The National Institute for Health and Care Research (NIHR) is a United Kingdom government agency which funds research into health and social care in England. With a budget of over £1.2 billion in 2019–20, its mission is to "improve the health and wealth of the nation through research". The NIHR was established in 2006 under the government's Best Research for Best Health strategy, and is funded by the Department of Health and Social Care. As a research funder and research partner of the NHS, public health and social care, the NIHR complements the work of the Medical Research Council. NIHR focuses on the all aspects of the research process, from translating laboratory findings to clinical research to applying the discoveries in health and social care.
TPS473 Background: The anti-CLDN18.2 antibody zolbetuximab + first-line chemotherapy demonstrated longer progression-free survival (PFS) and overall survival (OS) versus placebo + chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma whose tumors were CLDN18.2-positive (Shitara Lancet 2023; Shah Nat Med 2023; Shitara & Shah NEJM 2024). The anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab + first-line chemotherapy demonstrated longer OS versus placebo + chemotherapy in patients with HER2-negative, LA or mG/GEJ adenocarcinoma whose tumors had a programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1 (Rha Lancet Oncol 2023). Early reports from the ongoing phase 2 ILUSTRO trial (NCT03505320) suggest encouraging activity with zolbetuximab + third-line or later anti-PD-1 therapy (Klempner Clin Cancer Res 2023); ILUSTRO is also evaluating zolbetuximab + first-line chemotherapy and anti-PD-1 therapy. Methods: This phase 3, double-blind, randomized study aims to enroll ~500 adult patients with previously untreated, HER2-negative, LA unresectable or mG/GEJ adenocarcinoma whose tumors are CLDN18.2-positive (defined as ≥75% of tumor cells demonstrating moderate-to-strong membranous CLDN18 staining using the VENTANA CLDN18 [43-14A] RxDx Assay) and have a PD-L1 CPS ≥1. Patients will be randomly assigned 1:1 to receive IV zolbetuximab (800 mg/m 2 on cycle 1 day 1 followed by 400 mg/m 2 every 2 weeks or 600 mg/m 2 every 3 weeks [Q3W]) + IV pembrolizumab (200 mg Q3W or 400 mg every 6 weeks) and either a capecitabine and oxaliplatin regimen (CAPOX) or a modified folinic acid, fluorouracil, and oxaliplatin regimen (mFOLFOX6) or placebo + pembrolizumab and CAPOX/mFOLFOX6 for four 42-day cycles. Patients can continue beyond cycle 4 with zolbetuximab/placebo + pembrolizumab, and capecitabine or folinic acid and fluorouracil at investigator’s discretion, until disease progression, unacceptable toxicity, or other discontinuation criteria are met. Randomization will be stratified by region (Asia vs non-Asia) and CPS (≥1 to <10 vs ≥10). The primary endpoint is OS. Key secondary endpoints are PFS and objective response rate per RECIST v1.1 by investigator assessment. Additional secondary endpoints are duration of response per RECIST v1.1 by investigator assessment, safety, pharmacokinetics, and immunogenicity of zolbetuximab. Exploratory endpoints are biomarker expression, health-related quality of life, and PFS after subsequent therapy. Enrollment is ongoing across global sites. Clinical trial information: NCT06901531 .
Assessment of disease activity in inflammatory bowel disease and surveillance of colitis-associated neoplasia has benefited from advances in image-enhanced endoscopy. Confocal laser endomicroscopy (CLE) and endocytoscopy allow for real-time visualization of cellular architecture details of the gastrointestinal tract, further defining endoscopic mucosal healing or mild disease activity and guiding targeted biopsy for the disease monitoring as well as dysplasia surveillance. CLE and endocytoscopy are valid tools for both structural and functional assessment of the intestinal epithelium. CLE or endocytoscopy has even been proposed as a tool for optical biopsy. Magnification endoscopy equipped with the latest models of white-light endoscopy can highlight the mucosal structure and subepithelial microvasculature, especially in combined use with dye-based chromoendoscopy or narrow-band imaging. Optical coherence tomography has been used for the assessment of disrupted layered structures of bowel wall in the differential diagnosis between Crohn's disease and ulcerative colitis. We expect that the development of probe-based ultrasound elastography will help the distinction between inflammatory and fibrotic strictures.
The international consensus classification or the World Health Organization classifications underrepresented driver alterations enriched in pediatric acute myeloid leukemia (AML). To address this, we retrospectively characterized the genomic landscape of 105 pediatric patients with AML of East Asian ancestry using transcriptome and whole-exome sequencing (WES). In addition to the common recurrent fusions such as RUNX1::RUNX1T1 and CBFB::MYH11, we identified rearrangements involving KMT2A, NUP98, GLIS, as well as FLT3 and UBTF tandem duplications. The median somatic mutation rate in AML was 0.97 per megabase, as estimated by WES. Frequently mutated pathways included signaling: 68.6% (72/105), transcription: 37.1% (39/105), epigenetic regulation: 26.7% (28/105), cohesin: 7.6% (8/105), RNA binding: 3.8% (4/105), and protein modification: 5.7% (6/105). When analyzed together, high-risk genetic subtypes including GLISr, UBTF tandem duplications, PICALM::MLLT10, and HOXr were significantly associated with poorer 5 year overall survival (OS) in multivariable analysis (p-value = 0.037). Although FLT3 internal tandem duplications were significantly associated with inferior 5 year OS in univariable analysis, this effect was not significant in multivariable analysis (p-value = 0.382). Patients with RUNX1 mutations had inferior 5 year OS in multivariable analysis (p-value = 0.009). These findings suggest specific genomic alterations that may refine risk stratification and guide future therapeutic protocols in Taiwanese pediatric patients with AML.
BackgroundSeveral ablation strategies, including dominant frequency (DF), complex fractionated atrial electrograms (CFAEs), and rotors, have been used to target the drivers of atrial fibrillation (AF). The success rate of these strategies remains suboptimal.ObjectiveThis work aims to develop a model using recurrence quantification analysis (RQA) variables and machine learning (ML) algorithms to predict the responses of ablating intracardiac electrograms (EGMs) and their impact on terminating AF and cycle length changes.Methods3206 non-contact EGMs were collected from 10 persistent AF patients. Two classes were considered as labels based on EGM’s responses to ablation (positive and negative responses). Nine RQA-based variables were extracted from the EGMs. Ten ML classifiers were trained and tested using leave one patient out a 10-fold cross-validation (LOPOCV)).ResultsThe decision tree outperformed other ML models, achieving a balanced accuracy of 73.46%, F1_score of 74.05, and AUROC of 0.74. The high performance was achieved using the three most important features (determinism, longest diagonal line, and recurrence rate) with the importance of 30%, 23%, and 13%, respectively. Statistical analysis showed high values of all median RQA variables for the EGM’s negative responses over the positive ones.ConclusionsOur results show that RQA variables can effectively highlight the electrophysiological differences between EGM positive and negative responses to catheter ablation. The model might aid cardiologists in predicting ablation outcomes and reducing the number of unsuccessful ablations. A comparison between the proposed approach and previous works shows the superiority of this model.
Abstract Background/Aims The use of MRI is essential in the diagnosis and management of axial spondyloarthritis (axSpA), due to its ability to demonstrate active inflammation and structural changes in the spine and sacroiliac joints (SIJ). Effective communication between rheumatologists and radiologists is essential to ensuring the correct MRI protocol is utilised, relevant findings are identified and their clinical importance interpreted correctly. Recently, the Assessment of Spondyloarthritis International Society (ASAS) have developed guidelines on requesting and reporting of MRI in suspected axial spondyloarthritis to ensure standardised practice. Aims: To explore current standards of practice at the Leeds Teaching Hospitals NHS Trust (LTHT) in relation to the local inflammatory back pain protocol MRI requests and report against the standards developed by ASAS. Methods We identified all MRIs of the spine and SIJ requested at LTHT between September 2023 and December 2023 under the inflammatory back pain protocol. Report and request data were extracted and analysed against the audit standards. Results In total, 158 MRI requests and reports were identified within the audit period. In terms of requesting data, patient age was included in 11 requests (11.4%), sex in 6 (3.8%) and HLA-B27 in 35 (22.2%). Back pain was recorded in 138 (87.3%), of which location was reported in 72 (45.6%), duration in 30 (18.9%) and inflammatory features in 99 (62.7%). A suspected clinical diagnosis and alternative diagnosis were included in 149 and 27 requests, respectively (94.3% and 17.1%). In terms of the MRI report, bone marrow oedema was mentioned in 128 (81.0%) of reports, if present, the location and semi-quantitative assessment was reported in (97.0% and 89.6%), respectively. Erosions, fat metaplasia and non-axSpA findings were mentioned in 93 (58.5%), 10 (6.3%) and 102 (64.6%) of reports, respectively. Active inflammation was mentioned in 123 (77.8%) and chronic, structural post-inflammatory changes in 82 (51.2%) of reports. Only 98 (62.0%) of reports included a statement as to whether the findings were “in keeping with axSpA”. Conclusion MRI requests for suspected axSpA are missing important clinical and demographic variables which may limit interpretation of the MRI scan by radiologists. Similarly, many MRI reports lack details regarding chronic or structural findings and a significant proportion do not comment on whether findings may be suggestive of axSpA. Further work within the rheumatology and radiology departments to align expectations on requirements regarding both MRI requesting and reporting in axSpA is ongoing, which will be followed by a re-audit. Disclosure J. Weddell: None. H. De Boer: None. J. Wong: None. B. Pass: None. P. Robinson: None. A. Barr: None. C. Vandevelde: None. J. Freeston: None. D. McGonagle: None. H. Marzo-Ortega: None.
