tbuckley/cabot-search huggingface dataset:
DDRE-08. A BIOANALYTICAL LC-MS/MS ASSAY TO QUANTIFY TOTAL AND UNBOUND LY3214996, ABEMACICLIB AND ITS ACTIVE METABOLITES IN HUMAN PLASMA, CEREBROSPINAL FLUID AND HUMAN GLIOBLASTOMA
Authors: Tigran Margaryan, Mackenna Elliott, Garry Hook, Nader Sanai, Artak Tovmasyan
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Here, we report on our development and validation of a sensitive and rapid LC-MS/MS method for the determination of total and unbound concentrations of ERK inhibitor LY3214996, CDK4/6 inhibitor abemaciclib and its M2 and M20 active metabolites in human plasma, cerebrospinal fluid and human glioblastoma tissue. METHODS Analytes were extracted from patient plasma, CSF and glioblastoma homogenate samples by protein precipitation with methanol. Four levels of quality controls were used during validation. The method was validated according to FDA guidelines and CAP/CLIA regulations. Equilibrium dialysis was performed to determine unbound fraction of four analytes in plasma and brain tissue. The detection was performed on Sciex QTRAP 6500+ mass spectrometer in positive electrospray ionization mode. RESULTS The method was validated over a concentration range from 0.2-500 nmol/L for all four analytes. The analytical separation was optimized on Phenomenex Kinetex™ F5 column with total run time of 3.8 min using gradient elution. For all the analytes the maximum coefficient of variation for intra- and inter-day precision was 12.0% and the accuracy was within 90.2-119.7% in all matrixes. The analytes are stable in plasma and brain homogenate for at least 19 hours and 6 hours at room temperature (RT), respectively. Stability of stock and working solutions was demonstrated for at least 15 hours (RT) and 28 days (2-8°C). The unbound fraction of the analytes in pooled human plasma and brain were determined to be 0.371 and 0.065 for LY3214996, 0.026 and 0.013 for abemaciclib, 0.052 and 0.008 for M2, 0.024 and 0.021 for M20, respectively. CONCLUSIONS A bioanalytical method to quantify LY3214996, abemaciclib and its M2 and M20 metabolites is successfully developed and validated. The method is currently applied to evaluate plasma pharmacokinetics and CNS penetration of LY3214996 and abemaciclib in recurrent glioblastoma patients in an ongoing Phase 0 clinical trial (NCT04391595).
BIOM-05. CASE SERIES OF MULTI-INSTITUTIONAL UTILITY OF CNSide TO MANAGE LEPTOMENINGEAL DISEASE IN PATIENTS WITH METASTATIC BREAST CANCER
Authors: Priya Kumthekar, Barbara Blouw, Julie Mayer, Deanna Fisher, Michael Dugan, Amir Azadi, Nicholas Blondin
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Leptomeningeal Disease (LMD) occurs in 5% of breast cancer patients. Diagnosing LMD remains challenging. Current standard of care has limited sensitivity and is inadequate for monitoring treatment response. Biocept’s CNSide™ is a proprietary assay utilizing a 10-antibody capture cocktail with microfluidic chamber that quantitatively detects tumor cells in the cerebrospinal fluid (CSF). We present a case series using CNSide to manage LMD of 4 unique breast cancer patients treated at three different institutions and demonstrate its impact on clinical management. METHODS Patients were treated at Smilow Cancer Hospital at Yale-New Haven (1 patient), Northwestern Medicine Lou and Jean Malnati Brain Tumor Institute (1 patient) and Barrow Neurological Institute (2 patients). All patients received intrathecal treatment (IT) via an Ommaya Reservoir. CSF tumor cells were detected via cytology and CNSide at diagnosis (3 patients) and throughout treatment (4 patients). RESULTS At diagnosis, CNSide detected tumor cells in 3/3 patients, vs 2/3 patients for cytology. The fourth patient was diagnosed with LMD before CNSide was available. CNSide detected CSF tumor cells in 9/9 (100%) of measurements, vs 4/9 (44%) for cytology for samples analyzed in parallel. Throughout treatment, CNSide was able to track the quantitative LMD response and showed a decrease in CSF tumor cells in all four patients, ranging from 99.7% (from 773 to 2 cells, 1 patient) to 100% (from 4447 to 0 cells; and from 33 to 0 cells, 2 patients). CONCLUSION Intrathecal treatment of LMD via Ommaya reservoir is not widely adopted across the US. Our experience suggests that using CNSide for quantitative CSF tumor cell detection may aid in diagnosing LMD, as well as in quantifying response to treatment particularly in the setting of intrathecal therapy. However, larger prospective clinical trials are needed to establish the role of CNSide in the diagnosis and management of LMD.
BRMP-01. Awake cranial surgery with intraoperative language mapping for brain tumors. A single-center experience
Authors: Andrés Cervio, Sebastían Giovannini, Sonia Hasdeu, Lucía Pertierra, Blanca Diez
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Maximal safe resection of brain tumors affecting language areas has been a matter of increasing interest worldwide in the last decades. Functional MRI, tractography, and awake cranial surgery are standard procedures in our department since 2006. The aim of this study was to describe our experience in a series of 58 patients who underwent awake cranial surgery with intraoperative language mapping. METHODS Retrospective study of 58 adult patients who underwent awake surgery for brain tumors between January 2006 and January 2021. Preoperative neuropsychological assessment served as inclusion criteria. Language was evaluated according to the BDAE (Boston diagnostic aphasia examination) and WAB (Western aphasia battery) and strength according to the MRC (Medical Research Council) motor scale in the preoperative, immediate postoperative, and 3-months follow up. Functional MRI and tractography depicting white-matter tracts, neuronavigation, cortical and subcortical stimulation were performed in all cases. Conscious sedation was the anesthetic technique (propofol, fentanyl, and NSAIDs). Minimum follow-up was 6 months. FINDINGS The average age was 35 years (16–74). The anatomopathological findings were: low-grade glioma in 75,8% (n = 44), high-grade glioma in 15,6% (n = 9) and others in 8,6% (n = 5). No complications were registered during postoperative course. At the immediate postoperative evaluation 65% of patients presented with speech disturbances but at the 3-months follow up speech recovery was observed in all cases. Only 1 patient remained with moderate aphasia. mRS score at 3- months follow up was ≤ 1 in 96% of patients. Two patients had a persistent moderate hemiparesis. CONCLUSION Tumor resection in awake patients showed to be a safe procedure, and well tolerated by the patients. Preoperative planning of anatomical and functional aspects and intraoperative neurophysiological assessment are the cornerstones for pursuing maximal safe resection.
Abstract 12049: Orthostatic Hypertension is Associated With Lower Plasma aβ <sub>42</sub> /aβ <sub>40</sub> Ratio: The Multidomain Alzheimer Preventive Trial (MAPT)
Authors: Laure Rouch, Yves Rolland, Olivier Hanon, Jean-Sébastien Vidal, Sandrine Andrieu, Philipe de Souto Barreto, Bruno Vellas
Journal: Circulation (2021)

Introduction: Orthostatic hypertension (OHYPER), an emerging hemodynamic cardiovascular risk factor, is associated with cardiovascular events and mortality. Recent findings indicated that it could be an important risk factor for cognitive decline and dementia, including Alzheimer’s disease (AD). Hypothesis: We aimed to assess the association between OHYPER and low plasma Aβ 42 /Aβ 40 ratio, a surrogate biomarker for brain amyloidosis. Methods: We included 483 non-demented community-dwelling participants aged ≥ 70 years from the Multidomain Alzheimer Preventive Trial (MAPT). OHYPER was assessed at baseline and defined as an increase of at least 20 mmHg in systolic blood pressure (BP) and/or 10 mmHg in diastolic BP after standing. Plasma Aβ 42 and Aβ 40 were measured at 12 months, using an immunoprecipitation and liquid chromatography-mass spectrometry assay. Low plasma Aβ 42 /Aβ 40 ratio was defined as ≤ 0.107. Logistic regression models were used to assess the association between OHYPER and low plasma Aβ 42 /Aβ 40 ratio. Results: Of 483 participants (mean age 76 years, 59% female), 113 (23.6%) had OHYPER and 161 (33.3%) low plasma Aβ 42 /Aβ 40 ratio. OHYPER was associated with low plasma Aβ 42 /Aβ 40 ratio (OR = 1.58, 95% CI [1.02-2.44]) in unadjusted models. Adjustment for age, sex, education, MAPT randomization group, lying BP, antihypertensive drug use, MCI, and presence of 1 or 2 ApoE ε4 alleles did not change the results (OR = 1.67, 95% CI [1.02-2.72]). Sensitivity analyses using the 25 th percentile of plasma Aβ 42 /Aβ 40 ratio (≤ 0.103) as an alternative cutoff and long-term OHYPER (at least two-thirds of visits over 12 months) reported consistent findings. Conclusions: OHYPER was associated with lower plasma Aβ 42 /Aβ 40 ratio in community-dwelling older adults, even after accounting for potential confounders. Monitoring OHYPER may have clinical utility for identifying patients who are at risk for cognitive decline, AD or in the preclinical stages of the disease.
NCMP-06. THE RISK AND BURDEN OF THROMBOEMBOLIC AND HEMORRHAGIC EVENTS IN PATIENTS WITH MALIGNANT GLIOMA RECEIVING BEVACIZUMAB
Authors: Alexander Ou, Heather Lin, Ying Yuan, Charles Bornstein, Kristin Alfaro-Munoz, Vahid Afshar-Kharghan, Carlos Kamiya-Matsuoka, Nazanin Majd
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Patients with high-grade gliomas (HGG) often receive anti-angiogenic therapy with bevacizumab to slow disease progression and/or palliate neurological symptoms. Bevacizumab has been associated with an increased risk of two major vascular complications: venous thromboembolism (VTE) and intracranial hemorrhage (ICH). We sought to identify clinical, pathologic, and radiographic variables correlated with risk of either event occurring in patients with HGG receiving bevacizumab. METHODS We retrospectively identified 94 patients with HGG who received bevacizumab at our center from 2015-2021. Variables included demographics, performance status, IDH, MGMT, vascular risk factors, baseline anti-coagulant/anti-platelet use, concurrent chemotherapy, and presence of macrobleeds on MRI (&amp;gt;1 cm3 susceptibility) at the time of bevacizumab initiation. We conducted competing risk analysis using subdistribution hazard models with death as competing risk for ICH or VTE. The effects of covariates on the incidence of hemorrhage or VTE were evaluated in univariate and multivariate settings. RESULTS Of 94 patients, 36 (38.3%) and 27 (28.7%) developed VTE and ICH, respectively. 31 (33%) did not develop either. ICH and VTE events occurred after a mean of 4.46 and 5.94 cycles of bevacizumab, respectively. 20 had baseline anti-platelet/anticoagulant use, and 16 had prior VTEs. Patients with macrobleeds on MRI had a larger HR of developing acute hemorrhage [HR=2.368 (1.112, 5.043), p=0.0254]. Patients older than 50 trended toward larger HR of developing VTE in univariate analysis that approached significance [HR=1.799 (0.889, 3.637), p=0.1023]. Sex, performance status, IDH, MGMT, vascular risk factors, baseline anticoagulant/anti-platelet use and concurrent chemotherapy were not significantly associated with occurrence of VTE. CONCLUSIONS The presence of macrobleeds on MRI is associated with increased risk of developing acute ICH while on bevacizumab. Older age at diagnosis of HGG may be associated with an increased risk of VTE in patients receiving bevacizumab. Larger studies are needed to confirm these findings.
Abstract 11526: Nardilysin is a Potential Biomarker for the Early Diagnosis of Non-St-Segment Elevation Acute Coronary Syndrome, A Multicenter Prospective Cohort Study, Nardi-ACS Study
Authors: Mikiko Ohno, hiroki shiomi, Mariko Yano, Takanori Aizawa, Yukiko Nakano, Shintaro Yamagami, Masashi Kato, Masanobu Ohya, Po-Min Chen, Kazuya Nagao, Kenji Ando, Kazushige Kadota, Takafumi Yokomatsu, Inada Tsukasa, masato kurokawa, Takeshi Morimoto, Takeshi Kimura, Eiichiro Nishi
Journal: Circulation (2021)

Background: Rapid and accurate diagnosis of acute coronary syndrome (ACS) is critical to prevent the fatal complication accompanied with the delay of the treatment. However, the diagnosis of non-ST-segment elevation ACS (NSTE-ACS), especially shortly after the onset, is not straightforward because even high-sensitivity cardiac troponin (hs-cTn) is sometimes not elevated at that phase. We previously reported in a retrospective study that serum nardilysin is a potential biomarker for the early detection of NSTE-ACS. Here, we present the results of the Nardi-ACS study, a multicenter prospective study conducted at six centers in Japan to clarify the significance of nardilysin for the early detection of ACS. Methods and Results: We analyzed serum nardilysin and hs-cTnI (Architect; Abbott) in the sequential 2 independent cohorts; phase I primary cohort (435 patients with chest pain who consecutively visited to the emergency room (ER)) and phase II validation cohort (486 patients with a strong suspicion of ACS who underwent coronary angiography). The frequency of non-ACS, STEMI and NSTE-ACS was 64.4, 22.5, and 13.1 (%) in the phase I, and 14.0, 60.0, and 25.9 (%) in the phase II cohort, respectively. The cutoff value of serum nardilysin was set at 1350.9 pg/ml (mean +2SD) obtained in 246 healthy volunteers, while the cutoff of hs-cTnI was set at 52 pg/ml. The initial blood test in the phase I cohort revealed that nardilysin was significantly elevated in ACS patients, compared to non-ACS patients (p&lt;0.05). The sensitivity of hsTnI, nardilysin, and nardilysin combined with hsTnI for the diagnosis of NSTE-ACS was 52.6, 57.9, and 78.9 (%), and the negative predictive value (NPV) was 90.7, 88.7, and 92.4 (%), respectively. When focused on hsTnI-negative patients, the sensitivity and NPV of nardilysin in STEMI and NSTE-ACS were 64.7/91.4 and 55.6/91.4 (%), respectively. Furthermore, the sensitivity of nardilysin for the early detection of STEMI and NSTE-ACS patients, whose blood was examined within 3 hours after the onset was 77.6 and 60.4 (%), respectively, both of which were higher than that of hsTnI (51.2 and 56.3%). Conclusion: Nardilysin could be a potential biomarker for the early diagnosis of troponin-negative NSTE-ACS.
Red Blood Cell Adhesion Index in a Patient with Sickle Cell Disease Prior and Post Hematopoietic Stem Cell Transplant (HSCT)
Authors: Chiara Federici, Karamoja Monchamp, Allison Bode, Yuncheng Man, Erdem Kucukal, Lalitha V Nayak, Umut A. Gurkan
Journal: Blood (2021)
Abstract 9443: Improving Time to Defibrillation Following Ventricular Fibrillation and Ventricular Tachycardia Cardiac Arrest at Thomas Jefferson University Hospital
Authors: Sairamya Bodempudi, Lisa Wus, Juergen Kloo, Patrick Zeniecki, Frances Mae West, yair lev
Journal: Circulation (2021)

Problem Definition: Defibrillation within 2 minutes after ventricular fibrillation (VFib) and ventricular tachycardia (VTach) cardiac arrest has improved survival to discharge and five-year survival rates. The goal of this study was to identify how often patients were defibrillated within this recommended 2-minute interval at a single institution. A retrospective chart review of the code blue database over a 21-month time period revealed 24 VFib/VTach cardiac arrests. Time to defibrillation for each event, defined as time of identification of VFib/VTach arrest to time of delivery of the first defibrillation, was calculated. Approximately 67% (22/34) of patients who experienced VFib/VTach arrest were not defibrillated within 2 minutes and 8% (3/34) did not receive defibrillation at all. The data was further stratified based on event location (ICU versus non-ICU) and compared using chi-squared analysis, with statistical significance defined as p&lt;0.05. A significantly higher number of delayed defibrillations occurred in the non-ICU cohort compared to the ICU cohort (11/34 versus 3/34, p=0.0028). Intervention: We utilized code blue simulation sessions and an educational module to train nursing staff, who are often first at bedside, to promptly defibrillate VFib/VTach. Methods: 36 nurses out of 53 ACLS certified nurses were recruited from a single nursing unit. Groups of 2 or 3 nurses completed code blue simulation sessions to establish a baseline time to defibrillation. They were then given 2 weeks to complete an assigned educational module. Upon completion, they will be brought in for a second round of simulation sessions to assess whether their time to defibrillation has improved. Results: Out of the 15 simulation sessions that were done in the first round, 33% (5/15) ended with delayed defibrillation and 27% (4/15) ended with no defibrillation. The simulation data correlated with the retrospective chart review data. Next Steps: The second round of simulation sessions will take place in two weeks. Post-intervention data will be collected and analyzed to determine if the nursing educational module was effective. If it is, we hope to make the simulation sessions and educational module a hospital-wide initiative to improve time to defibrillation.
Abstract 9142: Predictors of New-Onset Atrial Fibrillation in the Setting of Acute Coronary Syndromes: A Nationwide Multi-Center Study
Authors: Jia Yi Anna Ne, Austin Chin Chwan Ng, Karice HYUN, Farzaneh Boroumand, Clara K Chow, Ben B Freedman, David Brieger
Journal: Circulation (2021)

Introduction: New-onset atrial fibrillation (AF) following acute myocardial infarction (AMI) is associated with adverse outcomes, though studies exploring the interaction between AF and the full spectrum of acute coronary syndromes (ACS) are scarce. We aim to identify predictors of new-onset AF in the setting of ACS by analyzing data from the prospective CONCORDANCE multi-center registry. Methods: Patients admitted to 41 Australian hospitals from 2009-2018 with ACS and had an angiogram were included. New-onset AF was defined as AF detected on index ECG and/or in-hospital AF. Independent predictors of new-onset AF were identified using multivariable logistic regression models. Results: Of 9070 consecutive patients admitted with ACS, 648 (7.1%) patients developed new-onset AF. These patients had higher rates of major adverse in-hospital events and all-cause mortality compared to patients without new-onset AF. Age (adjusted odds ratio [aOR] 1.04, 95% confidence interval [CI] 1.03-1.05), male sex (aOR 1.62, 95%CI 1.29-2.04), higher admission heart rate (aOR 1.02, 95%CI 1.01-1.02), cardiac arrest on admission (aOR 1.98, 95%CI 1.23-3.20), Killip classes 2 (aOR 1.38, 95%CI 1.10-1.73) and 3/4 (aOR 1.72, 95%CI 1.24-2.40) versus 1 were independent predictors of new-onset AF, whereas hypertension (aOR 0.81, 95%CI 0.67-0.99), higher minimum hemoglobin (aOR 0.98, 95%CI 0.97-0.98), pre-admission statins (aOR 0.71, 95%CI 0.56-0.89) and undergoing PCI (aOR 0.64, 95%CI 0.53-0.77) were associated with decreased risk of new-onset AF. When angiographic disease burden was included, double and triple-vessel disease were independent predictors of new-onset AF. However, sequential addition of CABG to the model nullified this association; (CABG (aOR 3.94, 95%CI 2.83-5.49), disease burden non-significant). In the CABG subgroup, peripheral arterial disease (aOR 1.98, 95%CI 1.20-3.27) was an independent predictor of new-onset AF (all p&lt;0.05). Conclusions: This present study identified patients at risk of new-onset AF in the setting of ACS. Such patients could be targeted for increased surveillance for AF and related adverse outcomes during the post-infarct period. In addition, future studies should explore strategies to prevent new-onset AF after ACS.
Abstract 11967: Benefit of Implantable Cardioverter Defibrillator Therapy in Patients With Advanced Renal Impairment: A Competing Risk Analysis From the MADIT Trials
Authors: Ido Goldenberg, Mehmet Aktas, Valentina Kutyifa, Wojciech Zareba, Arwa Younis, Mohan Rao
Journal: Circulation (2021)

Introduction: The life-saving benefit of the implantable cardioverter defibrillator (ICD) in patients with advanced chronic kidney disease (A-CKD) is still controversial. This is possibly due to a higher risk of dying from non-arrhythmic causes in A-CKD patients, and thereby die prior to receiving therapy from the ICD. We aimed to evaluate the competing risk for ventricular tachycardia/fibrillation (VT/VF) vs. death without prior VT/VF in ICD recipients by renal function. Methods: The study population comprised 3953 patients with an ICD enrolled in the landmark MADIT trials, categorized by renal function into: A-CKD (estimated Glomerular Filtration Rate [eGFR] ≤40 ml/min/1.73 m 2 [N=403]; Moderate CKD (eGFR 41-60 ml/min/1.73 m 2 [N=995]); and No-CKD (eGFR &gt;60 ml/min/1.73 m 2 [N=2555)). Cumulative incidence function curves were used to display the rate of fast VT/VF (&gt;200 bpm) and the competing risk of death without experiencing prior fast VT/VF using the Fine and Gray method. Results: At 4-years of follow-up, patients in the A-CKD group had a significantly lower cumulative incidence of VT/VF compared to patients with Moderate-CKD and No-CKD (13%, 17%, and 20%, respectively; p=0.006 for the overall difference [Figure: left panel]). In contrast, the corresponding 4-year rates of death without experiencing prior fast VT/VF were significantly highest among patients with A-CKD and attenuated among those with Moderate- and No-CKD (28%, 17%, and 9%, respectively; p&lt;0.001 for the overall difference [Figure: right panel]). Conclusion: Our data from 4 landmark primary prevention ICD trials show significant differences in the risk of VT/VF vs the competing risk of death without experiencing prior VT/VF by renal function. This suggests an attenuated benefit of ICD therapy with declining renal function.