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Item Tumour-Infiltrating Lymphocytes, Tumour Cell Density, and Response to Neoadjuvant Short-Course Radiotherapy in Rectal Cancer: A Translational Sub-Study from the MRC CR07 Clinical Trial.(2025)Background: Rectal cancer is common and frequently treated with neoadjuvant radiotherapy prior to surgery to reduce the risk of tumour recurrence. However, the therapeutic benefits and side effects of radiotherapy can vary between patients, and there are currently no validated biomarkers to predict treatment response. Tumour cell density (TCD) and tumour-infiltrating lymphocyte (TIL) density are proven prognostic biomarkers in colorectal cancer; however, their utility in predicting radiotherapy response remains unclear. We assessed the prognostic and predictive value of TCD and TIL density in rectal cancer patients treated with radiotherapy. Method(s): TCD was quantified using a manual point-counting method in 253 pre-treatment biopsies and across the entire tumour area of 569 resection specimens from the MRC CR07 clinical trial, which randomised patients to either neoadjuvant short-course radiotherapy (SCRT) or straight to surgery (control). TIL density was measured in 102 biopsies and matched resection specimens (73 SCRT, 29 control) across different tumour areas using deep learning-based cell detection in MIM (HeteroGenius Ltd., Leeds, UK). Cutoffs for low/high-TCD and TIL density were both pre-defined and derived from survival data using the survminer R package. Survival analyses were performed to evaluate the predictive and prognostic value of TCD/TIL in relation to overall and cancer-specific survival. Result(s): TCD in the resection specimens was lower in the SCRT group (19.9%, IQR 12.9-26.7%) than the control group (34.3%, IQR 27.7-40.5%, p < 0.001). In control resections, low-TCD was associated with a higher risk of all-cause mortality (HR 2.20, 95% CI 1.41-3.44, p < 0.001) and cancer-related death (HR 2.69, 95% CI 1.41-5.13, p = 0.0026). In contrast, after SCRT, low resection TCD was associated with a reduced risk of death (HR 0.63, 95% CI 0.40-0.98, p = 0.04). In the SCRT group, low biopsy TCD prior to radiotherapy was associated with a reduced risk of cancer-related death (HR 0.34, 95% CI 0.13-0.89, p = 0.028). Across both trial arms, TIL density was higher in pre-treatment biopsies than resections (2492 vs. 1304/mm2, p < 0.001). Low biopsy TIL density was associated with an increased risk of all-cause mortality (HR 2.43, 95% CI 1.24-4.76, p = 0.01). The SCRT group had lower TIL density in the resection compared with controls (1210 vs. 1615/mm2, p < 0.001), and low resection TIL density across the whole tumour area was associated with a higher risk of death (HR 2.55, 95% CI 1.11-5.87, p = 0.027). Conclusion(s): Our findings support the role of TCD and TIL density as quantitative biomarkers in rectal cancer patients. TCD can be used to assess the degree of response to radiotherapy, and contrasting survival associations are observed between straight-to-surgery and SCRT-treated patients. This study raises the possibility of using TCD as both a prognostic and predictive biomarker. TIL density failed to show predictive value but demonstrated expected prognostic associations.Item In Vitro Wire Tension in Circular External Fixation Frames.(2025)Circular frames are applied to control fracture and osteotomy mechanics, which is dependent on frame design. As the clinical application of these devices is individualised, clinical performance can be difficult to compare from one case to another. In fine wire constructs, stability is dependent on wire tension, which can degrade over time. As such, wire tension is a parameter that surgeons may attempt to keep consistent between cases or indeed adapt to the clinical situation. However, there is little evidence regarding what variables in fixator application might influence this. The aim of the study was to monitor wire tension in an in vitro symmetrical circular frame construct using strain gauge instrumented wires and to use these to investigate the clinical factors in assembly and use of a frame that may be associated with tension loss. The results demonstrated that variability in wire tension was associated with the application of the tensioner itself, along with wire slippage associated primarily with the bolt torque used to tighten the ends of the wires to the frame. These two variables could easily lead to a 50% variation in the actual wire tension achieved. Surprisingly, under dynamic loading, despite an initial loss in tension due to slippage, wire tension generally remained constant and was not significantly different between wires applied with different wire pre-tensions after the initial three cycles. A calibrated tensioner with a high initial tension (110 kg), along with a controlled wire clamp bolt torque (14 Nm), is required to achieve the most consistent frame performance.Item Erase or be erased. Social media referrals to healthcare regulators in the United Kingdom 2017 to 2024.(2026)Objectives: Social media (SM) use both professionally and personally is prevalent across all healthcare professionals (HCPs). Its use amongst HCPs is particularly well evidenced across a variety of domains, including health promotion, clinical education, policy debate, and patient interaction. However, as this use increases there is an increasing perception that even normal day-to-day use by HCPs may result in referral to their regulator. Our study aimed to understand which HCPs were being referred to their regulator in the United Kingdom for perceived negative SM behaviours including which behaviours specifically warranted referrals to fitness to practise hearings. Method(s): A retrospective case review following freedom of information requests to all HCP regulators in the UK was undertaken. Requests for information around cases involving SM from 2017 to 2024 were requested. Hand searching of outcomes was also done where possible. SM was defined as anything related to the use of applications including Facebook, Twitter (now X), Tik ToK, and posting on the internet in forums. Data analysis considered the number of referrals per year, and per regulator. A review of the fitness to practise (FtP) hearings and themes from the hearings was then undertaken. Result(s): There were a total of 189,913 concerns raised across regulators, and a total of 13,265 FtP hearings over the 8 years from 2017 - 2024. Therefore 7 % of referrals resulted in a FtP hearing. Over these 8 years there were 113 (0.85 %) FtP hearings which were SM-related across all regulators, or 0.04 % of SM concerns raised with regulators resulted in an FtP hearing. Suspension was the most common outcome followed by erasure from the register. Themes of FtP hearings were around COVID-19 misinformation, disclosure of confidential patient information onto social media, extreme and multiple racist posts, bullying, contacting a patient, highly sexualised content or sending this sexualised content to either a patient, colleague or child. Conclusion(s): This study may provide reassurance to HCPs who are significantly concerned regarding a looming threat of regulator referral for routine SM behaviour. However, rising referrals raised regarding doctors and nurses warrants specific further investigation amongst these populations, particularly concerning impact upon wellbeing and wider healthcare SM culture.Item EFFECTS of ORAL IPTACOPAN MONOTHERAPY, INCLUDING INCREASED PAROXYSMAL NOCTURNAL HEMOGLOBINURIA RED BLOOD CELL CLONE SIZE, ARE SUSTAINED in ANTI-C5-TREATED PATIENTS with ANEMIA: FINAL APPLY-PNH DATA.(2024)Background: In the 24-week (wk) randomized period of the Phase III APPLY-PNH trial (NCT04558918), iptacopan (a first-in-class, oral factor B inhibitor) showed superiority vs C5 inhibitors and was well tolerated in anti-C5-treated PNH patients (pts) with persistent anemia. Aim(s): We report final (48-wk) APPLY-PNH data, including PNH red blood cell (RBC) clone size and C3 fragment deposition, after a 24-wk extension period. Method(s): Adult PNH pts (receiving anti-C5 for >=6 months; mean hemoglobin [Hb] <10 g/dL) were randomized to receive iptacopan monotherapy 200 mg twice daily or continue anti-C5 for 24 wks. In an optional 24-wk extension, pts in the iptacopan arm continued iptacopan; pts in the anti-C5 arm switched to iptacopan monotherapy. Result(s): 95 pts entered the extension (iptacopan arm n=61/62; anti-C5-to-iptacopan arm n=34/35). In the iptacopan arm, improvements at Wk 24 were sustained at Wk 48, including increased Hb, normal/near-normal mean Hb and transfusion avoidance. Rapid improvements in these outcomes were seen in the anti-C5-to-iptacopan arm, reaching values comparable to the iptacopan arm. In the iptacopan and anti-C5-to-iptacopan arms, mean Hb at Wk 48 was 12.2 and 12.1 g/dL (SD 1.6 and 1.4; includes post-transfusion data), and 91.9% of pts (Wks 2-48) and 94.1% (Wks 26-48) achieved transfusion avoidance, respectively. The adjusted mean change from baseline (BL) to Wk 48 in Hb, Functional Assessment of Chronic Illness Therapy-Fatigue score and absolute reticulocyte count was +3.35 g/dL, +9.80 and-106.26 x 109/L in the iptacopan arm and +3.36 g/dL, +10.96 and-107.95 x 109/L in the anti-C5-to-iptacopan arm, respectively. In both arms, mean lactate dehydrogenase at Wk 48 was consistent with BL. In the iptacopan arm, the increase from BL to Wk 24 in total PNH RBC (type II and type III) clone size was sustained to Wk 48 (Wk 48 mean 90.9%; mean change from BL 26.2%), as was a reduction in C3 fragment deposition on PNH RBCs (Wk 48 mean 1.97%; mean change from BL-16.1%; Figure). In the anti-C5-to-iptacopan arm, PNH RBC clone size increased (Wk 48 mean 90.1%; mean change from Wk 24 to 48 30.3%) and C3 fragment deposition reduced (Wk 48 mean 0.12%; mean change from Wk 24 to 48-16.9%) rapidly after switching treatment. 6/62 pts in the iptacopan arm had clinical breakthrough hemolysis (BTH; all mild or moderate) during 48 wks of therapy; in the anti-C5-to-iptacopan arm, clinical BTH occurred in 6/35 pts during 24 wks of anti-C5 and in one additional pt after switching to iptacopan. No BTH led to iptacopan discontinuation. Three iptacopan-treated pts had major adverse vascular events; none were considered treatment related. There were no deaths or treatment discontinuations due to treatmentemergent adverse events (TEAEs) with iptacopan. No serious hemolysis TEAEs or serious infections caused by N. meningitidis, S. pneumoniae or H. influenzae occurred with iptacopan. Summary/Conclusion: In APPLY-PNH, long-term iptacopan monotherapy led to durable responses and was well tolerated in anti-C5-treated PNH pts with anemia. Pts in the iptacopan arm had sustained improvements in several hematological and clinical parameters. An increase in PNH RBC clone size and decrease in C3 fragment deposition was maintained, indicating sustained control of intravascular hemolysis with resolution of extravascular hemolysis. Pts in the anti-C5-to-iptacopan arm had rapid improvements in outcomes after treatment switch. These data suggest that oral iptacopan monotherapy may be a practicechanging option for PNH pts with suboptimal response to anti-C5 therapy. (Figure present).
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