Hemic and Lymphatic Diseases Commons^™

Preclinical Investigations Of The Efficacy Of The Glutaminase Inhibitor Cb-839 Alone And In Combinations In Chronic Lymphocytic Leukemia, Natalia Timofeeva, Mary L Ayres, Natalia Baran, Janice M Santiago-O'Farrill, Gamze Bildik, Zhen Lu, Marina Konopleva, Varsha Gandhi

Faculty, Staff and Student Publications

INTRODUCTION: Chronic lymphocytic leukemia (CLL) cells are metabolically flexible and adapt to modern anticancer treatments. Bruton tyrosine kinase (BTK) and B-cell lymphoma-2 (BCL-2) inhibitors have been widely used to treat CLL, but CLL cells become resistant to these treatments over time. CB-839 is a small-molecule glutaminase-1 (GLS-1) inhibitor that impairs glutamine use, disrupts downstream energy metabolism, and impedes the elimination of reactive oxygen species.

METHODS: To investigate the

RESULTS: We found that CB-839 caused dose-dependent decreases in GLS-1 activity and glutathione synthesis. CB-839-treated cells also showed increased mitochondrial superoxide metabolism and impaired energy metabolism, which were reflected in decreases in …

Impact Of Clonal Plasma Cells In Autografts On Outcomes In High-Risk Multiple Myeloma Patients, Oren Pasvolsky, Denái R Milton, Mikael Rauf, Sassine Ghanem, Adeel Masood, Ali H Mohamedi, Mark R Tanner, Qaiser Bashir, Samer Srour, Neeraj Saini, Paul Lin, Jeremy Ramdial, Yago Nieto, Guilin Tang, Hans C Lee, Krina K Patel, Partow Kebriaei, Sheeba K Thomas, Donna M Weber, Robert Z Orlowski, Katy Rezvani, Richard Champlin, Elizabeth J Shpall, Pei Lin, Muzaffar H Qazilbash

Faculty, Staff and Student Publications

Most patients with multiple myeloma (MM) undergoing autologous hematopoietic stem cell transplantation (autoHCT) eventually relapse, perhaps due to the presence of clonal plasma cells (CPC) in the autograft. We conducted a retrospective analysis to evaluate the impact of CPC in the autograft on the outcomes of high-risk chromosomal abnormalities (HRMM) patients undergoing autoHCT between 2008 and 2018. Patients were divided into CPC+ or CPC- in the autograft by next-generation flow cytometry (NGF). There were 75 CPC + autografts (18%) and 341 CPC- (82%). The CPC + group was less likely to achieve MRD-negative complete remission post-transplant (11% vs. 42%; p < 0.001). Median progression free survival (PFS) and overall survival (OS) were (12.8 vs. 32.1 months) and (36.4 vs. 81.2 months) in the CPC + and CPC- groups, respectively (both p < 0.001). Also in the subset of patients with MRD-negative ≥VGPR prior to autoHCT, those with CPC + autografts had inferior PFS (HR 4.21, p = 0.006) and OS (HR 7.04, p = 0.002) compared to CPC-. In multivariable analysis, the degree of CPC positivity in the autograft was independently predictive of worse PFS (HR 1.50, p = 0.001) and OS (HR 1.37, p = 0.001). In conclusion, both the presence and degree of CPC in the autograft were highly predictive of inferior PFS and OS.

Dna Methylation Analysis Is Used To Identify Novel Genetic Loci Associated With Circulating Fibrinogen Levels In Blood, Julie Hahn, Jan Bressler, Arce Domingo-Relloso, Ming-Huei Chen, Daniel L Mccartney, Alexander Teumer, Jenny Van Dongen, Marcus E Kleber, Dylan Aïssi, Brenton R Swenson, Jie Yao, Wei Zhao, Jian Huang, Yujing Xia, Michael R Brown, Ricardo Costeira, Eco J C De Geus, Graciela E Delgado, Dre'von A Dobson, Paul Elliott, Hans J Grabe, Xiuqing Guo, Sarah E Harris, Jennifer E Huffman, Sharon L R Kardia, Yongmei Liu, Stefan Lorkowski, Riccardo E Marioni, Matthias Nauck, Scott M Ratliff, Maria Sabater-Lleal, Tim D Spector, Pierre Suchon, Kent D Taylor, Florian Thibord, David-Alexandre Trégouët, Kerri L Wiggins, Gonneke Willemsen, Jordana T Bell, Dorret I Boomsma, Shelley A Cole, Simon R Cox, Abbas Dehghan, Andreas Greinacher, Karin Haack, Winfried März, Pierre-Emmanuel Morange, Jerome I Rotter, Nona Sotoodehnia, Maria Tellez-Plaza, Ana Navas-Acien, Jennifer A Smith, Andrew D Johnson, Myriam Fornage, Nicholas L Smith, Alisa S Wolberg, Alanna C Morrison, Paul S De Vries

Faculty, Staff and Student Publications

Background:

Fibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined by inter-individual differences in DNA methylation at CpG sites, and vice versa.

Methods:

We performed an epigenome-wide association study (EWAS) of circulating fibrinogen levels in 18,037 White, Black, American Indian, and Hispanic participants representing 14 studies from the CHARGE consortium. Circulating leukocyte DNA methylation was measured in 12,904 participants using the Illumina 450K array, and in 5,133 participants using the EPIC array. Each study performed an EWAS of fibrinogen using linear mixed models adjusted for potential confounders. Study-specific results were combined using array-specific …

Pathway-Driven Rare Germline Variants Associated With Transplant-Associated Thrombotic Microangiopathy (Ta-Tma), Zhihui Zhang, Wei Hong, Qian Wu, Spiridon Tsavachidis, Jian-Rong Li, Christopher I Amos, Chao Cheng, Sarah E Sartain, Vahid Afshar-Kharghan, Jing-Fei Dong, Pavan Bhatraju, Paul J Martin, Robert S Makar, Pavan K Bendapudi, Ang Li

Faculty, Staff and Student Publications

The significance of rare germline mutations in transplant-associated thrombotic microangiopathy (TA-TMA) is not well studied. We performed a genetic association study in 100 adult TA-TMA patients vs. 98 post-transplant controls after matching by race, sex, and year. We focused on 5 pathways in complement, von Willebrand factor (VWF) function and related proteins, VWF clearance, ADAMTS13 function and related proteins, and endothelial activation (3641variants in 52 genes). In the primary analysis focused on 189 functional rare variants, no differential variant enrichment was observed in any of the pathways; specifically, 29 % TA-TMA and 33 % controls had at least 1 rare …

Mastro I: Meta-Analysis And Systematic Review Of Thrombectomy Stent Retriever Outcomes: Comparing Functional, Safety And Recanalization Outcomes Between Embotrap, Solitaire And Trevo In Acute Ischemic Stroke, Osama O Zaidat, Shelly Ikeme, Sunil A Sheth, Shinichi Yoshimura, Xin-Guang Yang, Waleed Brinjikji, David F Kallmes, Patrick Brouwer, John Pederson, Ranita Tarchand, Annie Steffenson, Kevin M Kallmes, Jillienne Touchette, Tommy Andersson

Faculty, Staff and Student Publications

Aims:

Stent-retriever (SR) thrombectomy has demonstrated superior outcomes in patients with acute ischemic stroke compared with medical management alone, but differences among SRs remain unexplored. We conducted a Systematic Review/Meta-Analysis to compare outcomes between three SRs: EmboTrap^®, Solitaire™, and Trevo^®.

Methods:

We conducted a PRISMA-compliant Systematic Review among English-language studies published after 2014 in PubMed/MEDLINE that reported SRs in ≥25 patients. Functional and safety outcomes included 90-day modified Rankin scale (mRS 0-2), mortality, symptomatic intracranial hemorrhage (sICH), and embolization to new territory (ENT). Recanalization outcomes included modified thrombolysis in cerebral infarction (mTICI) and first-pass recanalization (FPR). …

Development Of A Computable Phenotype Using Electronic Health Records For Venous Thromboembolism In Medical Inpatients: The Medical Inpatient Thrombosis And Hemostasis Study, Ryan M Thomas, Katherine Wilkinson, Insu Koh, Ang Li, Janine S A Warren, Nicholas S Roetker, Nicholas L Smith, Chris E Holmes, Timothy B Plante, Allen B Repp, Mary Cushman, Neil A Zakai

Faculty, Staff and Students Publications

BACKGROUND: Accurate and efficient methods to identify venous thromboembolism (VTE) events in hospitalized people are needed to support large-scale studies. Validated computable phenotypes using a specific combination of discrete, searchable elements in electronic health records to identify VTE and distinguish between hospital-acquired (HA)-VTE and present-on-admission (POA)-VTE would greatly facilitate the study of VTE, obviating the need for chart review.

OBJECTIVES: To develop and validate computable phenotypes for POA- and HA-VTE in adults hospitalized for medical reasons.

METHODS: The population included admissions to medical services from 2010 to 2019 at an academic medical center. POA-VTE was defined as VTE diagnosed within …

A Rare Case Of Rapidly Progressive Cll/Sll Presenting As Bilateral Tonsillar Enlargement And Upper Airway Obstruction, William Mangin, Kashif Aslam

North Texas GME Research Forum 2023

Although chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) differ in clinical presentation, they are both arise from the same pathologic process, namely the clonal expansion of mature B-cells. This malignancy is usually quite indolent and carries a favorable prognosis. Thanks to a number of highly-effective oral targeted therapies, such as the Bruton tyrosine kinase (BTK) inhibitor, Ibrutinib, patient outcomes have improved significantly. Unfortunately, these therapies are not always well tolerated and many patients are forced to discontinue the medication due to side effects. Many patients experience a disease flair and some even transformation to a high-grade malignancy after …

Covid-19 Masking An Atypical Presentation Of Hairy Cell Leukemia, Kahmalia-Kalee Sada

North Texas GME Research Forum 2023

Hairy cell leukemia is a rare lymphoid neoplasm of small mature B cell lymphoid cells. Hairy cell leukemia only accounts for about 1 to 2 percent of adult leukemia cases. Early diagnosis of Hairy cell Leukemia is important, it is proven that without treatment the median survival of this cancer is four years. After numerous studies the age-adjusted risk of death with proper diagnosis and treatment has decreased by 85%. The greatest outcomes are seen in individuals who are younger with earlier diagnosis. Hairy Cell Leukemia is a rare leukemia seen with the classic triad of splenomegaly, pancytopenia, and “hairy” …

Acute Thalamic Stroke In A Covid Positive Adult: A Case Report, Norberto Escobales, Daniel Kiehl, Michelle Militello, Aleger Vorbes

South Atlantic Division GME Research Day 2023

No abstract provided.

A Case Of Type 1 Cryoglobulinemia With Waldenstrom’S Macroglobulinemia/Lymphoplasmocytic Lymphoma And Dry Gangrene, Abhinav Rao, Diego Garrido, Fahim Syed, Kody Dhaliwal, Charles Holladay, Julia Saylors, Matthew Madden, Jason Clark

South Atlantic Division GME Research Day 2023

No abstract provided.

Zoster-Associated Prothrombotic Plasma Exosomes And Increased Stroke Risk, Andrew N Bubak, Christina Coughlan, Janelle Posey, Anthony J Saviola, Christy S Niemeyer, Serena W R Lewis, Sara Bustos Lopez, Adriana Solano, Stephen K Tyring, Cassidy Delaney, Keith B Neeves, Ravi Mahalingam, Kirk C Hansen, Maria A Nagel

Faculty, Staff and Student Publications

Herpes zoster (HZ; shingles) caused by varicella zoster virus reactivation increases stroke risk for up to 1 year after HZ. The underlying mechanisms are unclear, however, the development of stroke distant from the site of zoster (eg, thoracic, lumbar, sacral) that can occur months after resolution of rash points to a long-lasting, virus-induced soluble factor (or factors) that can trigger thrombosis and/or vasculitis. Herein, we investigated the content and contributions of circulating plasma exosomes from HZ and non-HZ patient samples. Compared with non-HZ exosomes, HZ exosomes (1) contained proteins conferring a prothrombotic state to recipient cells and (2) activated platelets …

Interrogating Bromodomain Inhibitor Resistance In Kmt2a-Rearranged Leukemia Through Combinatorial Crispr Screens, Shaela Wright, Jianzhong Hu, Hong Wang, Judith Hyle, Yang Zhang, Guoqing Du, Marina Y Konopleva, Steven M Kornblau, Mohamed Nadhir Djekidel, Wojciech Rosikiewicz, Beisi Xu, Rui Lu, Jun J Yang, Chunliang Li

Faculty, Staff and Student Publications

Bromo- and extra-terminal domain inhibitors (BETi) have exhibited therapeutic activities in many cancers. However, the mechanisms controlling BETi response and resistance are not well understood. We conducted genome-wide loss-of-function CRISPR screens using BETi-treated KMT2A-rearranged (KMT2A-r) cell lines. We revealed that Speckle-type POZ protein (SPOP) gene (Speckle Type BTB/POZ Protein) deficiency caused significant BETi resistance, which was further validated in cell lines and xenograft models. Proteomics analysis and a kinase-vulnerability CRISPR screen indicated that cells treated with BETi are sensitive to GSK3 perturbation. Pharmaceutical inhibition of GSK3 reversed the BETi-resistance phenotype. Based on this observation, a combination therapy regimen inhibiting both …

Targeting Of Epigenetic Co-Dependencies Enhances Anti-Aml Efficacy Of Menin Inhibitor In Aml With Mll1-R Or Mutant Npm1, Warren Fiskus, Christopher P Mill, Christine Birdwell, John A Davis, Kaberi Das, Steffen Boettcher, Tapan M Kadia, Courtney D Dinardo, Koichi Takahashi, Sanam Loghavi, Michael J Soth, Tim Heffernan, Gerard M Mcgeehan, Xinjia Ruan, Xiaoping Su, Christopher R Vakoc, Naval Daver, Kapil N Bhalla

Faculty, Staff and Student Publications

Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse. Utilizing single-cell RNA-Seq, ChiP-Seq, ATAC-Seq, RNA-Seq, RPPA, and mass cytometry (CyTOF) analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy in AML cells harboring MLL1-r or mtNPM1. Notably, MI-mediated genome-wide, concordant, log2 fold-perturbations in ATAC-Seq and RNA-Seq peaks were observed at the loci of MLL-FP target genes, with upregulation of mRNAs associated with AML differentiation. MI treatment also reduced the number of AML cells expressing the stem/progenitor cell signature. A …

Mechanisms Of Response And Resistance To Combined Decitabine And Ipilimumab For Advanced Myeloid Disease, Livius Penter, Yang Liu, Jacquelyn O Wolff, Lin Yang, Len Taing, Aashna Jhaveri, Jackson Southard, Manishkumar Patel, Nicole M Cullen, Kathleen L Pfaff, Nicoletta Cieri, Giacomo Oliveira, Seunghee Kim-Schulze, Srinika Ranasinghe, Rebecca Leonard, Taylor Robertson, Elizabeth A Morgan, Helen X Chen, Minkyung H Song, Magdalena Thurin, Shuqiang Li, Scott J Rodig, Carrie Cibulskis, Stacey Gabriel, Pavan Bachireddy, Jerome Ritz, Howard Streicher, Donna S Neuberg, F Stephen Hodi, Matthew S Davids, Sacha Gnjatic, Kenneth J Livak, Jennifer Altreuter, Franziska Michor, Robert J Soiffer, Jacqueline S Garcia, Catherine J Wu

Faculty, Staff and Student Publications

The challenge of eradicating leukemia in patients with acute myelogenous leukemia (AML) after initial cytoreduction has motivated modern efforts to combine synergistic active modalities including immunotherapy. Recently, the ETCTN/CTEP 10026 study tested the combination of the DNA methyltransferase inhibitor decitabine together with the immune checkpoint inhibitor ipilimumab for AML/myelodysplastic syndrome (MDS) either after allogeneic hematopoietic stem cell transplantation (HSCT) or in the HSCT-naïve setting. Integrative transcriptome-based analysis of 304 961 individual marrow-infiltrating cells for 18 of 48 subjects treated on study revealed the strong association of response with a high baseline ratio of T to AML cells. Clinical responses were …

Molecular Mechanisms Of Ferroptosis And Updates Of Ferroptosis Studies In Cancers And Leukemia, Hiroki Akiyama, Bing Z Carter, Michael Andreeff, Jo Ishizawa

Faculty, Staff and Student Publications

Ferroptosis is a mode of cell death regulated by iron-dependent lipid peroxidation. Growing evidence suggests ferroptosis induction as a novel anti-cancer modality that could potentially overcome therapy resistance in cancers. The molecular mechanisms involved in the regulation of ferroptosis are complex and highly dependent on context. Therefore, a comprehensive understanding of its execution and protection machinery in each tumor type is necessary for the implementation of this unique cell death mode to target individual cancers. Since most of the current evidence for ferroptosis regulation mechanisms is based on solid cancer studies, the knowledge of ferroptosis with regard to leukemia is …

Swi/Snf Blockade Disrupts Pu1-Directed Enhancer Programs In Normal Hematopoietic Cells And Acute Myeloid Leukemia, Courtney Chambers, Katerina Cermakova, Yuen San Chan, Kristen Kurtz, Katharina Wohlan, Andrew Henry Lewis, Christiana Wang, Anh Pham, Milan Dejmek, Michal Sala, Mario Loeza Cabrera, Rogelio Aguilar, Radim Nencka, H Daniel Lacorazza, Rachel E Rau, H Courtney Hodges

Faculty, Staff and Students Publications

UNLABELLED: In acute myeloid leukemia (AML), SWI/SNF chromatin remodeling complexes sustain leukemic identity by driving high levels of MYC. Previous studies have implicated the hematopoietic transcription factor PU.1 (SPI1) as an important target of SWI/SNF inhibition, but PU.1 is widely regarded to have pioneer-like activity. As a result, many questions have remained regarding the interplay between PU.1 and SWI/SNF in AML as well as normal hematopoiesis. Here we found that PU.1 binds to most of its targets in a SWI/SNF-independent manner and recruits SWI/SNF to promote accessibility for other AML core regulatory factors, including RUNX1, LMO2, and MEIS1. SWI/SNF inhibition …

Effect Of Thromboprophylaxis On Clinical Outcomes After Covid-19 Hospitalization, Tracy Y Wang, Abdus S Wahed, Alison Morris, Lisa Baumann Kreuziger, John G Quigley, Gervasio A Lamas, Alexandra J Weissman, Jose Lopez-Sendon, M Margaret Knudson, Deborah M Siegal, Raj S Kasthuri, Andrew J Alexander, Lana Wahid, Bassel Atassi, Peter J Miller, Janice W Lawson, Bela Patel, Jerry A Krishnan, Nancy L Shapiro, Deborah E Martin, Andrei L Kindzelski, Eric S Leifer, Jungnam Joo, Lingyun Lyu, Annie Pennella, Brendan M Everett, Mark W Geraci, Kevin J Anstrom, Thomas L Ortel, Activ-4c Study Group

Faculty, Staff and Student Publications

BACKGROUND: Patients hospitalized with COVID-19 have an increased incidence of thromboembolism. The role of extended thromboprophylaxis after hospital discharge is unclear.

OBJECTIVE: To determine whether anticoagulation is superior to placebo in reducing death and thromboembolic complications among patients discharged after COVID-19 hospitalization.

DESIGN: Prospective, randomized, double-blind, placebo-controlled clinical trial. (ClinicalTrials.gov: NCT04650087).

SETTING: Done during 2021 to 2022 among 127 U.S. hospitals.

PARTICIPANTS: Adults aged 18 years or older hospitalized with COVID-19 for 48 hours or more and ready for discharge, excluding those with a requirement for, or contraindication to, anticoagulation.

INTERVENTION: 2.5 mg of apixaban versus placebo twice daily for …

Enoxaparin May Be Associated With Lower Rates Of Mortality Than Unfractionated Heparin In Neurocritical And Surgical Patients, Sophie Samuel, Catherine To, Yaobin Ling, Kai Zhang, Xiaoqian Jiang, Elmer V Bernstam

Faculty, Staff and Student Publications

Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are often administered to prevent venous thromboembolism (VTE) in critically ill patients. However, the preferred prophylactic agent (UFH or LMWH) is not known. We compared the all-cause mortality rate in patients receiving UFH to LMWH for VTE prophylaxis. We conducted a retrospective propensity score adjusted analysis of patients admitted to neuro-critical, surgical, or medical intensive care units. Patients were included if they were screened with venous duplex ultrasonography or computed tomography angiography for detection of VTE. The primary outcome was all-cause mortality. Secondary outcomes included the prevalence of VTE, deep vein …

Clinical Outcomes Associated With Npm1 Mutations In Patients With Relapsed Or Refractory Aml, Ghayas C Issa, Aram Bidikian, Sangeetha Venugopal, Marina Konopleva, Courtney D Dinardo, Tapan M Kadia, Gautam Borthakur, Elias Jabbour, Naveen Pemmaraju, Musa Yilmaz, Nicholas J Short, Abhishek Maiti, Koji Sasaki, Lucia Masarova, Sherry Pierce, Koichi Takahashi, Guilin Tang, Sanam Loghavi, Keyur Patel, Michael Andreeff, Kapil Bhalla, Guillermo Garcia-Manero, Farhad Ravandi, Hagop Kantarjian, Naval Daver

Faculty, Staff and Student Publications

Mutations in Nucleophosmin 1 (NPM1) are associated with a favorable prognosis in newly diagnosed acute myeloid leukemia (AML), however, their prognostic impact in relapsed/refractory (R/R) settings are unknown. In a retrospective analysis, we identified 206 patients (12%) with mutated NPM1 (NPM1c) and compared their outcomes to 1516 patients (88%) with NPM1 wild-type (NPM1wt). NPM1c was associated with higher rates of complete remission or complete remission with incomplete count recovery compared with NPM1wt following each line of salvage therapy (first salvage, 56% vs 37%; P < .0001; second salvage, 33% vs 22%; P = .02; third salvage, 24% vs 14%; P = .02). However, NPM1 mutations had no impact on relapse-free survival (RFS) and overall survival (OS) with each salvage therapy with a median OS following salvage 1, 2 or 3 therapies in NPM1c vs NPM1wt of 7.8 vs 6.0; 5.3 vs 4.1; and 3.5 vs 3.6 months, respectively. Notably, the addition of venetoclax to salvage regimens in patients with NPM1c improved RFS and OS (median RFS, 15.8 vs 4.6 months; P = .05; median OS, 14.7 vs 5.9 months; P = .02). In conclusion, NPM1 mutational status has a minimal impact on prognosis in relapsed or refractory AML; therefore, novel treatment strategies are required to improve outcomes in this entity.

Pd-L1 + Macrophages Are Associated With Favorable Features In Primary Mediastinal (Thymic) Large B-Cell Lymphoma, Raphael E Steiner, Edwin R Parra, Francisco Vega, Lei Feng, Jason R Westin, Sattva S Neelapu, Paolo Strati, Michael R Green, Christopher R Flowers, Luisa M Solis, Ignacio I Wistuba, Sairah Ahmed, Ranjit Nair, Fredrick B Hagemeister, Mansoor Noorani, Mario L Marques-Piubelli

Faculty, Staff and Student Publications

Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is a rare, aggressive subtype of non-Hodgkin lymphoma and has a complex inflammatory microenvironment. Although most patients can be cured with standard-of-care immunochemotherapy, patients who have disease relapse have an unfavorable prognosis. Pre-treatment prognostic biomarkers in PMBCL are needed. In this retrospective study, we analyzed the clinical features and outcomes of PMBCL patients and their association with immune cell subpopulations identified by multiplex immunofluorescence at initial diagnosis. Two different antibody panels were used to assess macrophages in tissue biopsy specimens collected before the initiation of induction therapy. Twelve PMBCL patients, including five patients …

Towards A Biomarker For Acute Arterial Thrombosis Using Complete Blood Count And White Blood Cell Differential Parameters In Mice, Hee Jeong Jang, Dawid Schellingerhout, Jiwon Kim, Jinyong Chung, Dong-Eog Kim

Faculty, Staff and Student Publications

There is no blood biomarker diagnostic of arterial thrombosis. We investigated if arterial thrombosis per se was associated with alterations in complete blood count (CBC) and white blood cell (WBC) differential count in mice. Twelve-week-old C57Bl/6 mice were used for FeCl3-mediated carotid thrombosis (n = 72), sham-operation (n = 79), or non-operation (n = 26). Monocyte count (/µL) at 30-min after thrombosis (median 160 [interquartile range 140-280]) was ~ 1.3-fold higher than at 30-min after sham-operation (120 [77.5-170]), and twofold higher than in non-operated mice (80 [47.5-92.5]). At day-1 and -4 post-thrombosis, compared with 30-min, monocyte count decreased by about …

Building The Foundation For A Community-Generated National Research Blueprint For Inherited Bleeding Disorders: Research Priorities To Transform The Care Of People With Hemophilia, Duc Q Tran, Craig C Benson, Judith A Boice, Meera Chitlur, Amy L Dunn, Miguel A Escobar, Kalpna Gupta, Jill M Johnsen, James Jorgenson, Scott D Martin, Suzanne Martin, Shannon L Meeks, Alfredo A Narvaez, Doris V Quon, Mark T Reding, Ulrike M Reiss, Brittany Savage, Kim Schafer, Bruno Steiner, Courtney Thornburg, Lena M Volland, Annette Von Drygalski

Faculty, Staff and Student Publications

BACKGROUND: Decades of research have transformed hemophilia from severely limiting children's lives to a manageable disorder compatible with a full, active life, for many in high-income countries. The direction of future research will determine whether exciting developments truly advance health equity for all people with hemophilia (PWH). National Hemophilia Foundation (NHF) and American Thrombosis and Hemostasis Network conducted extensive inclusive all-stakeholder consultations to identify the priorities of people with inherited bleeding disorders and those who care for them.

RESEARCH DESIGN AND METHODS: Working group (WG) 1 of the NHF State of the Science Research Summit distilled the community-identified priorities for …

Risk Factors And Prognostic Significance Of Platelet Count Abnormalities In Children With Hiv Infection On Antiretroviral Therapy, Joseph Lubega, Taylor O Kim, Gladstone Airewele, Amanda Grimes, Shaun Bulsara, Erin Peckham, Sebastian R Wanless, Heather Haq, Peter Elyanu, Philippa Musoke, Mwita Lumumba, Adeodata Kekitiinwa, Mogomotsi Matshaba, Michael Scheurer, Jenny Despotovic

Faculty, Staff and Students Publications

OBJECTIVES: To establish the incidence, risk factors and correlation with survival of thrombocytopenia and thrombocytosis (T/T) among children with HIV infection (CWH).

DESIGN: A retrospective nested case control study of patients 0-18 years in five Baylor International Pediatric AIDS Initiative (BIPAI) centers in sub-Sahara Africa, 2004-2014.

METHODS: Clinical and laboratory variables including complete blood counts (CBC) were extracted from the BIPAI electronic medical record system. Incident cases of T/T were identified and frequency-matched on follow-up time with controls with normal platelets. We calculated the prevalence and incidence density of T/T and used conditional logistic regression to evaluate their association with …

Exploiting Prmt5 As A Target For Combination Therapy In Mantle Cell Lymphoma Characterized By Frequent Atm And Tp53 Mutations, Yuxuan Che, Yang Liu, Yixin Yao, Holly A Hill, Yijing Li, Qingsong Cai, Fangfang Yan, Preetesh Jain, Wei Wang, Lixin Rui, Michael Wang

Faculty, Staff and Student Publications

Constant challenges for the treatment of mantle cell lymphoma (MCL) remain to be recurrent relapses and therapy resistance, especially in patients harboring somatic mutations in the tumor suppressors ATM and TP53, which are accumulated as therapy resistance emerges and the disease progresses, consistent with our OncoPrint results that ATM and TP53 alterations were most frequent in relapsed/refractory (R/R) MCL. We demonstrated that protein arginine methyltransferase-5 (PRMT5) was upregulated in R/R MCL, which predicted a poor prognosis. PRMT5 inhibitors displayed profound antitumor effects in the mouse models of MCL with mutated ATM and/or TP53, or refractory to CD19-targeted CAR T-cell therapy. …

Hemoglobinopathy Is Associated With Total Hip Arthroplasty Indication Even Beyond Sickle Cell Anemia, Maxwell J. Rakutt, Daniel N. Bracey, Anna Cohen-Rosenblum, Peter K. Sculco, Franco M. Sabatini, Cale A. Jacobs, Stephen T. Duncan, David C. Landy

School of Medicine Faculty Publications

Background: The extent to which hemoglobinopathies other than sickle anemia (HbSS) are associated with hip osteonecrosis is unknown. Sickle cell trait (HbS), hemoglobin SC (HbSC), and sickle/β-thalassemia (HbSβTh) may also predispose to osteonecrosis of the femoral head (ONFH). We sought to compare the distributions of indications for a total hip arthroplasty (THA) in patients with and without specific hemoglobinopathies. Methods: PearlDiver, an administrative claims database, was used to identify 384,401 patients aged 18 years or older undergoing a THA not for fracture from 2010 to 2020, with patients grouped by diagnosis code (HbSS N = 210, HbSC N = 196, …

Endovascular Vs Medical Management For Late Anterior Large Vessel Occlusion With Prestroke Disability: Analysis Of Clear And Rescue-Japan, James E Siegler, Muhammad M Qureshi, Raul G Nogueira, Kanta Tanaka, Simon Nagel, Patrik Michel, Nicholas Vigilante, Marc Ribo, Hiroshi Yamagami, Shinichi Yoshimura, Mohamad Abdalkader, Diogo C Haussen, Mahmoud H Mohammaden, Stefania Nannoni, Markus A Möhlenbruch, Hilde Henon, Sunil A Sheth, Santiago Ortega-Gutierrez, Marta Olive-Gadea, Francois Caparros, Fatih Seker, Syed Zaidi, Alicia C Castonguay, Kazutaka Uchida, Nobuyuki Sakai, Ajit S Puri, Mudassir Farooqui, Kazunori Toyoda, Sergio Salazar-Marioni, Masataka Takeuchi, Behzad Farzin, Hesham E Masoud, Anna Luisa Kuhn, Ameena Rana, Masafumi Morimoto, Masunari Shibata, Tadashi Nonaka, Piers Klein, Anvitha Sathya, Nicole L Kiley, Charlotte Cordonnier, Davide Strambo, Jelle Demeestere, Peter A Ringleb, Daniel Roy, Osama O Zaidat, Tudor G Jovin, Johannes Kaesmacher, Urs Fischer, Jean Raymond, Thanh N Nguyen

Faculty, Staff and Student Publications

BACKGROUND AND OBJECTIVES: Current guidelines do not address recommendations for mechanical thrombectomy (MT) in the extended time window (>6 hours after time last seen well [TLSW]) for large vessel occlusion (LVO) patients with preexisting modified Rankin Scale (mRS) > 1. In this study, we evaluated the outcomes of MT vs medical management in patients with prestroke disability presenting in the 6- to 24-hour time window with acute LVO.

METHODS: We analyzed a multinational cohort (61 sites, 6 countries from 2014 to 2020) of patients with prestroke (or baseline) mRS 2 to 4 and anterior circulation LVO treated 6-24 hours from …

Factors And Behaviors Related To Successful Transition Of Care After Hospitalization For Ischemic Stroke, Chuanhui Dong, Hannah Gardener, Tatjana Rundek, Erika Marulanda, Carolina M Gutierrez, Iszet Campo-Bustillo, Gillian Gordon Perue, Karlon H Johnson, Ralph L Sacco, Jose G Romano, Transitions Of Care Stroke Disparities Study (Tcsd-S) Investigators

Faculty, Staff and Student Publications

BACKGROUND: Our objective is to describe adoption of the posthospitalization behaviors associated with successful transition of care and related baseline characteristics.

METHODS: This study includes 550 participants in the Transition of Care Stroke Disparities Study, a prospective observational cohort derived from the Florida Stroke Registry. Participants had an ischemic stroke (2018-2021), discharged home or to rehabilitation, with modified Rankin Scale score=0-3 (44% women, 24% Black, 48% White, 26% Hispanic, 35% foreign-born). We collected baseline sociodemographic and clinical characteristics. A structured telephone interview at 30-day postdischarge evaluated outcomes including medication adherence, medical appointment attendance, outpatient therapy, exercise, diet modification, toxic habit …

Association Of Endovascular Thrombectomy Vs Medical Management With Functional And Safety Outcomes In Patients Treated Beyond 24 Hours Of Last Known Well, Amrou Sarraj, Timothy J Kleinig, Ameer E Hassan, Pere Cardona Portela, Santiago Ortega-Gutierrez, Michael G Abraham, Nathan W Manning, James E Siegler, Nitin Goyal, Laith Maali, Spiros Blackburn, Teddy Y Wu, Jordi Blasco, Arturu Renú, Navdeep S Sangha, Juan F Arenillas, Margy E Mccullough-Hicks, Adam Wallace, Daniel Gibson, Deep K Pujara, Faris Shaker, Mercedes De Lera Alfonso, Marta Olivé-Gadea, Mudassir Farooqui, Juan S Vivanco Suarez, Zachary Iezzi, Jane Khalife, Colleen G Lechtenberg, Syed K Qadri, Rami B Moussa, Mohammad A Abdulrazzak, Tareq S Almaghrabi, Osman Mir, James Beharry, Balaji Krishnaiah, Megan Miller, Najwa Khalil, Gagan J Sharma, Aristeidis H Katsanos, Ali Fadhil, Kelsey R Duncan, Yin Hu, Sheryl B Martin-Schild, Georgios K Tsivgoulis, Dennis Cordato, Anthony Furlan, Leonid Churilov, Peter J Mitchell, Adam S Arthur, Mark W Parsons, James C Grotta, Clark W Sitton, Marc Ribo, Gregory W Albers, Bruce C V Campbell

Faculty, Staff and Student Publications

IMPORTANCE: The role of endovascular thrombectomy is uncertain for patients presenting beyond 24 hours of the time they were last known well.

OBJECTIVE: To evaluate functional and safety outcomes for endovascular thrombectomy (EVT) vs medical management in patients with large-vessel occlusion beyond 24 hours of last known well.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective observational cohort study enrolled patients between July 2012 and December 2021 at 17 centers across the United States, Spain, Australia, and New Zealand. Eligible patients had occlusions in the internal carotid artery or middle cerebral artery (M1 or M2 segment) and were treated with EVT or …

Association Of Endovascular Thrombectomy Vs Medical Management With Functional And Safety Outcomes In Patients Treated Beyond 24 Hours Of Last Known Well, Amrou Sarraj, Timothy J Kleinig, Ameer E Hassan, Pere Cardona Portela, Santiago Ortega-Gutierrez, Michael G Abraham, Nathan W Manning, James E Siegler, Nitin Goyal, Laith Maali, Spiros Blackburn, Teddy Y Wu, Jordi Blasco, Arturu Renú, Navdeep S Sangha, Juan F Arenillas, Margy E Mccullough-Hicks, Adam Wallace, Daniel Gibson, Deep K Pujara, Faris Shaker, Mercedes De Lera Alfonso, Marta Olivé-Gadea, Mudassir Farooqui, Juan S Vivanco Suarez, Zachary Iezzi, Jane Khalife, Colleen G Lechtenberg, Syed K Qadri, Rami B Moussa, Mohammad A Abdulrazzak, Tareq S Almaghrabi, Osman Mir, James Beharry, Balaji Krishnaiah, Megan Miller, Najwa Khalil, Gagan J Sharma, Aristeidis H Katsanos, Ali Fadhil, Kelsey R Duncan, Yin Hu, Sheryl B Martin-Schild, Georgios K Tsivgoulis, Dennis Cordato, Anthony Furlan, Leonid Churilov, Peter J Mitchell, Adam S Arthur, Mark W Parsons, James C Grotta, Clark W Sitton, Marc Ribo, Gregory W Albers, Bruce C V Campbell

Faculty, Staff and Student Publications

IMPORTANCE: The role of endovascular thrombectomy is uncertain for patients presenting beyond 24 hours of the time they were last known well.

OBJECTIVE: To evaluate functional and safety outcomes for endovascular thrombectomy (EVT) vs medical management in patients with large-vessel occlusion beyond 24 hours of last known well.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective observational cohort study enrolled patients between July 2012 and December 2021 at 17 centers across the United States, Spain, Australia, and New Zealand. Eligible patients had occlusions in the internal carotid artery or middle cerebral artery (M1 or M2 segment) and were treated with EVT or …

Smart Start: Rituximab, Lenalidomide, And Ibrutinib In Patients With Newly Diagnosed Large B-Cell Lymphoma, Jason Westin, R Eric Davis, Lei Feng, Fredrick Hagemeister, Raphael Steiner, Hun Ju Lee, Luis Fayad, Loretta Nastoupil, Sairah Ahmed, Alma Rodriguez, Michelle Fanale, Felipe Samaniego, Swaminathan P Iyer, Ranjit Nair, Yasuhiro Oki, Nathan Fowler, Michael Wang, Man Chun John Ma, Francisco Vega, Timothy Mcdonnell, Chelsea Pinnix, Donna Griffith, Yang Lu, Sanjit Tewari, Ryan Sun, David W Scott, Christopher R Flowers, Sattva Neelapu, Michael R Green

Faculty, Staff and Student Publications

PURPOSE: Chemoimmunotherapy for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) is largely unchanged for decades. Both preclinical models and clinical data suggest the combination of lenalidomide and ibrutinib may have synergy in DLBCL, particularly in the non-germinal center B-cell-like subset.

METHODS: We enrolled 60 patients with newly diagnosed non-germinal center B-cell-like DLBCL in this investigator-initiated, single-arm phase II trial of rituximab, lenalidomide, and ibrutinib (RLI) with the sequential addition of chemotherapy (ClinicalTrials.gov identifier: NCT02636322). Patients were treated with rituximab 375 mg/m

RESULTS: The median age was 63.5 years (range, 29-83 years) with 28% age 70 years or older. …