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Abstract: Variances in global access to drugs and treatment practices make it challenging to understand the benefit of contemporary therapies in patients with relapsed and refractory (R/R) mature T-cell and natural killer-cell lymphomas (MTCL and MNKCL). We conducted an international retrospective cohort study of 925 patients with R/R MTCL and MNKCL. In peripheral T-cell lymphoma-not otherwise specified and anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (ALK- ALCL), patients with relapsed lymphoma demonstrated a superior median overall survival (OS) relative to refractory from the time of second-line treatment. We identified several independent predictors of OS for R/R lymphoma including age >60 years, primary refractory disease, histological subtype other than angioimmunoblastic T-cell lymphoma (AITL), extranodal sites >1, Ki67 ≥40%, and absolute lymphocyte count less than the lower limit of normal. A multivariable model incorporating these formed the basis for a prognostic index for R/R TCL, in which patients are stratified into low-risk (0-1 risk factor), intermediate-risk (2-3 risk factors), or high-risk (≥4 risk factors) groups, which were associated with 3-year OS of 57.14%, 23.3%, and 7%, respectively. Patients received either a "novel" single agent (SA; 35%) or cytotoxic chemotherapy (CC; 60%) for their second-line treatment. Higher progression-free survival was observed with SA over CC for the entire cohort with a higher 3-year OS in AITL and ALK- ALCL. Among the SA, small-molecule inhibitors demonstrated OS advantage relative to CC in AITL. Our results highlight continued efficacy of novel drugs globally and the potential of a new prediction model in informing heterogeneous prognosis within the R/R population of MTCL and MNKCL., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Aims: Electronic healthcare records (EHR) are at the forefront of advances in epidemiological research emerging from large-scale population biobanks and clinical studies. Hospital admissions, diagnoses, and procedures (HADP) data are often used to identify disease cases. However, this may result in incomplete ascertainment of chronic conditions such as atrial fibrillation (AF), which are principally managed in primary care (PC). We examined the relevance of EHR sources for AF ascertainment, and the implications for risk factor associations, patient management, and outcomes in UK Biobank., Methods and Results: UK Biobank is a prospective study, with HADP and PC records available for 230 000 participants (to 2016). AF cases were ascertained in three groups: from PC records only (PC-only), HADP only (HADP-only), or both (PC + HADP). Conventional statistical methods were used to describe differences between groups in terms of characteristics, risk factor associations, ascertainment timing, rates of anticoagulation, and post-AF stroke and death. A total of 7136 incident AF cases were identified during 7 years median follow-up (PC-only: 22%, PC + HADP: 49%, HADP-only: 29%). There was a median lag of 1.3 years between cases ascertained in PC and subsequently in HADP. AF cases in each of the ascertainment groups had comparable baseline demographic characteristics. However, AF cases identified in hospital data alone had a higher prevalence of cardiometabolic comorbidities and lower rates of subsequent anticoagulation (PC-only: 44%, PC + HADP: 48%, HADP-only: 10%, P < 0.0001) than other groups. HADP-only cases also had higher rates of death [PC-only: 9.3 (6.8, 12.7), PC + HADP: 23.4 (20.5, 26.6), HADP-only: 81.2 (73.8, 89.2) events per 1000 person-years, P < 0.0001] compared to other groups., Conclusion: Integration of data from primary care with that from hospital records has a substantial impact on AF ascertainment, identifying a third more cases than hospital records alone. However, about a third of AF cases recorded in hospital were not present in the primary care records, and these cases had lower rates of anticoagulation, as well as higher mortality from both cardiovascular and non-cardiovascular causes. Initiatives aimed at enhancing information exchange of clinically confirmed AF between healthcare settings have the potential to benefit patient management and AF-related outcomes at an individual and population level. This research underscores the importance of access and integration of de-identified comprehensive EHR data for a definitive understanding of patient trajectories, and for robust epidemiological and translational research into AF., Competing Interests: Conflict of interest: The Nuffield Department of Population Health receives research grants from industry that are governed by University of Oxford contracts that protect its independence, and has a staff policy of not taking personal payments from industry; further details can be found at https://www.ndph.ox.ac.uk/about/independence-of-research. All authors have declared no further conflicts of interest., (© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Transcriptional dysregulation, possibly affected by genetic variation, contributes to disease etiology. Due to dissimilarities in development, function, and remodeling during disease progression, transcriptional differences between the left atrium (LA) and right atrium (RA) may provide insight into diseases such as atrial fibrillation., Methods: Lateral differences in atrial transcription were evaluated in CATCH ME (Characterizing Atrial fibrillation by Translating its Causes into Health Modifiers in the Elderly) using a 2-stage discovery and replication design. The design took advantage of the availability of 32 paired samples, for which both LA and RA tissue were obtained, as a discovery cohort, and 98 LA and 69 RA unpaired samples utilized as a replication cohort., Results: A total of 714 transcripts were identified and replicated as differentially expressed (DE) between LA and RA, as well as 98 exons in 55 genes. Approximately 50% of DE transcripts were colocated with another frequently correlated DE transcript ( P FDR ≤0.05 for 579 regions). These "transcription disequilibrium" blocks contained examples including side-specific differential exon usage, such as the PITX2 locus, where ENPEP showed evidence of differential exon usage. Analysis of this region in conjunction with BMP10 identified rs9790621 as associated with ENPEP transcription in LA, while rs7687878 was associated with BMP10 expression in RA. In RA, BMP10 and ENPEP were strongly correlated in noncarriers, which was attenuated in risk-allele carriers, where BMP10 and PITX2 expression were strongly correlated., Conclusions: These results significantly expand knowledge of the intricate, tissue-specific transcriptional landscape in human atria, including DE transcripts and side-specific isoform expression. Furthermore, they suggest the existence of blocks of transcription disequilibrium influenced by genetics., Competing Interests: Dr Schotten received consultancy fees or honoraria from Università della Svizzera Italiana (USI, Switzerland), Roche Diagnostics (Switzerland), EP Solutions, Inc (Switzerland), and Johnson & Johnson Medical Limited (United Kingdom). Dr Schotten is cofounder and shareholder of YourRhythmics BV, a spin-off company of the University of Maastricht. Dr Casadei has received in kind research support from iRhythm for a randomized trial of AF screening. The other authors report no conflicts.

Background: Anti-CD19 CAR T-cells have revolutionized outcomes in relapsed/refractory large B-cell lymphomas. Long-term follow-up underscored the role of hematological toxicity in nonrelapse mortality, largely driven by infections, leading to the development of the CAR-HEMATOTOX (HT) score for predicting neutropenia. The European scientific community (EHA/EBMT) later reached a consensus, defining a new entity: immune effector cell-associated hematotoxicity (ICAHT)., Aims: To validate the ability of the HT score to predict ICAHT and survival., Methods: The CART-SIE is an ongoing multicenter prospective observational study collecting data on patients affected by B-cell lymphoma treated with commercial anti-CD19 CAR T-cells (ClinicalTrials.gov ID: NCT06339255)., Results: Since 2019 to 2024, 1002 consecutive patients were enrolled. Out of 746 patients infused, the HT score at infusion was evaluable in 389. Median age was 59 years (48-66). Patients with high HT score had greater disease burden and a greater need for bridge therapy. Patients with a HT HIGH score had a 4-fold higher risk of experiencing late ICAHT of grade≥3 (OR = 3.99, 95% CI = 1.16-13.77, P = .03). Patients with a HT HIGH score also showed lower overall response rates (ORR) and complete response rates (CRR) at 90 days (CRR at 90 days: 59% HT LOW versus 38% HT HIGH , OR = 0.42, 95% CI = 0.27-0.66, P = .0002; ORR at 90 days: 67% HT LOW versus 49% HT HIGH , OR = 0.47, 95% CI = 0.29-0.74, P = .001). Adjusted logistic models confirmed that the effect of HT score was independent from baseline characteristics. With a median follow-up of 18 months, patients with a HT HIGH score have lower OS and PFS (1-year OS: 78% HT LOW versus 62% HT HIGH , P = .0002; 1-year PFS: 49% versus 39%, P = .003). Adjusted Cox models confirmed that HT was an independent prognostic factor for OS. A high HT-score was found to be associated with higher risk of secondary primary malignancy (HR=2.8, 95% CI = 1.03-7.8, P = .04). A simplified version of HT (simpleHT), based solely on the platelet count and C-reactive protein at infusion, was calculated for 560 patients and proved significant in predicting both OS and PFS (1-year was 72% simpleHT LOW versus 37% simpleHT HIGH , P < .0001, 1-year PFS was 48% simpleHT LOW versus 22% simpleHT HIGH , P < .0001)., Conclusion: In our prospective real-world study, we validated the ability of the HT score to predict ICAHT and survival. SimpleHT identified a population at very high risk with an impaired progression free and overall survival., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Standardized definitions for outcome measures in randomized clinical trials and observational studies are essential for robust and valid evaluation of medical products, interventions, care, and outcomes. The European Unified Registries for Heart Care Evaluation and Randomised Trials (EuroHeart) project of the European Society of Cardiology aimed to create international data standards for cardiovascular clinical study outcome measures., Methods: The EuroHeart methods for data standard development were used. From a Global Cardiovascular Outcomes Consortium of 82 experts, five Working Groups were formed to identify and define key outcome measures for: cardiovascular disease (generic outcomes), acute coronary syndrome and percutaneous coronary intervention (ACS/PCI), atrial fibrillation (AF), heart failure (HF) and transcatheter aortic valve implantation (TAVI). A systematic review of the literature informed a modified Delphi method to reach consensus on a final set of variables. For each variable, the Working Group provided a definition and categorized the variable as mandatory (Level 1) or optional (Level 2) based on its clinical importance and feasibility., Results: Across the five domains, 24 Level 1 (generic: 5, ACS/PCI: 8, AF: 2; HF: 5, TAVI: 4) and 48 Level 2 (generic: 18, ACS-PCI: 7, AF: 6, HF: 2, TAVI: 15) outcome measures were defined., Conclusions: Internationally derived and endorsed definitions for outcome measures for a range of common cardiovascular diseases and interventions are presented. These may be used for data alignment to enable high-quality observational and randomized clinical research, audit, and quality improvement for patient benefit., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

First-line therapy for patients with extranodal marginal zone lymphoma (EMZL) is not well established, except for eradication therapy for Helicobacter pylori in early gastric MZL. Various regimens, for example, locoregional treatment and systemic chemo-immunotherapy, can be used depending on the site and stage of disease. Single-agent rituximab is a useful approach in the setting of localized, low-intermediate risk EMZL. The aim our research was to analyze the effectiveness and safety of single-agent rituximab (375 mg/m 2 once weekly for 4 weeks) in naïve EMZL in a real-life setting. The primary endpoint was the overall response rate (ORR), secondary endpoints were progression-free (PFS), overall (OS) and disease-free survivals (DFS), and drug tolerability. Fifty-nine patients were analyzed. Median time between diagnosis and rituximab was 3.6 months. The ORR was 89.9%, with 67.8% complete response (CR). Median DFS and PFS were reached at 6.3 and 5.3 years, respectively. After a median follow-up of 5 years, median OS was not reached. The most common adverse event was infusion reaction, reported in 28 cases, mainly during the first infusion and easily manageable. Single-agent rituximab may represent a valid therapeutic option in the first-line treatment of EMZL, at least for localized disease, with a favorable toxicity profile., (© 2024 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

The optimization of bridging regimen before chimeric antigen receptor (CAR)-T cell therapy in diffuse large B-cell lymphoma (DLBCL) may impact CAR-T efficacy and outcome. This retrospective study evaluates CAR-T outcome after bridging with radiotherapy (RT) and other bridging strategies. Among 148 patients with relapsed/refractory DLBCL who underwent leukapheresis for CAR-T manufacturing, 31 received RT-bridging, 84 chemotherapy (CT), 33 no-bridging or steroid-only. CAR-T cell were infused in 96.8% of RT-group, 89.2% of CT-group and 78.8% of no-bridge-group (p = 0.079). Response to bridging was generally poor, but patients receiving RT had a significant reduction in LDH levels between pre- and post-bridging (p = 0.05). The one-year PFS was 51.2% in the RT-group, 28.2% in the CT-group, and 47.6% in the no-bridge-group (p = 0.044, CT-bridging vs RT-bridging); 1-year OS was 86.7% in the RT-group, 52.7% in the CT-group and 69% in the no-bridge-group (p = 0.025, CT-bridging vs RT-bridging). We observed a higher incidence of ICANS in patients who received CT than in others (20.0% CT-group, 3.3% RT-group, 7.7% no-bridge group; p = 0.05). In conclusion, RT-bridging is associated with lower drop-out rate and CAR-T toxicity, and it might be preferred to other bridging strategies for patients with localized disease or for those with one prevalent symptomatic site., Competing Interests: Competing interests: The authors decalre no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)