East Midlands Evidence Repository (EMER)

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Welcome to the East Midlands Evidence Repository.

The East Midlands Evidence Repository (EMER) is the official institutional research repository for; Derbyshire Community Health Services, Leicester Partnership Trust, NHS Nottingham and Nottinghamshire CCG, Nottinghamshire Healthcare, Sherwood Forest Hospitals, University Hospitals of Derby and Burton and the University Hospitals Of Leicester

EMER is intended to make NHS research more visible and discoverable by capturing, storing and preserving the East Midlands research output and making it available to the research community through open access protocols.

Wherever possible, full-text content is provided for all research publications in the repository. Content grows daily as new collections are added.

 

 

  • Safety, pharmacokinetics, pharmacodynamics, and antitumor activity from a phase I study of simlukafusp alfa (FAP-IL2v) in advanced/metastatic solid tumors

    Ahmed, Samreen (2024-04-17)
    Purpose: Simlukafusp alfa (FAP-IL2v), a tumor-targeted immunocytokine, comprising an interleukin-2 variant moiety with abolished CD25 binding fused to human immunoglobulin G1, is directed against fibroblast activation protein-α. This phase I, open-label, multicenter, dose-escalation and extension study (NCT02627274) evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of FAP-IL2v in patients with advanced/metastatic solid tumors. Methods: Participants received FAP-IL2v intravenously once weekly. Dose escalation started at 5 mg; flat dosing (≤25 mg) and intra-participant up-titration regimens (15/20 mg, 20/25 mg, 20/20/35 mg, 20/35/35 mg) were evaluated. Primary objectives were dose-limiting toxicities (DLT), maximum tolerated dose (MTD), recommended expansion dose, and pharmacokinetics. Results: Sixty-one participants were enrolled. DLTs included fatigue (flat dose 20 mg: n = 1), asthenia (25 mg: n = 1), drug-induced liver injury (up-titration regimen 20/25 mg: n = 1), transaminase increase (20/25 mg: n = 1), and pneumonia (20/35/35 mg: n = 1). Up-titration regimen 15/20 mg was the MTD and was selected as the recommended expansion dose. Increases in peripheral blood absolute immune cell counts were seen for all tested doses (natural killer cells, 13-fold; CD4+ T cells [including Tregs], 2-fold; CD8+ T cells, 3.5-fold), but without any percentage change in Tregs. Clinical activity was observed from 5 mg (objective response rate, 5.1% [n = 3]; disease control rate, 27.1% [n = 16]). Responses were durable (n = 3; 2.8 [censored], 6.3, and 43.4 months). Conclusions: FAP-IL2v had a manageable safety profile and showed initial signs of antitumor activity in advanced/metastatic solid tumors.
  • The 1000 Mitoses Project: a consensus-based international collaborative study on mitotic figures classification

    Oswald, Nicola K (2024-04-16)
    Introduction. The identification of mitotic figures is essential for the diagnosis, grading, and classification of various different tumors. Despite its importance, there is a paucity of literature reporting the consistency in interpreting mitotic figures among pathologists. This study leverages publicly accessible datasets and social media to recruit an international group of pathologists to score an image database of more than 1000 mitotic figures collectively. Materials and Methods. Pathologists were instructed to randomly select a digital slide from The Cancer Genome Atlas (TCGA) datasets and annotate 10-20 mitotic figures within a 2 mm2 area. The first 1010 submitted mitotic figures were used to create an image dataset, with each figure transformed into an individual tile at 40x magnification. The dataset was redistributed to all pathologists to review and determine whether each tile constituted a mitotic figure. Results. Overall pathologists had a median agreement rate of 80.2% (range 42.0%-95.7%). Individual mitotic figure tiles had a median agreement rate of 87.1% and a fair inter-rater agreement across all tiles (kappa = 0.284). Mitotic figures in prometaphase had lower percentage agreement rates compared to other phases of mitosis. Conclusion. This dataset stands as the largest international consensus study for mitotic figures to date and can be utilized as a training set for future studies. The agreement range reflects a spectrum of criteria that pathologists use to decide what constitutes a mitotic figure, which may have potential implications in tumor diagnostics and clinical management.
  • Intraoperative and intraprocedural use of 3-dimensional transesophageal echocardiography: an International European Association of Cardiothoracic Anesthesia and Intensive Care survey of cardiac surgical centers

    Bence, Johan (2024-03-09)
    Objective: To assess the intraoperative use of 3-dimensional transesophageal echocardiography (3D TEE) in cardiac surgical centers, the authors created a survey aimed at evaluating the availability of equipment and the use of 3D TEE for specific surgical and interventional procedures and single-image modalities. The respondents were asked to identify the perceived impact on patient management and current limitations to its routine use. Design: A multiple choice 25-question online survey submitted to the members of the European Association of Cardiothoracic Anesthesia and Intensive Care (EACTAIC) on December 6, 2021, and closed on January 31, 2022. Setting: An online survey. Participants: Registered EACTAIC members in 2021. Interventions: None. Measurements and main results: A total of 239 respondents from 44 different countries took part in the survey (27% of the total 903 EACTAIC members). Most respondents (59%) were TEE-certified by the National Board of Echocardiography, European Association of Cardiovascular Imaging (EACVI/EACTAIC), or had a national certificate. Of the respondents, 68% had no formal 3D TEE training. Eight percent of respondents had no 3D machines, whereas 40% had one for each operating room, and 33% had only one for the entire operating room block. 3D TEE was performed most frequently in more than 67% of cases for mitral valve surgery, and in more than 54% of cases for mitral and tricuspid clips, aortic valve, tricuspid valve, and aortic surgery. Conclusion: Current guidelines suggest integrating 3D TEE into all comprehensive examinations. The authors' survey reported that intraoperative 3D TEE was used in the majority of mitral valve surgery and only one-half of the other valve surgeries and transcatheter procedures. Its use may be explained by the availability of 3D machines, trained personnel, and limited time to perform TEE in the operating room. Educational initiatives for training in 3D TEE may further increase its routine use.

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