tbuckley/cabot-search huggingface dataset:
CMET-35. COMPETING RISKS ANALYSIS OF FACTORS INFLUENCING DEVELOPMENT OF LEPTOMENINGEAL METASTASIS IN BREAST CANCER PATIENTS RECEIVING STEREOTACTIC RADIOSURGERY FOR LIMITED BRAIN METASTASES
Authors: Michael Zhang, Ann Lazar, Jason Chan, Chelsea Xu, August Anderson, Javier Villanueva-Meyer, Mike McDermott, Michelle Melisko, Patricia Sneed, Olivier Morin, Steve Braunstein
Journal: Neuro-Oncology (2019)

Abstract Leptomeningeal metastasis (LM) is a late stage manifestation of advanced breast cancer frequently managed with whole brain radiotherapy (WBRT) and/or intrathecal chemotherapy. A subset of breast cancer patients who undergo stereotactic radiosurgery (SRS) for limited brain metastases (BM) ultimately develop LM. We hypothesized that this subset of high-risk patients may be identified by patient, disease, and/or treatment parameters. Clinical records from 133 breast cancer patients from a single institution who underwent SRS for BM between February 2010 and March 2018 were retrospectively analyzed. Variables including histopathology, BM features, systemic disease burden, and prior treatments were analyzed. Cumulative incidence rates were estimated with death as a competing risk. Dichotomous variable cutoffs were based on the 75th percentile value. In our cohort, 27 (20.3%) patients ultimately developed LM. With a median follow up of 21.2 months after diagnosis of BM, the actuarial rate of LM at 24 months was 15.2% (95% CI, 8.7%-21.7%). Median OS after diagnosis of LM was 7.0 (95% CI, 3.1–15.4) months. There was significantly increased risk of LM with ≥9 vs &lt; 9 BM at BM diagnosis (28.1% vs 10.8% [24-month actuarial risk], subdistribution HR 2.4, p=0.027), and ≥11 vs &lt; 11 cumulative number of BM treated (25.7% vs 11.7% [24-month actuarial risk], subdistribution HR 2.7, p=0.01). Variables not significantly associated with the risk of LM included tumor receptor status (ER, PR, HER2, triple negative), graded prognostic assessment, KPS, extracranial metastases, total BM volume, prior WBRT, or prior surgical resection. Time intervals between SRS treatments immediately preceding LM diagnosis was not significantly different from other time intervals. In conclusion, patients with a larger number of brain metastases at BM diagnosis (≥9) or cumulatively treated (≥11) appear to be at higher risk of developing LM and may benefit from stronger consideration of WBRT, intrathecal chemotherapy, and/or brain-penetrating systemic therapy.
Eltanexor (KPT-8602), a Second-Generation Selective Inhibitor of Nuclear Export (SINE) Compound, in Patients with Higher-Risk Myelodysplastic Syndrome
Authors: Sangmin Lee, Bhavana Bhatnagar, Sanjay R Mohan, William T. Senapedis, Erkan Baloglu, Hongwei Wang, Jatin J. Shah, Sharon Shacham, Michael G. Kauffman
Journal: Blood (2019)
Neurohormonal Blockade and Clinical Outcomes in Patients With Heart Failure Supported by Left Ventricular Assist Devices
Authors: Megan McCullough, Cesar Caraballo, Neal G. Ravindra, P. Elliott Miller, Catherine Mezzacappa, Andrew Levin, Jadry Gruen, Benjamin Rodwin, Samuel Reinhardt, David van Dijk, Ayyaz Ali, Tariq Ahmad, Nihar R. Desai
Journal: JAMA Cardiology (2019)

<h3>Importance</h3> Left ventricular assist devices (LVADs) improve outcomes in patients with advanced heart failure, but little is known about the role of neurohormonal blockade (NHB) in treating these patients. <h3>Objective</h3> To analyze the association between NHB blockade and outcomes in patients with LVADs. <h3>Design, Setting, and Participants</h3> This retrospective cohort analysis of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) included patients from more than 170 centers across the United States and Canada with continuous flow LVADs from 2008 to 2016 who were alive with the device in place at 6 months after implant. The data were analyzed between February and November 2019. <h3>Exposures</h3> Patients were stratified based on exposure to NHB and represented all permutations of the following drug classes: angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, β-blockers, and mineralocorticoid antagonists. <h3>Main Outcomes and Measures</h3> The outcomes of interest were survival at 4 years and quality of life at 2 years based on Kansas City Cardiomyopathy Questionnaire scores and a 6-minute walk test. <h3>Results</h3> A total of 12 144 patients in INTERMACS met inclusion criteria, of whom 2526 (20.8% ) were women, 8088 (66.6%) were white, 3024 (24.9%) were African American, and 753 (6.2%) were Hispanic; the mean (SD) age was 56.8 (12.9) years. Of these, 10 419 (85.8%) were receiving NHB. Those receiving any NHB medication at 6 months had a better survival rate at 4 years compared with patients not receiving NHB (56.0%; 95% CI, 54.5%-57.5% vs 43.9%; 95% CI, 40.5%-47.7%). After sensitivity analyses with an adjusted model, this trend persisted with patients receiving triple therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, β-blocker, and mineralocorticoid antagonist having the lowest hazard of death compared with patients in the other groups (hazard ratio, 0.34; 95% CI, 0.28-0.41). Compared with patients not receiving NHB, use of NHB was associated with a higher Kansas City Cardiomyopathy Questionnaire score (66.6; bootstrapped 95% CI, 65.8-67.3 vs 63.0; bootstrapped 95% CI, 60.1-65.8;<i>P</i> = .02) and a 6-minute walk test (1103 ft; bootstrapped 95% CI, 1084-1123 ft vs 987 ft; bootstrapped 95% CI, 913-1060 ft;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> Among patients with LVADs who tolerated NHB therapy, continued treatment was associated with improved survival and quality of life. The optimal heart failure regimen for patients after LVAD implant may be the initiation and continuation of guideline-directed medical therapy.
Outcome of Hematopoietic Stem Cell Gene Therapy for Wiskott-Aldrich Syndrome
Authors: Roxane Labrosse, Julia Chu, Myriam Armant, Jet van der Spek, Alexandra Miggelbrink, Johnson Fong, John K. Everett, Hayley Raymond, Lyanna Kessler, Colleen Dansereau, Brenda Mackinnon, Stephanie Koo, Emily Morris, Wendy B. London, Ahmet Ozen, Safa Baris, Jenny M. Despotovic, Lisa Forbes, Akihiko Saitoh, Takayuki Takachi, Alejandra King, Thi Mai Anh Thi Nguyen, Vy Do Uyen Vu, Frederic D. Bushman, Anne Galy, Luigi Notarangelo, David A Williams, Sung-Yun Pai
Journal: Blood (2019)
Updates in Clinical Data on FDA Fast Track Drugs for Relapsed Refractory Multiple Myeloma: A Systematic Review of Literature
Authors: Muhammad Abdullah Yousaf, Muhaddis Ejaz Ahmad, Maaz Ahmed Yusufi, Asim Tameez ud din, Muhammad Qudrat Ullah, Muhammad Yasir Anwar, Abdul Rafae, Mustafa Nadeem Malik, Zunairah Shah, Ahmed Ibrahim, Faiz Anwer
Journal: Blood (2019)
TMOD-18. EXPLORING THE FACTORS LEAD TO SUCCESS OF CAR T-CELL THERAPY IN GLIOBLASTOMA WITH COMPUTATIONAL MODELING AND IN VITRO DATA
Authors: Prativa Sahoo, Xin Yang, Daniel Abler, Davide Maestrini, Vikram Adhikarla, Christine E Brown, Russell Rockne
Journal: Neuro-Oncology (2019)

Abstract Chimeric antigen receptor (CAR) T-cell therapy is an emerging targeted immunotherapy which has shown success in liquid cancers such as leukemias. CAR T-cells are also being used for the treatment of solid tumors such as glioblastoma, which is a primary brain tumor. Ongoing phase I trials have been designed to evaluate CAR T-cell dosing, scheduling, and route of administration in order to understand and improve the efficacy of CAR T-cell therapy. A better understanding of factors leading to the success of CAR T-cell immunotherapy for solid tumors will be necessary to improve outcomes for patients with solid tumors and to advance the field of CAR T-cell immuno-oncology. Here we use mathematical model to explore factors in determining a successful response to CAR T-cell therapy: proliferation, persistence, and killing capacity of CAR T-cells. Using a novel in vitro experimental apparatus, we are able to measure the density of cancer cells over several days in 15 minute interval time resolution. This highly temporally resolved data provides a unique opportunity to confidently estimate parameters of the model and to provide insights into the dynamics of CAR T-cell proliferation, persistence, and killing capacity. Furthermore we explore the relationship between these factor with CAR T-cell dose level. We will show results from experiments using patient-derived cancer cell lines as well as cancer cells engineered to express specific levels of the target antigen (IL13Rα2) to quantitatively evaluate the roles of proliferation, persistence, and killing in cells with different levels of antigen expression. We will discuss the interpretation of the model parameters and demonstrate the clinical value of this analysis through an application of CAR T-cell treatment tailored to the dynamics of an individual patient’s cancer growth rate.
NCMP-09. NEUROLYMPHOMATOSIS, A RARE INDEX MANIFESTATION OF CD5/CD10 NEGATIVE MATURE B CELL LYMPHOMA PRESENTING AS SUBACUTE SENSORIMOTOR LAMBOSACRAL POLYRADICULONEUROPATHY
Authors: Maya Hrachova, Kong Xiao-Tang, Xiaohui Zhao
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Neurolymphomatosis (NL) is a rare entity characterized by direct invasion of neoplastic cells into endoneurium of cranial or peripheral nerves, nerve roots or plexuses. It is most commonly seen with non-Hodgkin’s lymphoma with occurrence rate of 0.2%. Here we report a case of subacute length-dependent sensorimotor lumbosacral polyradiculoneuropathy secondary to NL as the first manifestation of CD5−/CD10− mature B-cell lymphoma. CASE REPORT: A 54-year old man with diabetes mellitus type 2, hypertension and psoriasis presented with subacute onset of progressive lower extremity weakness with pertinent examination findings of bilateral mildly asymmetrical distal greater than proximal lower extremities weakness, length depended hypoesthesia, fasciculations and decreased reflexes. EMG/NCS study showed active and chronic denervation changes concerning for multilevel lumbosacral polyradiculopathy. Routine blood investigations produced normal findings. CSF examination showed nucleated cells at 125 cells/HPF with lymphocyte predominance, protein at 538 mg/dL, and glucose 18 mg/dL. Flow cytometry identified mature CD5-/CD10- B cell lymphocytes. MRI spine identified marked enhancement, thickening, nodularity of cauda equine nerve roots and focus of myelopathy at the left posterior conus. Based on the clinical and radiographic findings a diagnosis of neurolymphomatosis was made and her underwent workup for systemic lymphoma. DISCUSSION Our case demonstrates the importance of comprehensive evaluation of sensorimotor polyradiculoneuropathy as rare entities such as neurolymphomatosis could mimic common etiologies.
DDIS-05. IDENTIFICATION OF 2-FLUORO PALMITIC ACID AS A POTENTIAL THERAPEUTIC AGENT AGAINST GLIOBLASTOMA
Authors: Shabierjiang Jiapaer, Yu Dong, Tomohiro Kitabayashi, Taskuya Furuta, Hemragul Sabit, Jiakang Zhang, guangtao Zhang, Shingo Tanaka, Mitsutoshi Nakada
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Glioblastoma (GBM) represents the most aggressive and frequent type of primary malignant brain tumors with a dismal clinical outcome. Though adjuvant temozolomide (TMZ) chemotherapy followed by surgical resection can extend patient`s post-operative survival, a considerable number of GBM cases are refractory to TMZ. Novel therapeutic agents that can overcome chemoresistance against TMZ are urgent. Drug repositioning is a process of identifying new indications for existing drugs and provides potential possibilities to discover new drugs. In this study, we explored novel anti-glioma agents which enhances the effect of TMZ with the strategy of drug repositioning. METHODS Drug library which contains 1300 diverse chemical compounds was screened using 2 kinds of glioma stem cell (GSC) lines to select novel therapeutic candidate. The effect of candidate drug on the proliferation of GSCs was estimated by sphere formation assay. To evaluate its efficacy against glioma cell biology, proliferation assay, matrigel invasion assay were performed. To clarify the mechanism of drug effects, we investigated target molecules by gelatin zymography and western blot. RESULTS Acyl CoA synthetase inhibitor named 2-fluoropalmitic acid (2-FPA) was selected as a novel candidate. 2-FPA suppressed proliferation of glioma cell lines by single administration and/or combination with TMZ. The sphere formation of GSCs was suppressed by combination therapy. Combination therapy enhanced TMZ effect. 2-FPA also suppressed invasion of glioma cell lines in a dose dependent manner. 2-FPA suppressed MMP-2 activity and phosphorylation of STAT3. CONCLUSION 2-FPA was identified as a novel potential therapeutic agent against GBM.
Serum Bioavailable, Rather Than Total, 25‐hydroxyvitamin D Levels Are Associated With Hepatocellular Carcinoma Survival
Authors: Ai‐Ping Fang, Jing‐An Long, Yao‐Jun Zhang, Zhao‐Yan Liu, Qi‐Jiong Li, Dao‐Ming Zhang, Yun Luo, Rong‐Huan Zhong, Zhong‐Guo Zhou, Yan‐Jun Xu, Xiao‐Jun Xu, Wen‐Hua Ling, Min‐Shan Chen, Hui‐Lian Zhu
Journal: Hepatology (2019)

Background and Aims Free and bioavailable 25‐hydroxyvitamin D (25OHD) are emerging measurements of vitamin D status. It remains unclear whether circulating free or bioavailable 25OHD are relevant to hepatocellular carcinoma (HCC) prognosis. Our aim was to test the hypothesis that bioavailable 25OHD may be a better serum biomarker of vitamin D status than total 25OHD on the association with HCC survival. Approach and Results We included 1,031 newly diagnosed, previously untreated patients with HCC from the Guangdong Liver Cancer Cohort enrolled between September 2013 and April 2017. Serum total 25OHD levels were measured using an electrochemiluminescence immunoassay. Serum‐free 25OHD levels were measured using a two‐step enzyme‐linked immunosorbent assay. Bioavailable 25OHD levels were calculated from measured free 25OHD and albumin using a previously validated equation. Primary outcomes were liver cancer–specific (LCSS) and overall survival (OS). Cox proportional hazards models were performed to calculate the multivariable hazard ratios (HRs) and 95% confidence intervals (CIs). During a median follow‐up of 726 days, 430 patients had deceased, including 393 deaths from HCC. In multivariable analyses, higher bioavailable 25OHD levels were significantly associated with better survival, independent of nonclinical and clinical prognostic factors including serum C‐reactive protein, Barcelona Clinic Liver Cancer stage, and cancer treatment. The multivariable‐adjusted HRs in the highest versus lowest quartile of bioavailable 25OHD levels were 0.69 (95% CI: 0.51, 0.93; P for trend = 0.014) for LCSS and 0.71 (95% CI: 0.53, 0.94; P for trend = 0.013) for OS. In contrast, neither total nor free 25OHD levels were associated with LCSS or OS. Conclusions Higher bioavailable, rather than total, 25OHD levels were independently associated with improved survival in a population‐based HCC cohort, suggesting a potential utility of bioavailable 25OHD in HCC prognosis.
HOUT-22. EVALUATING CLINICAL IMPACT UTILIZING THE RANO-PRO COLLABORATIVE’S STANDARDIZED PRIORITY CONSTRUCTS
Authors: Elizabeth Vera, Mark Gilbert, Orwa Aboud, Ramya Antony, Lisa Boris, Christine Bryla, Eric Burton, Christine Cordova, Sonja Crandon, Nicole Leggiero, Marta Penas-Prado, Jennifer Reyes, Christine Siegel, Brett Theeler, Kathleen Wall, Jing Wu, Terri Armstrong
Journal: Neuro-Oncology (2019)

Abstract Increasing recognition of the symptom burden and functional limitations among primary brain tumor (PBT) patients has led to proposing clinical outcomes assessments as an additional measure of a treatment’s effectiveness. The RANO-PRO Collaborative recommended core symptoms for evaluation in clinical care and research for malignant glioma are weakness, walking, seizures, communication, memory, and treatment-specific symptoms. We evaluated these symptoms using the MDASI-Brain Tumor (BT) in the PBT patient sample of the NCI-NOB Natural History Study, in relation to disease progression, by descriptive statistics, and independent- and paired-samples t-tests. The sample included 434 PBT patients (59% male, median age=50 (18–83), 82% white, 43% with a prior recurrence). In the 60% with a malignant glioma, weakness, walking, seizures, difficulty remembering, and fatigue were significantly worse in the group with progression at time of imaging compared to the group with stable disease (p&lt; 0.05). In a subset of 114 patients with progression after study entry, reported severity in all symptoms (except seizures) significantly worsened from study entry to time of progression (-1.7&lt; mean difference&lt; -0.1, p&lt; 0.02, 0.3&lt; r&lt; 0.5). Walking, weakness, difficulty remembering, and fatigue each had a difference greater than 1-point, the minimally important difference for MDASI-BT. No one core symptom accounted for the severity change; each was reported by 17%-35% of patients as their largest change in severity. Utilizing the symptom with the largest change increased the magnitude of the worsening and its effect size (mean difference=-2.9, r=0.5). The analysis was repeated in the larger PBT sample with similar statistical findings but with smaller mean differences. RANO-PRO Collaborative core symptoms were shown to worsen at time of progression on imaging, highlighting the importance of continual symptom assessment and validating this core symptom group. Further analysis will focus on degree of change with each core symptom and validation in other datasets.
Ivo-Nivo: A Phase II Study of the IDH1 Inhibitor Ivosidenib (AG-120) in Combination with the Checkpoint Blockade Inhibitor Nivolumab for Patients with IDH1 Mutated Relapsed/Refractory AML and High Risk MDS
Authors: Namrata S Chandhok, Wei Wei, Stephanie Halene, Thomas Prebet
Journal: Blood (2019)
Hispanic Ethnicity Is Associated with Low End of Induction Absolute Lymphocyte Count in Pediatric Acute Lymphoblastic Leukemia
Authors: Adriana Saavedra-Simmons, Wanda LeJeune, Geraldine Aubert, Kellen Gandy, Lisa R. Hartman, Jill Hartley, Rodrigo Erana, Juan C. Bernini, Olga Taylor, Philip J. Lupo, Michael E. Scheurer, Karen R. Rabin, Maria Monica Monica Gramatges
Journal: Blood (2019)
A Phase 2 Study of Glasdegib for the Treatment of Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients with High Risk of Post-Allogeneic Stem Cell Transplantation Relapse
Authors: Andrew Kent, Sumithira Vasu, Derek Schatz, Natalie Monson, Steven Devine, Clayton Smith, Jonathan A Gutman, Daniel A Pollyea
Journal: Blood (2019)
Salvage Autologous Stem Cell Transplant in Relapsed Myeloma Patients in the Era of Modern Treatment: Is There a Role?
Authors: Sahar Khan, Eshetu G Atenafu, Christine I Chen, Esther Masih-Khan, Lavinia Aileen Jeyanathan, Anca Prica, Donna E Reece, Rodger E Tiedemann, Suzanne Trudel, Vishal Kukreti
Journal: Blood (2019)
Establishing a Novel in Vitro Informed Precision Clinical Trial Pathway for Refractory Pediatric Leukemia
Authors: Chunfen Zhang, Ritul Sharma, Thakur Satbir, Allison Cheney, Olena Vaske, Lauren Sanders, Jessica Boklan, Victor A. Lewis, Ronald Anderson, Olga Kovalchuk, Norman J. Lacayo, Aru Narendran, Kevin J. Bielamowicz
Journal: Blood (2019)
COMP-11. SINGLE CELL MASS CYTOMETRY SIGNALING PROFILES AND A NOVEL COMPUTATIONAL TOOL IDENTIFY HIGH RISK GLIOBLASTOMA CELLS
Authors: Nalin Leelatian, Justine Sinnaeve, Akshitkumar Mistry, Sierra Barone, Kirsten Diggins, Allison Greenplate, Todd Bartkowiak, Caroline Roe, Kyle Weaver, Reid Thompson, Lola Chambless, Bret Mobley, Jonathan Irish, Rebecca Ihrie
Journal: Neuro-Oncology (2019)

Abstract In glioblastoma, changes in signaling, gene sequence, copy number, or transcript expression can define patient subgroups, but these subgroups are not yet associated with differential outcome for most patients with high-risk, IDH wild-type disease. Single cell interrogation of phospho-protein signaling has successfully revealed novel cell types associated with patient outcomes in blood cancers, suggesting that a comparable approach could be used in brain tumors. The goal of this study was to combine a single cell phospho-protein profiling approach with novel, automated computational analysis to identify abnormal glioblastoma cells that stratify patient clinical risk. Effective tissue dissociation strategies and validated antibody panels were created for mass cytometry analyses of resected glioblastoma tissue. These panels simultaneously measured 45 determinants of neural and glioma cell identity, including transcription factors, phospho-proteins, and surface receptors. 28 glioblastoma tumors were stained and analyzed using traditional gating, existing computational tools, and a new risk assessment population identification algorithm (RAPID, https://www.biorxiv.org/content/10.1101/632208v3). RAPID revealed two malignant cell types closely associated with differential patient outcomes. Glioblastoma negative prognostic (GNP) cells were associated with poor survival and defined by phospho-protein signaling in cells with aberrant neural developmental phenotypes. Glioblastoma positive prognostic (GPP) cells were associated with better progression free survival and defined by increased immunogenic signaling. A Cox proportional-hazards regression model was created to assess the influence of GNP and GPP cells on OS and PFS as continuous variables while accounting for other well-known clinical predictors. Each 1% increase of GNP cells was associated with an 7% increase in annual mortality rate (HR=1.07 [95% CI 1.03–1.12], p=0.001). Tumors containing GNP cells also significantly lacked CD45+ immune cell infiltration (Pearson r=-0.8). The signaling events that define these clinically significant glioblastoma cells represent a useful molecular classification, may indicate responsiveness to immunotherapy, and are themselves important targets of opportunity for new therapeutic approaches.
Change of Treatment for Control of Chronic Graft-Versus-Host Disease (cGVHD) as a Time-Dependent Covariate for Nonrelapse Mortality and Survival.
Authors: Mary E.D. Flowers, Barry Storer, Paul Carpenter, Afonso Vigorito, Paulo Campregher, Carina Moravec, Hans-Peter Kiem, Fero Matthew, George Georges, Edus Warren, Stephanie Lee, Jean Sanders, Paul Martin
Journal: Blood (2007)
β-Thalassemia in the American Negro
Authors: Shlomo Friedman, Robert W. Hamilton, Elias Schwartz
Journal: Journal of Clinical Investigation (1973)

In Italian patients with high hemoglobin A2 β-thalassemia trait, the synthesis of β-chains of adult hemoglobin in the peripheral blood is approximately one-half that of α-chains. In this study the relative rates of β- and α-chain synthesis were determined in 26 Negro heterozygotes and five homozygotes for β-thalassemia in six families. The β/α ratio of globin synthesis was decreased in only 15 heterozygotes, whereas in the other 11, β/α globin synthesis was in the normal range or was slightly increased. These unusual findings did not appear to be due to the presence of α-thalassemia or a hyperactive “normal” β-allele. This study demonstrates that the β/α ratio of globin synthesis in the peripheral blood is normal in some patients with β-thalassemia trait. In five Negro homozygotes with relatively mild clinical disease the β/α ratios were similar to those of Caucasians with Cooley's anemia. Further studies are needed to explore the relationship between normal synthesis ratios in many Negro heterozygotes and milder clinical disease in homozygotes in the same families.