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      High incidence of thromboembolism in patients with chronic GVHD: association with severity of GVHD and donor-recipient ABO blood group

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          Abstract

          Chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT) is associated with systemic inflammation and endothelial dysfunction, increasing risk for thromboembolic events (TEE). In 145 adult recipients who developed cGVHD after a matched sibling or umbilical cord blood donor HCT from 2010 to 2018, 32(22%) developed at least 1 TEE event, and 14(10%) developed 2 TEE events. The 5-year cumulative incidence of TEE was 22% (95% CI, 15–29%) with a median time from cGVHD to TEE of 234 days (range, 12–2050). Median time to the development of LE DVT or PE was 107 (range, 12–1925) compared to 450 days (range, 158–1300) for UE DVT. Cumulative incidence of TEE was 9% (95% CI, 0–20%), 17% (95% CI, 9–25%), and 38% (95% CI, 22–55%) in those with mild, moderate, and severe GVHD, respectively. Higher risk for TEE was associated with cGVHD severity (hazard ratio [HR] 4.9, [95% CI, 1.1–22.0]; p = 0.03), non-O-donor to recipient ABO match compared to O-donor to O-recipient match (HR 2.7, [95% CI, 1.0–7.5]; p = 0.053), and personal history of coronary artery disease (HR 2.4, [95% CI, 1.1–5.3]; p = 0.03). TEE was not associated with 2-year non-relapse mortality or 5-year overall survival.

          Key points

          • Patients with chronic GVHD after allogeneic hematopoietic cell transplantation are at high risk for thromboembolic events occurring years after diagnosis.

          • More severe chronic GVHD, non-O donor-recipient ABO compared to O-O match and personal history of coronary artery disease are associated with higher risk of thromboembolic events.

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          Most cited references30

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          A Proportional Hazards Model for the Subdistribution of a Competing Risk

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            In situ click chemistry generation of cyclooxygenase-2 inhibitors

            Cyclooxygenase-2 isozyme is a promising anti-inflammatory drug target, and overexpression of this enzyme is also associated with several cancers and neurodegenerative diseases. The amino-acid sequence and structural similarity between inducible cyclooxygenase-2 and housekeeping cyclooxygenase-1 isoforms present a significant challenge to design selective cyclooxygenase-2 inhibitors. Herein, we describe the use of the cyclooxygenase-2 active site as a reaction vessel for the in situ generation of its own highly specific inhibitors. Multi-component competitive-binding studies confirmed that the cyclooxygenase-2 isozyme can judiciously select most appropriate chemical building blocks from a pool of chemicals to build its own highly potent inhibitor. Herein, with the use of kinetic target-guided synthesis, also termed as in situ click chemistry, we describe the discovery of two highly potent and selective cyclooxygenase-2 isozyme inhibitors. The in vivo anti-inflammatory activity of these two novel small molecules is significantly higher than that of widely used selective cyclooxygenase-2 inhibitors.
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              Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT.

              We previously reported that the Charlson Comorbidity Index (CCI) was useful for predicting outcomes in patients undergoing allogeneic hematopoietic cell transplantation (HCT). However, the sample size of patients with scores of 1 or more, captured by the CCI, did not exceed 35%. Further, some comorbidities were rarely found among patients who underwent HCT. Therefore, the current study was designed to (1) better define previously identified comorbidities using pretransplant laboratory data, (2) investigate additional HCT-related comorbidities, and (3) establish comorbidity scores that were suited for HCT. Data were collected from 1055 patients, and then randomly divided into training and validation sets. Weights were assigned to individual comorbidities according to their prognostic significance in Cox proportional hazard models. The new index was then validated. The new index proved to be more sensitive than the CCI since it captured 62% of patients with scores more than 0 compared with 12%, respectively. Further, the new index showed better survival prediction than the CCI (likelihood ratio of 23.7 versus 7.1 and c statistics of 0.661 versus 0.561, respectively, P < .001). In conclusion, the new simple index provided valid and reliable scoring of pretransplant comorbidities that predicted nonrelapse mortality and survival. This index will be useful for clinical trials and patient counseling before HCT.
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                Author and article information

                Contributors
                neljurdi@umn.edu
                Journal
                Blood Cancer J
                Blood Cancer J
                Blood Cancer Journal
                Nature Publishing Group UK (London )
                2044-5385
                18 May 2021
                18 May 2021
                May 2021
                : 11
                : 5
                : 96
                Affiliations
                [1 ]GRID grid.17635.36, ISNI 0000000419368657, Blood and Marrow Transplant Program, Department of Medicine, , University of Minnesota, ; Minneapolis, MN USA
                [2 ]GRID grid.17635.36, ISNI 0000000419368657, Division of Hematology, Oncology, and Transplantation, Department of Medicine, , University of Minnesota, ; Minneapolis, MN USA
                [3 ]GRID grid.17635.36, ISNI 0000000419368657, Biostatistics and Informatics, Clinical and Translational Science Institute, , University of Minnesota, ; Minneapolis, MN USA
                [4 ]GRID grid.411015.0, ISNI 0000 0001 0727 7545, Department of Pediatrics, , University of Alabama, ; Tuscaloosa, AL USA
                Author information
                http://orcid.org/0000-0002-9268-9655
                http://orcid.org/0000-0003-3439-4362
                http://orcid.org/0000-0001-9605-6436
                http://orcid.org/0000-0002-9325-432X
                http://orcid.org/0000-0002-1997-3799
                http://orcid.org/0000-0003-0782-1170
                http://orcid.org/0000-0001-9323-8007
                http://orcid.org/0000-0002-1732-6694
                http://orcid.org/0000-0002-0755-0852
                http://orcid.org/0000-0001-8078-8579
                Article
                488
                10.1038/s41408-021-00488-2
                8131386
                34006823
                a2550616-e1cd-46b1-9599-a2817d74fd85
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 15 March 2021
                : 20 April 2021
                : 29 April 2021
                Funding
                Funded by: FundRef https://doi.org/10.13039/100005440, U.S. Department of Health & Human Services | NIH | Center for Scientific Review (NIH Center for Scientific Review);
                Award ID: P30 CA77598
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100006108, U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS);
                Award ID: UL1TR002494
                Award Recipient :
                Categories
                Article
                Custom metadata
                © The Author(s) 2021

                Oncology & Radiotherapy
                medical research,cancer
                Oncology & Radiotherapy
                medical research, cancer

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