Hemic and Lymphatic Diseases Commons^™

Addition Of Aspirin To Venous Thromboembolism Chemoprophylaxis Safely Decreases Venous Thromboembolism Rates In Trauma Patients, Daniel Lammers, Michelle Scerbo, Annamaria Davidson, Matthew Pommerening, Jeffrey Tomasek, Charles E Wade, Jessica Cardenas, Jan Jansen, Charles C Miller, John B Holcomb

Faculty, Staff and Student Publications

Background: Trauma patients exhibit a multifactorial hypercoagulable state and have increased risk of venous thromboembolism (VTE). Despite early and aggressive chemoprophylaxis (CP) with various heparin compounds ("standard" CP; sCP), VTE rates remain high. In high-quality studies, aspirin has been shown to decrease VTE in postoperative elective surgical and orthopedic trauma patients. We hypothesized that inhibiting platelet function with aspirin as an adjunct to sCP would reduce the risk of VTE in trauma patients.

Methods: We performed a retrospective observational study of prospectively collected data from all adult patients admitted to an American College of Surgeons Level I Trauma center from …

Refractory Thrombocytopenia During Liver Transplantation Requiring Splenectomy, Ivana Wrobleski Wilder, Alexander Reskallah, Catherine M Pivalizza, John S Bynon, Evan G Pivalizza

Faculty, Staff and Student Publications

Although thrombocytopenia is common in end-stage liver disease, severe, refractory thrombocytopenia during liver transplantation is rare, and if immune based, usually presents months or years later. This case describes an adult woman in whom preoperative evaluation had not determined an immune-related cause of thrombocytopenia. Clot strength was dramatically impaired as measured by thrombelastography during the transplant. Following a lack of response to repeat platelet transfusions, splenectomy was performed after graft reperfusion with rapid temporal restoration of clot strength. This case shows a severe manifestation of perioperative thrombocytopenia during liver transplantation and clinically guided management when measured clot strength is too …

Membranous Nephropathy In Chronic Lymphocytic Leukemia Responsive To Ibrutinib: A Case Report, Anna-Eve Turcotte, William F Glass, Jamie S Lin, Jan A Burger

Faculty, Staff and Student Publications

Membranous nephropathy (MN) is an uncommon renal presentation in patients with chronic lymphocytic leukemia (CLL), and as such, there is no standard therapy for these patients. A few cases of MN in CLL have been described with varying success in MN treatment involving alkylating agents and fludarabine. Here we report the first case of MN in a patient with CLL treated with ibrutinib with complete renal response. This presentation underlines the importance of recognizing rare glomerular diseases that may occur with CLL and offers a new therapeutic avenue to the treatment of CLL-associated MN.

Improved Outcomes With “7+3” Induction Chemotherapy For Acute Myeloid Leukemia Over The Past Four Decades: Analysis Of Swog Trial Data, Megan Othus, Guillermo Garcia-Manero, John E Godwin, James K Weick, Frederick R Appelbaum, Harry P Erba, Elihu H Estey

Faculty, Staff and Student Publications

We have previously shown that complete response (CR) rates and overall survival of patients with acute myeloid leukemia have improved since the 1980s. However, we have not previously evaluated how the length of first CR (CR1) has changed over this time period. To address this, we analyzed 1,247 patients aged 65 or younger randomized to "7+3" arms from five SWOG studies: S8600 (n=530), S9031 (n=98), S9333 (n=57), S0106 (n=301), and S1203 (n=261). We evaluated length of CR1 and survival after relapse from CR1 over the four decades that these studies represent. Both length of CR1 and survival after relapse from …

Strengthening Deep-Learning Models For Intracranial Hemorrhage Detection: Strongly Annotated Computed Tomography Images And Model Ensembles, Dong-Wan Kang, Gi-Hun Park, Wi-Sun Ryu, Dawid Schellingerhout, Museong Kim, Yong Soo Kim, Chan-Young Park, Keon-Joo Lee, Moon-Ku Han, Han-Gil Jeong, Dong-Eog Kim

Faculty, Staff and Student Publications

BACKGROUND AND PURPOSE: Multiple attempts at intracranial hemorrhage (ICH) detection using deep-learning techniques have been plagued by clinical failures. We aimed to compare the performance of a deep-learning algorithm for ICH detection trained on strongly and weakly annotated datasets, and to assess whether a weighted ensemble model that integrates separate models trained using datasets with different ICH improves performance.

METHODS: We used brain CT scans from the Radiological Society of North America (27,861 CT scans, 3,528 ICHs) and AI-Hub (53,045 CT scans, 7,013 ICHs) for training. DenseNet121, InceptionResNetV2, MobileNetV2, and VGG19 were trained on strongly and weakly annotated datasets and …

Integrated Clinical Genotype-Phenotype Characteristics Of Early T-Cell Precursor Acute Lymphoblastic Leukemia, Matthew T Ye, Yi Wang, Zhuang Zuo, Steliana Calin, Hua He, Zhenya Tang, Elias J Jabbour, Gautam Borthakur, Yizhuo Zhang, Yaling Yang, M James You

Faculty, Staff and Student Publications

Background: Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a distinct subtype of T-ALL with a unique immunophenotype and high treatment failure rate. The molecular genetic abnormalities and their prognostic impact in ETP-ALL patients are poorly understood.

Methods: The authors performed systematic analyses of the clinicopathologic features with an emphasis on molecular genetic aspects of 32 patients with ETP-ALL.

Results: The median age was 43 years (range, 16-71). The blasts were positive for cytoplasmic CD3 and CD7 and negative for CD1a and CD8. Other markers expressed included CD34 (88%), CD33 (72%), CD117 (68%), CD13 (58%), CD5 (partial, 56%), CD2 (38%), …

Induction Of Thrombotic Thrombocytopenic Purpura By Dengue Virus Infection In A Critical Patient: Role Of Therapeutic Plasma Exchange, Rathindra Nath Biswas, Sudipta Sekhar Das, Anupam Chakrapani, Subrata Sen

Faculty, Staff and Student Publications

Thrombotic thrombocytopenic purpura (TTP) secondary to dengue fever is a very unusual occurrence. Both conditions are fatal and can result in significant mortality and morbidity if left untreated. In this case, we present a young lady who suffered dengue fever followed by microangiopathic anemia, thrombocytopenic purpura, and altered sensorium. Investigations revealed microangiopathic hemolysis; there was no evidence of disseminated intravascular coagulation. As soon as, we diagnosed the patient as having TTP, we treated her with serial plasma exchange therapy, steroids, and monoclonal antibodies such as rituximab. The patient responded very well to the treatment and completely recovered from neurological symptoms …

Development And Validation Of Early Death Risk Score Model For Emergency Status Prediction In Very Severe Aplastic Anemia, Xu Liu, Wenrui Yang, Li Zhang, Liping Jing, Lei Ye, Kang Zhou, Yuan Li, Jianping Li, Huihui Fan, Yang Yang, Youzhen Xiong, Xin Zhao, Fengkui Zhang

Faculty, Staff and Student Publications

This study developed and validated the Early Death Risk Score Model for early identification of emergency patients with very severe aplastic anemia (VSAA). All 377 patients with VSAA receiving first-line immunosuppressive therapy (IST) were categorized into training (n=252) and validation (n=125) cohorts. In the training cohort, age >24 years, absolute neutrophil count ≤0.015×109/L, serum ferritin >900ng/mL and times of fever before IST >1 time were significantly associated with early death. Covariates were assigned scores and categorized as: low (score 0-4), medium (score 5-7) and high (score ≥8) risk. Early death rate was significantly different between risk groups and the validation …

Acute Myeloid Leukemia With Concurrent Npm1 And Runx1 Mutations, Zhuang Zuo, L Jeffrey Medeiros, C Cameron Yin

Faculty, Staff and Student Publications

NPM1 mutation, as a founding genetic event, cooperates with other gene mutations, such as DNMT3A and FLT3, to promote the development of acute myeloid leukemia. NPM1 mutation, however, has been reported to be mutually exclusive with RUNX1 mutation in acute myeloid leukemia cases. In this study, we analyzed mutation panel testing data from a relatively large cohort of rare AML cases with both NPM1 and RUNX1 mutations. We describe the dynamic process of the emergence of these mutations, as well as molecular genetic features and clinical outcome of these patients. We show that concurrence of both mutations in acute …

Mdm2 Antagonist Improves Therapeutic Activity Of Azacitidine In Myelodysplastic Syndromes And Chronic Myelomonocytic Leukemia, Yue Wei, Hong Zheng, Pamela Pennington Lockyer, Faezeh Darbaniyan, Ziyi Li, Rashmi Kanagal-Shamanna, Kelly A Soltysiak, Hui Yang, Irene Ganan-Gomez, Guillermo Montalban-Bravo, Kelly S Chien, Kim-Anh Do, Naval Daver, Guillermo Garcia-Manero

Faculty, Staff and Student Publications

Failure of hypomethylation agent (HMA) treatments is an important issue in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Recent studies indicated that function of wildtype TP53 positively impacts outcome of HMA treatments. We investigated the combination of the HMA azacitidine (AZA) with DS-3032b and DS-5272, novel antagonists of the TP53 negative regulator MDM2, in cellular and animal models of MDS and CMML. In TP53 wildtype myeloid cell line, combinational effects of DS-3032b or DS-5272 with AZA were observed. In Tet2-knockout mouse model of MDS and CMML, DS-5272 and AZA combination ameliorated disease-like phenotype. RNA-Seq analysis in mouse bone …

Clinical And Molecular Profiling Of Aml Patients With Chromosome 7 Or 7q Deletions In The Context Of Tp53 Alterations And Venetoclax Treatment, Hussein A Abbas, Edward Ayoub, Hanxiao Sun, Rashmi Kanagal-Shamanna, Nicholas J Short, Ghayas Issa, Musa Yilmaz, Sherry Pierce, Daniel Rivera, Brent Cham, Shane Wing, Ziyi Li, Danielle Hammond, Elias Jabbour, Gautam Borthakur, Guillermo Garcia-Manero, Michael Andreeff, Naval Daver, Tapan Kadia, Marina Konopleva, Courtney Dinardo, Farhad Ravandi

Faculty, Staff and Student Publications

Deletions in chromosome 7 (del(7)) or its long arm (del(7q)) constitute the most common adverse cytogenetic events in acute myeloid leukemia (AML). We retrospectively analyzed 243 treatment-naive patients with AML and del(7) (168/243; 69%) or del(7q) (75/243; 31%) who did not receive any myeloid-directed therapy prior to AML diagnosis. This is the largest comprehensive clinical and molecular analysis of AML patients with del(7) and del(7q). Our results show that relapse-free survival was significantly longer for AML patients with del(7q) compared to del(7), but the overall survival and remission duration were similar. TP53 mutations and del5/5q were the most frequent co-occurring …

Development Of A Distributed International Patient Data Registry For Hairy Cell Leukemia, Leslie A Andritsos, Mirela Anghelina, Jasmine Neal, James S Blachly, Puneet Mathur, Omkar Lele, Claire Dearden, Sunil Iyengar, Matthew Cross, Clive S Zent, Kerry A Rogers, Narendranath Epperla, Gerard Lozanski, Christopher C Oakes, Eric Kraut, Amy S Ruppert, Qiuhong Zhao, Seema A Bhat, Francesco Forconi, Versha Banerji, Sasanka Handunnetti, Constantine S Tam, John F Seymour, Monica Else, Robert J Kreitman, Alan Saven, Timothy Call, Sameer A Parikh, Farhad Ravandi, James B Johnston, Enrico Tiacci, Xavier Troussard, Martin S Tallman, Sascha Dietrich, Tamar Tadmor, Alessandro Gozzetti, Pier Luigi Zinzani, Tadeusz Robak, Graeme Quest, Judit Demeter, Kanti Rai, Soledad A Fernandez, Michael Grever

Faculty, Staff and Student Publications

Hairy cell leukemia (HCL) is a rare lymphoproliferative disorder, comprising only 2% of all leukemias. The Hairy Cell Leukemia Foundation (HCLF) has developed a patient data registry to enable investigators to better study the clinical features, treatment outcomes, and complications of patients with HCL. This system utilizes a centralized registry architecture. Patients are enrolled at HCL Centers of Excellence (COE) or via a web-based portal. All data are de-identified, which reduces regulatory burden and increases opportunities for data access and re-use. To date, 579 patients have been enrolled in the registry. Efforts are underway to engage additional COE's to expand …

Association Of Hematologic Response And Assay Sensitivity On The Prognostic Impact Of Measurable Residual Disease In Acute Myeloid Leukemia: A Systematic Review And Meta-Analysis, Nicholas J Short, Chenqi Fu, Donald A Berry, Roland B Walter, Sylvie D Freeman, Christopher S Hourigan, Xuelin Huang, Graciela Nogueras Gonzalez, Hyunsoo Hwang, Xinyue Qi, Hagop Kantarjian, Shouhao Zhou, Farhad Ravandi

Faculty, Staff and Student Publications

Measurable residual disease (MRD) is associated with relapse and survival in acute myeloid leukemia (AML). We aimed to quantify the impact of MRD on outcomes across clinical contexts, including its association with hematologic response and MRD assay sensitivity. We performed systematic literature review and meta-analysis of 48 studies that reported the association between MRD and overall survival (OS) or disease-free survival (DFS) in AML and provided information on the MRD threshold used and the hematologic response of the study population. Among studies limited to patients in complete remission (CR), the estimated 5-year OS for the MRD-negative and MRD-positive groups was …

Genomic Profiling For Clinical Decision Making In Myeloid Neoplasms And Acute Leukemia, Eric J Duncavage, Adam Bagg, Robert P Hasserjian, Courtney D Dinardo, Lucy A Godley, Ilaria Iacobucci, Siddhartha Jaiswal, Luca Malcovati, Alessandro M Vannucchi, Keyur P Patel, Daniel A Arber, Maria E Arcila, Rafael Bejar, Nancy Berliner, Michael J Borowitz, Susan Branford, Anna L Brown, Catherine A Cargo, Hartmut Döhner, Brunangelo Falini, Guillermo Garcia-Manero, Torsten Haferlach, Eva Hellström-Lindberg, Annette S Kim, Jeffery M Klco, Rami Komrokji, Mignon Lee-Cheun Loh, Sanam Loghavi, Charles G Mullighan, Seishi Ogawa, Attilio Orazi, Elli Papaemmanuil, Andreas Reiter, David M Ross, Michael Savona, Akiko Shimamura, Radek C Skoda, Francesc Solé, Richard M Stone, Ayalew Tefferi, Matthew J Walter, David Wu, Benjamin L Ebert, Mario Cazzola

Faculty, Staff and Student Publications

Myeloid neoplasms and acute leukemias derive from the clonal expansion of hematopoietic cells driven by somatic gene mutations. Although assessment of morphology plays a crucial role in the diagnostic evaluation of patients with these malignancies, genomic characterization has become increasingly important for accurate diagnosis, risk assessment, and therapeutic decision making. Conventional cytogenetics, a comprehensive and unbiased method for assessing chromosomal abnormalities, has been the mainstay of genomic testing over the past several decades and remains relevant today. However, more recent advances in sequencing technology have increased our ability to detect somatic mutations through the use of targeted gene panels, whole-exome …

Phase Ii Study Of Venetoclax Added To Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine In Older Patients With Newly Diagnosed Acute Myeloid Leukemia, Tapan M Kadia, Patrick K Reville, Xuemei Wang, Caitlin R Rausch, Gautam Borthakur, Naveen Pemmaraju, Naval G Daver, Courtney D Dinardo, Koji Sasaki, Ghayas C Issa, Maro Ohanian, Guillermo Montalban-Bravo, Nicholas J Short, Nitin Jain, Alessandra Ferrajoli, Kapil N Bhalla, Elias Jabbour, Koichi Takahashi, Rashmi Malla, Kelly Quagliato, Rashmi Kanagal-Shamanna, Uday R Popat, Michael Andreeff, Guillermo Garcia-Manero, Marina Y Konopleva, Farhad Ravandi, Hagop M Kantarjian

Faculty, Staff and Student Publications

PURPOSE: The combination of venetoclax and 5-azacitidine (5-AZA) for older or unfit patients with acute myeloid leukemia (AML) improves remission rates and survival compared with 5-AZA alone. We hypothesized that the addition of venetoclax to cladribine (CLAD)/low-dose araC (low-dose cytarabine [LDAC]) alternating with 5-AZA backbone may further improve outcomes for older patients with newly diagnosed AML.

METHODS: This is a phase II study investigating the combination of venetoclax and CLAD/LDAC alternating with venetoclax and 5-AZA in older (≥ 60 years) or unfit patients with newly diagnosed AML. The primary objective was composite complete response (CR) rate (CR plus CR with …

Preclinical Evaluation Of Combination Nemtabrutinib And Venetoclax In Chronic Lymphocytic Leukemia, Elizabeth M Muhowski, Janani Ravikrishnan, Britten Gordon, Lianbo Yu, Shrilekha Misra, Brandi Walker, Sudharshan Eathiraj, Deepa Sampath, Kerry A Rogers, John C Byrd, Jennifer A Woyach

Faculty, Staff and Student Publications

Inhibitors of B cell receptor (BCR) signaling such as the Bruton's tyrosine kinase (BTK) inhibitors are effective therapeutics for chronic lymphocytic leukemia (CLL). The first-in-class covalent BTK inhibitor, ibrutinib, produces durable responses in most CLL patients; however, complete responses are only observed in a minority of patients. B cell lymphoma 2 (BCL2), an anti-apoptotic protein that contributes to CLL cell survival, has also been investigated as a therapeutic target. The BCL2 inhibitor venetoclax is effective in patients with CLL and can produce undetectable minimal residual disease, allowing discontinuation of therapy. In combination, ibrutinib and venetoclax have shown preclinical synergy and …

A High-Resolution 3d Atlas Of The Spectrum Of Tuberculous Andcovid-19 Lung Lesions, Gordon Wells, Joel N Glasgow, Kievershen Nargan, Kapongo Lumamba, Rajhmun Madansein, Kameel Maharaj, Leon Y Perumal, Malcolm Matthew, Robert L Hunter, Hayden Pacl, Jacelyn E Peabody Lever, Denise D Stanford, Satinder P Singh, Prachi Bajpai, Upender Manne, Paul V Benson, Steven M Rowe, Stephan Le Roux, Alex Sigal, Muofhe Tshibalanganda, Carlyn Wells, Anton Du Plessis, Mpumelelo Msimang, Threnesan Naidoo, Adrie J C Steyn

Faculty, Staff and Student Publications

Our current understanding of the spectrum of TB and COVID-19 lesions in the human lung is limited by a reliance on low-resolution imaging platforms that cannot provide accurate 3D representations of lesion types within the context of the whole lung. To characterize TB and COVID-19 lesions in 3D, we applied micro/nanocomputed tomography to surgically resected, postmortem, and paraffin-embedded human lung tissue. We define a spectrum of TB pathologies, including cavitary lesions, calcium deposits outside and inside necrotic granulomas and mycetomas, and vascular rearrangement. We identified an unusual spatial arrangement of vasculature within an entire COVID-19 lobe, and 3D segmentation of …

Tp53-Mutated Myelodysplastic Syndrome And Acute Myeloid Leukemia: Biology, Current Therapy, And Future Directions, Naval G Daver, Abhishek Maiti, Tapan M Kadia, Paresh Vyas, Ravindra Majeti, Andrew H Wei, Guillermo Garcia-Manero, Charles Craddock, David A Sallman, Hagop M Kantarjian

Faculty, Staff and Student Publications

UNLABELLED: TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) form a distinct group of myeloid disorders with dismal outcomes. TP53-mutated MDS and AML have lower response rates to either induction chemotherapy, hypomethylating agent-based regimens, or venetoclax-based therapies compared with non-TP53-mutated counterparts and a poor median overall survival of 5 to 10 months. Recent advances have identified novel pathogenic mechanisms in TP53-mutated myeloid malignancies, which have the potential to improve treatment strategies in this distinct clinical subgroup. In this review, we discuss recent insights into the biology of TP53-mutated MDS/AML, current treatments, and emerging therapies, including immunotherapeutic and nonimmune-based approaches …

Targeting The Eif2ak1 Signaling Pathway Rescues Red Blood Cell Production In Sf3b1-Mutant Myelodysplastic Syndromes With Ringed Sideroblasts, Vera Adema, Feiyang Ma, Rashmi Kanagal-Shamanna, Natthakan Thongon, Guillermo Montalban-Bravo, Hui Yang, Scott A Peslak, Feng Wang, Pamela Acha, Francesc Sole, Pamela Lockyer, Margherita Cassari, Jaroslaw P Maciejewski, Valeria Visconte, Irene Gañán-Gómez, Yuanbin Song, Carlos Bueso-Ramos, Matteo Pellegrini, Tuyet M Tan, Rafael Bejar, Jennifer S Carew, Stephanie Halene, Valeria Santini, Gheath Al-Atrash, Karen Clise-Dwyer, Guillermo Garcia-Manero, Gerd A Blobel, Simona Colla

Faculty, Staff and Student Publications

SF3B1 mutations, which occur in 20% of patients with myelodysplastic syndromes (MDS), are the hallmarks of a specific MDS subtype, MDS with ringed sideroblasts (MDS-RS), which is characterized by the accumulation of erythroid precursors in the bone marrow and primarily affects the elderly population. Here, using single-cell technologies and functional validation studies of primary SF3B1-mutant MDS-RS samples, we show that SF3B1 mutations lead to the activation of the EIF2AK1 pathway in response to heme deficiency and that targeting this pathway rescues aberrant erythroid differentiation and enables the red blood cell maturation of MDS-RS erythroblasts. These data support the development of …

Stroke Genetics Informs Drug Discovery And Risk Prediction Across Ancestries, Aniket Mishra, Rainer Malik, Tsuyoshi Hachiya, Tuuli Jürgenson, Shinichi Namba, Daniel C Posner, Frederick K Kamanu, Masaru Koido, Quentin Le Grand, Mingyang Shi, Yunye He, Marios K Georgakis, Ilana Caro, Kristi Krebs, Yi-Ching Liaw, Felix C Vaura, Kuang Lin, Bendik Slagsvold Winsvold, Vinodh Srinivasasainagendra, Livia Parodi, Hee-Joon Bae, Ganesh Chauhan, Michael R Chong, Liisa Tomppo, Rufus Akinyemi, Gennady V Roshchupkin, Naomi Habib, Yon Ho Jee, Jesper Qvist Thomassen, Vida Abedi, Jara Cárcel-Márquez, Marianne Nygaard, Hampton L Leonard, Chaojie Yang, Ekaterina Yonova-Doing, Maria J Knol, Adam J Lewis, Renae L Judy, Tetsuro Ago, Philippe Amouyel, Nicole D Armstrong, Mark K Bakker, Traci M Bartz, David A Bennett, Joshua C Bis, Constance Bordes, Sigrid Børte, Anael Cain, Paul M Ridker, Kelly Cho, Zhengming Chen, Carlos Cruchaga, John W Cole, Phil L De Jager, Rafael De Cid, Matthias Endres, Leslie E Ferreira, Mirjam I Geerlings, Natalie C Gasca, Vilmundur Gudnason, Jun Hata, Jing He, Alicia K Heath, Yuk-Lam Ho, Aki S Havulinna, Jemma C Hopewell, Hyacinth I Hyacinth, Michael Inouye, Mina A Jacob, Christina E Jeon, Christina Jern, Masahiro Kamouchi, Keith L Keene, Takanari Kitazono, Steven J Kittner, Takahiro Konuma, Amit Kumar, Paul Lacaze, Lenore J Launer, Keon-Joo Lee, Kaido Lepik, Jiang Li, Liming Li, Ani Manichaikul, Hugh S Markus, Nicholas A Marston, Thomas Meitinger, Braxton D Mitchell, Felipe A Montellano, Takayuki Morisaki, Thomas H Mosley, Mike A Nalls, Børge G Nordestgaard, Martin J O'Donnell, Yukinori Okada, N Charlotte Onland-Moret, Bruce Ovbiagele, Annette Peters, Bruce M Psaty, Stephen S Rich, Jonathan Rosand, Marc S Sabatine, Ralph L Sacco, Danish Saleheen, Else Charlotte Sandset, Veikko Salomaa, Muralidharan Sargurupremraj, Makoto Sasaki, Claudia L Satizabal, Carsten O Schmidt, Atsushi Shimizu, Nicholas L Smith, Kelly L Sloane, Yoichi Sutoh, Yan V Sun, Kozo Tanno, Steffen Tiedt, Turgut Tatlisumak, Nuria P Torres-Aguila, Hemant K Tiwari, David-Alexandre Trégouët, Stella Trompet, Anil Man Tuladhar, Anne Tybjærg-Hansen, Marion Van Vugt, Riina Vibo, Shefali S Verma, Kerri L Wiggins, Patrik Wennberg, Daniel Woo, Peter W F Wilson, Huichun Xu, Qiong Yang, Kyungheon Yoon, Compass Consortium, Invent Consortium, Dutch Parelsnoer Initiative (Psi) Cerebrovascular Disease Study Group, Estonian Biobank, Precise4q Consortium, Finngen Consortium, Ninds Stroke Genetics Network (Sign), Megastroke Consortium, Siren Consortium, China Kadoorie Biobank Collaborative Group, Va Million Veteran Program, International Stroke Genetics Consortium (Isgc), Biobank Japan, Charge Consortium, Gigastroke Consortium, Iona Y Millwood, Christian Gieger, Toshiharu Ninomiya, Hans J Grabe, J Wouter Jukema, Ina L Rissanen, Daniel Strbian, Young Jin Kim, Pei-Hsin Chen, Ernst Mayerhofer, Joanna M M Howson, Marguerite R Irvin, Hieab Adams, Sylvia Wassertheil-Smoller, Kaare Christensen, Mohammad A Ikram, Tatjana Rundek, Bradford B Worrall, G Mark Lathrop, Moeen Riaz, Eleanor M Simonsick, Janika Kõrv, Paulo H C França, Ramin Zand, Kameshwar Prasad, Ruth Frikke-Schmidt, Frank-Erik De Leeuw, Thomas Liman, Karl Georg Haeusler, Ynte M Ruigrok, Peter Ulrich Heuschmann, W T Longstreth, Keum Ji Jung, Lisa Bastarache, Guillaume Paré, Scott M Damrauer, Daniel I Chasman, Jerome I Rotter, Christopher D Anderson, John-Anker Zwart, Teemu J Niiranen, Myriam Fornage, Yung-Po Liaw, Sudha Seshadri, Israel Fernández-Cadenas, Robin G Walters, Christian T Ruff, Mayowa O Owolabi, Jennifer E Huffman, Lili Milani, Yoichiro Kamatani, Martin Dichgans, Stephanie Debette

Faculty, Staff and Student Publications

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary …

Immune Dysfunction Signatures Predict Outcomes And Define Checkpoint Blockade-Unresponsive Microenvironments In Acute Myeloid Leukemia, Sergio Rutella, Jayakumar Vadakekolathu, Francesco Mazziotta, Stephen Reeder, Tung-On Yau, Rupkatha Mukhopadhyay, Benjamin Dickins, Heidi Altmann, Michael Kramer, Hanna A Knaus, Bruce R Blazar, Vedran Radojcic, Joshua F Zeidner, Andrea Arruda, Bofei Wang, Hussein A Abbas, Mark D Minden, Sarah K Tasian, Martin Bornhäuser, Ivana Gojo, Leo Luznik

Faculty, Staff and Student Publications

Background

Immune exhaustion and senescence are dominant dysfunctional states of effector T cells and major hurdles for the success of cancer immunotherapy. In the current study, we characterized how acute myeloid leukemia (AML) promotes the generation of senescent-like CD8⁺ T cells and whether they have prognostic relevance.

METHODS

We analyzed NanoString, bulk RNA-Seq and single-cell RNA-Seq data from independent clinical cohorts comprising 1,896 patients treated with chemotherapy and/or immune checkpoint blockade (ICB).

Results

We show that senescent-like bone marrow CD8⁺ T cells were impaired in killing autologous AML blasts and that their proportion negatively correlated with overall survival …

Protein Profiling By Reverse Phase Protein Array (Rppa) In Classical Hairy Cell Leukemia (Hcl) And Hcl-Variant, Fieke W Hoff, Ti'ara L Griffen, Yihua Qiu, Steven M Kornblau

Faculty, Staff and Student Publications

Classical hairy cell leukemia (HCL-c) and HCL variant (HCL-v) are recognized as separate entities with HCL-v having significantly shorter overall survival. Proteomic studies, shown to be prognostic in various forms of leukemia, have not been performed in HCL. We performed reverse phase protein array-based protein profiling with 384 antibodies in HCL-c (

Evaluation Of Allogeneic And Autologous Membrane-Bound Il-21-Expanded Nk Cells For Chronic Lymphocytic Leukemia Therapy, Max Yano, Chia Sharpe, J Rachel Lance, Janani Ravikrishnan, Kevan Zapolnik, Xiaokui Mo, Jennifer A Woyach, Deepa Sampath, Adam S Kittai, Sumithira Vasu, Seema Bhat, Kerry A Rogers, Dean A Lee, Natarajan Muthusamy, John C Byrd

Faculty, Staff and Student Publications

Successes with anti-CD20 antibodies in chronic lymphocytic leukemia (CLL) and enhanced activity of Fc-engineered vs unmodified antibody therapy suggest a potentially impactful role for natural killer (NK) cells and other innate immune cells in controlling this disease. Stimulated NK cells have shown promise as a cellular therapy, but their application has been constrained by limited expansion capacity and low cytotoxic activity against CLL cells. Here, we demonstrate that both healthy donor-derived and CLL patient-derived NK cells expand rapidly when stimulated with feeder cells expressing membrane-bound interleukin-21 (mbIL-21) and have potent cytotoxic activity against allogeneic or autologous CLL cells. Combination with …

Serological Evidence Of Severe Fever With Thrombocytopenia Syndrome Virus And Igm Positivity Were Identified In Healthy Residents In Vietnam, Xuan Chuong Tran, Sung Hye Kim, Jeong-Eun Lee, So-Hee Kim, Su Yeon Kang, Nguyen D Binh, Pham V Duc, Phan T K Phuong, Nguyen T P Thao, Wonwoo Lee, Joon-Yong Bae, Man-Seong Park, Misun Kim, Jeong Rae Yoo, Sang Taek Heo, Kyeong Ho An, Jung Mogg Kim, Nam-Hyuk Cho, Sun-Ho Kee, Keun Hwa Lee

Faculty, Staff and Student Publications

Severe fever with thrombocytopenia syndrome (SFTS), an emerging tick-borne viral disease, is prevalent in East Asia and has also been reported in Southeast Asia since 2019. SFTS patients in Vietnam were first reported in 2019. However, the seroprevalence of severe fever with thrombocytopenia syndrome virus (SFTSV) in Vietnam has not been reported. To investigate the seroprevalence of SFTSV in Vietnam, we collected serum samples from 714 healthy residents in Thua Thien Hue and Quang Nam Province, Vietnam, and the seroprevalence of SFTSV was assessed using immunofluorescence antibody assay (IFA), Enzyme-Linked Immunosorbent Assays (ELISAs) and the 50% focus reduction neutralization test …

Thromboembolism In Children With Multisystem Inflammatory Syndrome: A Literature Review, Neethu M Menon, Lakshmi V Srivaths

Faculty, Staff and Student Publications

Multisystem inflammatory syndrome in children (MIS-C) is a hyperinflammatory response observed in children several weeks to months after acute infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). On review of all published cases of thromboembolism (TE) as a complication of MIS-C, 33 cases of TE were found with incidence ranging from 1.4 to 6.5%. TE occurred mostly in children aged 12 years and above. One-third of the cases were cerebral infarcts and the remaining cases included intracardiac and radial arterial thromboses, upper and lower extremity deep vein thrombosis, pulmonary embolism, and splenic infarcts. Five were asymptomatic cases and 3/33 (9%) …

Metabolic, Physiological And Anatomical Responses Of Soybean Plants Under Water Deficit And High Temperature Condition, Roberto Gomes Vital, Caroline Müller, Francisco Bruno Silva Freire, Fábia Barbosa Silva, Priscila Ferreira Batista, David Fuentes, Arthur Almeida Rodrigues, Luciana Minervina Freitas Moura, Danilo Menezes Daloso, Adinan Alves Silva, Andrew Merchant, Alan Carlos Costa

Faculty, Staff and Student Publications

Water deficit (WD) combined with high temperature (HT) is the major factor limiting agriculture worldwide, and it is predicted to become worse according to the current climate change scenario. It is thus important to understand how current cultivated crops respond to these stress conditions. Here we investigated how four soybean cultivars respond to WD and HT isolated or in combination at metabolic, physiological, and anatomical levels. The WD + HT increased the level of stress in soybean plants when compared to plants under well-watered (WW), WD, or HT conditions. WD + HT exacerbates the increases in ascorbate peroxidase activity, which …

Clinical Relevance Of Proteomic Profiling In De Novo Pediatric Acute Myeloid Leukemia: A Children’S Oncology Group Study, Fieke W Hoff, Anneke D Van Dijk, Yihua Qiu, Chenyue W Hu, Rhonda E Ries, Andrew Ligeralde, Gaye N Jenkins, Robert B Gerbing, Alan S Gamis, Richard Aplenc, E Anders Kolb, Todd A Alonzo, Soheil Meshinchi, Amina A Qutub, Eveline S J M De Bont, Terzah M Horton, Steven M Kornblau

Faculty, Staff and Student Publications

Pediatric acute myeloid leukemia (AML) remains a fatal disease for at least 30% of patients, stressing the need for improved therapies and better risk stratification. As proteins are the unifying feature of (epi)genetic and environmental alterations, and are often targeted by novel chemotherapeutic agents, we studied the proteomic landscape of pediatric AML. Protein expression and activation levels were measured in 500 bulk leukemic patients' samples and 30 control CD34+ cell samples, using reverse phase protein arrays with 296 strictly validated antibodies. The multistep MetaGalaxy analysis methodology was applied and identified nine protein expression signatures (PrSIG), based on strong recurrent protein …

Tigit Is The Central Player In T-Cell Suppression Associated With Car T-Cell Relapse In Mantle Cell Lymphoma, Vivian Changying Jiang, Dapeng Hao, Preetesh Jain, Yijing Li, Qingsong Cai, Yixin Yao, Lei Nie, Yang Liu, Jingling Jin, Wei Wang, Heng-Huan Lee, Yuxuan Che, Enyu Dai, Guangchun Han, Ruiping Wang, Kunal Rai, Andrew Futreal, Christopher Flowers, Linghua Wang, Michael Wang

Faculty, Staff and Student Publications

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy using brexucabtagene autoleucel (BA) induces remission in many patients with mantle cell lymphoma (MCL), and BA is the only CAR T-cell therapy approved by the FDA for MCL. However, development of relapses to BA is recognized with poor patient outcomes. Multiple CAR T-cell therapies have been approved for other lymphomas and the resistance mechanisms have been investigated. However, the mechanisms underlying BA relapse in MCL have not been investigated and whether any previously reported resistance mechanisms apply to BA-relapsed patients with MCL is unknown.

METHODS: To interrogate BA resistance mechanisms in MCL, we …

Association Between Abnormal Lipid Profile And Inflammation And Progression Of Myelodysplastic Syndrome To Acute Leukemia, Wei Qiao, Elliana Young, Chun Feng, Suyu Liu, Jeff Jin, Laila Noor, Cristhiam M Rojas Hernandez, Gautam Borthakur, Olga Gorlova, Vahid Afshar-Kharghan

Faculty, Staff and Student Publications

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with a small risk of developing hematologic malignancies and a higher risk of cardiovascular diseases (CVD). We asked whether the reverse correlation exists and cardiometabolic risk factors have an impact on the progression of myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML). We investigated the association between abnormal lipid profiles and inflammation in MDS, which shares many genetic mutations with CHIP, and the risk of developing acute leukemia. We examined the medical records of 11071 MDS patients. Among them, 5422 had at least one lipid profile or C-reactive protein (CRP) measurement. In …

International Consensus Classification Of Myeloid Neoplasms And Acute Leukemias: Integrating Morphologic, Clinical, And Genomic Data, Daniel A Arber, Attilio Orazi, Robert P Hasserjian, Michael J Borowitz, Katherine R Calvo, Hans-Michael Kvasnicka, Sa A Wang, Adam Bagg, Tiziano Barbui, Susan Branford, Carlos E Bueso-Ramos, Jorge E Cortes, Paola Dal Cin, Courtney D Dinardo, Hervé Dombret, Eric J Duncavage, Benjamin L Ebert, Elihu H Estey, Fabio Facchetti, Kathryn Foucar, Naseema Gangat, Umberto Gianelli, Lucy A Godley, Nicola Gökbuget, Jason Gotlib, Eva Hellström-Lindberg, Gabriela S Hobbs, Ronald Hoffman, Elias J Jabbour, Jean-Jacques Kiladjian, Richard A Larson, Michelle M Le Beau, Mignon L-C Loh, Bob Löwenberg, Elizabeth Macintyre, Luca Malcovati, Charles G Mullighan, Charlotte Niemeyer, Olatoyosi M Odenike, Seishi Ogawa, Alberto Orfao, Elli Papaemmanuil, Francesco Passamonti, Kimmo Porkka, Ching-Hon Pui, Jerald P Radich, Andreas Reiter, Maria Rozman, Martina Rudelius, Michael R Savona, Charles A Schiffer, Annette Schmitt-Graeff, Akiko Shimamura, Jorge Sierra, Wendy A Stock, Richard M Stone, Martin S Tallman, Jürgen Thiele, Hwei-Fang Tien, Alexandar Tzankov, Alessandro M Vannucchi, Paresh Vyas, Andrew H Wei, Olga K Weinberg, Agnieszka Wierzbowska, Mario Cazzola, Hartmut Döhner, Ayalew Tefferi

Faculty, Staff and Student Publications

The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As …