 (6.0 or 9.0 μg/mL), transient (median of 3 cycles) low dose Avastin (5mg/kg q2w or 7.5mg/kg q3w) was used for symptom control and steroid sparring. Among these subjects, mOS amongst all comers (N=9) and the IL4Rhi + IL4Rlo/hd group (N=8) increased to 21.8 and 18.6 months with OS-24 of 44% and 38%, respectively. CONCLUSIONS MDNA55 shows potential to benefit all rGBM patients treated at high dose irrespective of IL4R expression. In the 1:1 randomized Phase 3 trial, the study will enrol two-thirds of subjects in the SOC arm from a matched external control arm. Unlike conventional RCTs, the hybrid design sets a new precedent for GBM trials, allowing robust OS analysis while significantly reducing the number of subjects randomized to SOC arm.
Mechanisms of oxygenation responses to proning and recruitment in COVID-19 pneumonia
Authors: Sandra Rossi, Maria Michela Palumbo, Nicola Sverzellati, Mattia Busana, Laura Malchiodi, Paolo Bresciani, Patrizia Ceccarelli, Emanuele Sani, Federica Romitti, Matteo Bonifazi, Simone Gattarello, Irene Steinberg, Paola Palermo, Stefano Lazzari, Francesca Collino, Massimo Cressoni, Peter Herrmann, Leif Saager, Konrad Meissner, Michael Quintel, Luigi Camporota, John J. Marini, Luciano Gattinoni
Journal: Intensive Care Medicine (2021)

This study aimed at investigating the mechanisms underlying the oxygenation response to proning and recruitment maneuvers in coronavirus disease 2019 (COVID-19) pneumonia.Twenty-five patients with COVID-19 pneumonia, at variable times since admission (from 1 to 3 weeks), underwent computed tomography (CT) lung scans, gas-exchange and lung-mechanics measurement in supine and prone positions at 5 cmH2O and during recruiting maneuver (supine, 35 cmH2O). Within the non-aerated tissue, we differentiated the atelectatic and consolidated tissue (recruitable and non-recruitable at 35 cmH2O of airway pressure). Positive/negative response to proning/recruitment was defined as increase/decrease of PaO2/FiO2. Apparent perfusion ratio was computed as venous admixture/non aerated tissue fraction.The average values of venous admixture and PaO2/FiO2 ratio were similar in supine-5 and prone-5. However, the PaO2/FiO2 changes (increasing in 65% of the patients and decreasing in 35%, from supine to prone) correlated with the balance between resolution of dorsal atelectasis and formation of ventral atelectasis (p = 0.002). Dorsal consolidated tissue determined this balance, being inversely related with dorsal recruitment (p = 0.012). From supine-5 to supine-35, the apparent perfusion ratio increased from 1.38 ± 0.71 to 2.15 ± 1.15 (p = 0.004) while PaO2/FiO2 ratio increased in 52% and decreased in 48% of patients. Non-responders had consolidated tissue fraction of 0.27 ± 0.1 vs. 0.18 ± 0.1 in the responding cohort (p = 0.04). Consolidated tissue, PaCO2 and respiratory system elastance were higher in patients assessed late (all p < 0.05), suggesting, all together, "fibrotic-like" changes of the lung over time.The amount of consolidated tissue was higher in patients assessed during the third week and determined the oxygenation responses following pronation and recruitment maneuvers.
Abstract 10857: Evaluating for Equity in a Safety Net Hospital: Socioeconomic Status, Adherence, and Outcomes in Cardiac Rehabilitation
Authors: Tulani Washington-plaskett, Joshua P Gilman, Na Wang, Stephanie Zombeck, Gary Balady
Journal: Circulation (2021)

Objective: To evaluate whether adherence and outcomes in cardiac rehabilitation are associated with socioeconomic status in a safety net hospital that provides care for a diverse patient population. Introduction: Uncovering the racial/ethnic health disparities that exist within cardiovascular medicine offers potential to mitigate treatment gaps that might affect outcomes. Since race is considered a social construct, socioeconomic status may be a more appropriate underlying factor to assess. The area deprivation index (ADI) reflects income, education, employment, and housing quality within a given 9-digit zip code. A higher ADI indicates more disadvantage (range 1-10). Methods: We identified 770 consecutive enrollees of the Cardiac Rehabilitation Program at Boston Medical Center from 2016-2020. The 9-digit zip codes of each enrollee were used to obtain their ADI. Associations between ADI and adherence (attending &gt;70% of sessions) was evaluated while controlling for age, sex, race, education, diagnosis, smoking and transport times. Secondary outcomes included associations of ADI with change in exercise capacity, LDL cholesterol, weight, quality of life, nutrition, and depression scores. Results: Among 770 enrollees, 197 had missing covariates and 147 did not have a zip code with associated ADI, leaving 426 patients for analysis. Enrollees had a mean age of 59.8 years, 34% were female, 44% self-reported as black and 9% as Hispanic. The ADI for patients varied (mean =5; median =6) ( Figure 1 ). The primary outcome adjusted for age, sex, race, education, diagnosis, smoking, and transport time, revealed no association for ADI with adherence to cardiac rehab (OR, 1.03 95% CI:0.99-1.07) or attendance rate (OR, 0.98 95% CI: 0.96-1.004). Secondary outcomes improved among patients regardless of ADI. Conclusion: In our safety net hospital that provides care without exception, we found equity in cardiac rehabilitation program outcomes despite socioeconomic status.
Abstract 13294: Percutaneous Coronary Intervention in Cancer Patients Using Drug Eluting Stent Compared With Bare Metal Sent
Authors: Homam Moussa Pacha, Talha Ahmad, Antoine Addoumieh, Nikhil Agrawal, Juhee Song, Susan C Gilchrist, Salman A Arain, Abhijeet Dhoble, Cezar Iliescu
Journal: Circulation (2021)

Introduction: It is unclear whether bare-metal stent (BMS) use in cancer patient is associated with similar outcome compared with drug-eluting stent (DES). We aim to compare outcome of percutaneous coronary intervention (PCI) in cancer patient who were treated with BMS versus DES. Methods: We identified cancer patients who underwent PCI using BMS or DES between 2013 and 2020. Outcome of interest was overall survival and number of revascularizations. Kaplan-Meier method was used to estimate the survival probability. Multivariate Cox regression model were utilized to compare overall survival between BMS and DES. Results: We included 347 cancer patients who underwent PCI with median follow-up of 34.1 months (95% CI, 28.4-38.7). 42 patients were treated with BMS (12.1%) and 305 with DES (87.9%). Age and gender were similar between BMS and DES groups (p = 0.08 and 0.94 respectively). DES use was more frequent in Caucasians while African American patients had more BMS (p=0.03). There was no significant difference in number of revascularizations between BMS and DES groups (p=0.36). Median survival was 46 months (95%CI, 34-66) with no significant difference in overall survival between BMS and DES groups in multivariate analysis (p = 0.37). Independent predictors for survival include age &gt; 65 (hazard ratio [HR]:1.53 [95% CI, 1.046-2.240]), BMI &gt; 30 (HR:0.58 [95% CI, 0.374-0.895) and hemoglobin level &gt; 12 mg/dl (HR:0.44 [95% CI, 0.303-0.639]). Conclusions: PCI using bare-metal stent in cancer patients appears to be associated with similar overall survival and number of revascularizations compared with drug-eluting stent.
NCOG-41. HISTOLOGICAL ANALYSIS OF SLEEP AND CIRCADIAN BRAIN CIRCUITRY IN CRANIAL RADIATION-INDUCED HYPERSOMNOLENCE (C-RIH) MOUSE MODEL
Authors: Dorela Shuboni-Mulligan, Demarrius Young Jr., Julianie De La Cruz Minyety, Nicole Briceno, Amanda King, Mark Gilbert, DeeDee Smart, Terri Armstrong
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Disrupted sleep, including daytime hypersomnolence, is a core symptom reported by primary brain tumor patients and often manifests after radiotherapy. The biological mechanisms driving cranial radiation-induced hypersomnolence (C-RIH) remain unclear but we hypothesize this may result from damage to neural circuits controlling sleep behavior. We developed a mouse model of C-RIH to explore the impact of radiation on the brain: examining region-specific differences in acute DNA damage response and neuroanatomic structure. METHODS Mice received whole brain radiation then behaviors were monitored using PhenoTyper® cages to determine optimal dose and long-term effects. To test short-term neurologic effects, brains were collected 1hr post-radiation then stained for γH2AX, a signal for DNA damage. Long-term effects were quantified 1-month post-treatment using neuroimaging to determine brain volume and T1 mapping changes in regions associated with sleep, circadian rhythms, and cognition. RESULTS Mice displayed decreased general activity and increased daytime sleep in a dose-dependent and sustained manner. Histologic staining demonstrated that DNA damage following radiation varies across the brain, with homeostatic sleep regions and cognitive regions expressing higher levels of γH2AX than the circadian suprachiasmatic nucleus. These findings were supported by in vitro studies comparing radiation effects in SCN and cortical astrocytes using both trypan blue (F(1,18)=235.937, p&amp;lt; 0.001) and clonogenic assays (F(1,24)=40.796, &amp;lt; 0.001). Brain volumes were significantly smaller in irradiated than sham animals in the hippocampus (t(4)=3.833, p=0.019) and the pontine central grey (t(4)=3.504, p=0.025). T1 maps also showed significant changes in relaxation times in many cognitive regions but not sleep or circadian areas. CONCLUSIONS These findings suggest that the homeostatic sleep region and cognitive circuits are vulnerable to radiation and may be relevant to the development of treatment plans in patients. We plan to introduce intracranial tumor to the model to evaluate the impact of timing of treatment and C-RIH on survival.
Title: Efficacy and Safety of Ferric Derisomaltose for Treatment of Anemia in Chronic Kidney Disease Patients: A Systematic Review
Authors: Atif Irfan Khan, Anam Khan, Keren Sam, Fatima Sajid, Sara Ashraf, Ayesha Habib, Padma Sri Katikaneni, Karthi Vignesh Raj K, Usman Ali Akbar, Faiz Anwer
Journal: Blood (2021)
Abstract 11820: Physician-Adjudicated Heart Failure Phenotypes Among Patients With Chronic Inflammatory Diseases
Authors: Daniel Underberg, Adovich Rivera, Arjun Sinha, Matthew J Feinstein
Journal: Circulation (2021)

Objective: To characterize clinical phenotypes of incident heart failure (HF) among patients with various chronic inflammatory diseases (CIDs). Background: Several CIDs are associated with increased HF risk, but differences in HF phenotypes across CIDs are incompletely understood. No prior studies to our knowledge have adjudicated HF phenotypes with physician chart review across a spectrum of CIDs. Methods: We screened for patients with CIDs (and controls without CIDs) who had possible HF in a large urban medical system, then performed physician adjudication of HF endpoints. Possible HF was based on the intentionally sensitive criterion of a single inpatient or outpatient administrative code for HF; we then determined if HF was definite/probable vs. not present using standardized, validated criteria. Charts of patients with adjudicated HF were queried to define specific HF phenotypes. We then compared clinical, demographic, and HF phenotypic characteristics for HF patients with specific CIDs vs. non-CID controls using Fisher’s exact test. Results: Out of 415 patients with at least one code for HF, 192 had definite/probable HF. We observed significant differences in HF phenotypes across CIDs (Table 1). Isolated right-sided HF was more than twice as common in patients with scleroderma (27.8%) than in any other CID. Left ventricular systolic dysfunction was most common in patients with HIV and lupus (SLE); mean LVEF was 45.0% ± 18.6% for HIV and 41.3% ± 17.1% for SLE, while it was 57.7% ± 10.7% for scleroderma. Those with HIV and multiple CIDs were most likely to have coronary artery disease. Conclusions: Different CIDs are associated with different phenotypic presentations of physician-adjudicated HF, which may reflect different underlying inflammatory pathophysiologies. Future studies in larger, multi-center cohorts are needed to confirm these findings, as are mechanistic studies focused on understanding specific immunoregulatory contributors to HF.
A Phase 2 Open-Label, Multicenter, Dose Optimization Clinical Study of the Safety, Tolerability, and Pharmacokinetic (PK) and Pharmacodynamic (PD) Profiles of Cfi-400945 As a Single Agent or in Combination with Azacitidine or Decitabine in Patients with Acute Myeloid Leukemia, Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia (TWT-202)
Authors: Gautam Borthakur, Brian A. Jonas, Emily L Roberts-Thomson, Glenn C. Michelson, Mark R Bray
Journal: Blood (2021)
Blocking IFNγ in CAR-T Reduces Checkpoint Inhibitors and Cell-Mediated Toxicity without Compromising Therapeutic Efficacy in CD19 +malignancies
Authors: Stefanie R. Bailey, Sonika Vatsa, Rebecca Larson, Amanda A Bouffard, Irene Scarfò, Kathleen M.E. Gallagher, Matthew J. Frigault, Marcela V. Maus
Journal: Blood (2021)