Guy's Hospital

The SOURCE phase 3 oral corticosteroid (OCS)-sparing study of tezepelumab indicated an OCS-sparing effect with tezepelumab versus placebo in patients with OCS-dependent asthma and baseline blood eosinophil counts (BECs) of at least 150 cells per μL. The WAYFINDER study aimed to further evaluate the ability of tezepelumab to reduce or discontinue OCS use in a larger cohort of patients with OCS-dependent severe, uncontrolled asthma. WAYFINDER was a phase 3b, multicentre, single-arm, open-label, OCS-sparing study. Adults (aged 18-80 years) with severe, uncontrolled asthma receiving a maintenance OCS dose of 5-40 mg per day (or equivalent) of prednisone or prednisolone were recruited from 68 clinical centres across 11 countries (Argentina, Belgium, Bulgaria, France, Germany, Latvia, Mexico, Poland, Spain, UK, and USA). Participants received tezepelumab 210 mg subcutaneously once every 4 weeks for up to 52 weeks. The co-primary endpoints, assessed at weeks 28 and 52, were the proportion of participants who reduced their prescribed maintenance OCS dose to 5 mg per day or less without loss of asthma control and the proportion of participants who discontinued OCS without loss of asthma control. OCS dose reductions to below 5 mg per day were contingent on participants demonstrating preserved adrenal function. This completed study was registered with ClinicalTrials.gov (NCT05274815). WAYFINDER was conducted between May 17, 2022, and Sept 9, 2024. Overall, 382 participants were enrolled and 298 participants (206 female [69·1%]) received tezepelumab and were included in the efficacy and safety analyses. The mean baseline maintenance OCS dose was 10·8 (SD 6·5) mg per day. The proportion of participants who had a maintenance OCS dose of 5 mg per day or less without loss of asthma control was 265 of 298 (88·9% [95% CI 84·8-92·3]) at week 28 and 268 of 298 (89·9% [85·9-93·1]) at week 52. The proportion of participants who discontinued OCS without loss of asthma control was 96 of 298 (32·2% [26·9-37·8]) at week 28 and 150 of 298 (50·3% [44·5-56·2]) at week 52. OCS reduction and discontinuation were achieved across pre-specified subgroups based on baseline BEC, fractional exhaled nitric oxide level, or allergy status. Serious adverse events were reported in 28 (9·4%) of 298 participants (asthma [13 participants] and pneumonia [three participants] were the most common), and four participants (1·3%) had adverse events leading to tezepelumab discontinuation. Two participants died during the study but neither death was considered to be causally related to tezepelumab treatment. After 52 weeks of open-label tezepelumab treatment, nearly 90% of patients with OCS-dependent severe, uncontrolled asthma had a maintenance OCS dose of 5 mg per day or less and more than 50% completely discontinued OCS, while maintaining asthma control. These findings indicate that tezepelumab treatment can help enable patients with severe asthma to reduce their OCS use and its associated burden, with broad applicability across patient phenotypes. AstraZeneca and Amgen.

Interleukin-12 (IL-12) is a pleiotropic pro-inflammatory cytokine with potent antitumour activity and has been extensively explored as a candidate for cancer immunotherapy. However, its clinical development has been severely limited by the substantial systemic toxicities observed following systemic administration of recombinant IL-12. Nevertheless, the capacity of IL-12 to remodel the immunosuppressive tumour microenvironment (TME) by enhancing immune effector cell activation, proliferation, and infiltration, as well as by shifting suppressive immune cells toward a proinflammatory phenotype, underscores the need to engineer safe delivery strategies that confine cytokine activity to the tumour site. Herein, this review provides a broad and updated overview of diverse strategies for targeted IL-12 delivery to tumours. Specifically, we focus on immunocytokines, adoptive T-cell therapies, and biodegradable polymeric microspheres, while also briefly touching on protein-engineering and nanotechnology-based approaches. By reviewing their modes of action and comparing their benefits and challenges, we illustrate how modern engineering approaches have the potential to overcome the historical barriers to IL-12 therapy while preserving its potent and pleiotropic antitumour functions. Although numerous IL-12-based platforms have recently emerged, an integrative framework that connects advances across diverse engineering modalities has been lacking. Finally, we consider how combination strategies incorporating multiple therapeutic components may enable the safe deployment of IL-12 while fully realising its antitumour potential.

Chronic urticaria (CU) diagnosis includes the patient's clinical history and physical examination. However, atypical presentations or misdiagnosis can lead to diagnostic delay (DD). The impact and contributing factors of DD in CU are unknown and were assessed in the present study. We retrospectively analysed data from CU adult patients from the international, multicenter Chronic Urticaria Registry (CURE). Of 4332 CU patients, 61% had standalone chronic spontaneous urticaria (sCSU), 18% had ≥ 1 form of chronic inducible urticaria (CIndU), and 21% had a combination of both (CSU + CIndU). Diagnosis of CU was delayed in 24% of patients by at least 1 year. CIndU patients showed a longer DD compared to those with sCSU or CSU + CIndU (median, [IQR]: 4, [0-22] vs. 1, [0-6] vs. 2, [0-9] months, p < 0.001). Among CIndU patients, symptomatic dermographism (n = 264) and cholinergic urticaria (n = 103) patients had the longest DD compared to all other CIndU subgroups (median: 4 months, p = 0.005 for both). In CIndU patients, a longer DD was associated with having an additional CIndU (OR: 12.8, p = 0.03), younger age, comorbidities, lower disease control, and lack of second-generation H1-antihistamine treatment. In CSU patients, a DD of ≥ 6 months was associated with lower CSU activity (median weekly Urticaria Activity Score of 14 vs. 21, p = 0.02) compared to that of DD < 6 months. Diagnosis of CU is delayed in one out of four patients. Greater awareness of the guideline-recommended CU classification, clinical presentation, and diagnostic work-up can facilitate CU diagnosis.

Alveolar air leaks following pulmonary resection present a significant challenge in thoracic surgery, resulting in complications and increased healthcare costs. Surgical sealants are employed to reduce air leak duration, but evidence supporting their routine use remains limited. Our individual patient data meta-analysis of randomised controlled trials aimed to assess the impact of sealant use on the duration of hospital length of stay, air leak, and chest drainage following lung resection. Our systematic literature search identified 22 randomized controlled trials, from which individual patient data were obtained from 7 trials involving 552 patients. The primary outcome was hospital length of stay, with air leak duration and chest drain duration as secondary outcomes. A one-stage individual patient data meta-analysis approach was used, applying Kaplan-Meier survival analysis, log-rank tests, and Cox proportional hazards models. Exploratory sub-group analyses were conducted to assess potential effect modification by extent of resection and presence of COPD on hospital length of stay. Sealant use significantly reduced hospital stay duration (HR=0.82;0.69-0.97; p=0.02), air leak duration (HR=0.70;0.56-0.87; p=0.002) and chest drain duration (HR=0.78;0.63-0.97; p=0.02). In the subgroup analyses based on the extent of resection, sealants demonstrated benefit in the lobectomy (HR=0.77;0.63-0.94; p=0.01) and segmentectomy (HR=0.54;0.36- 0.82; p=0.003) groups. In the COPD patient subgroup, sealants did not lead to a significant reduction in all primary and secondary outcomes. The use of surgical sealants after failed control of air leak following pulmonary resection results in a one-day reduction in hospital length of stay as compared to standard closure techniques.

Introduction: Heart failure (HF) poses a major clinical and economic burden within UK hospitals, with poor inpatient monitoring often undermining guideline-directed medical therapy. In the Acute Medical Unit (AMU) at Darent Valley Hospital, pre-intervention audits revealed suboptimal adherence to National Institute for Health and Care Excellence monitoring standards for chronic heart failure (CHF). The areas of monitoring include functional capacity, fluid status, cognitive status using the Glasgow Coma Scale, nutritional status, urea and electrolytes (U+Es) and the locally recommended daily 12-lead ECG within the first 24 hours of admission. CHF monitoring adherence was assessed by scoring completion of these six predefined parameters. Completion of fluid status monitoring and nutritional status was particularly poor. This five-month quality improvement project (QIP), led by medical students, aimed to improve adherence to inpatient monitoring requirements for patients presenting with acute CHF decompensation (acute-on-chronic HF) within the first 24 hours of admission by implementing a CHF care bundle.Methods: Using the Plan-Do-Study-Act (PDSA) model, we conducted two iterative intervention cycles. Baseline data were collected from 19 patients, followed by 13 and 19 patients in subsequent cycles. The intervention involved distributing a simplified care bundle flowchart to staff working in the AMU and providing orientation. Quantitative adherence data were collected from electronic health records and bedside documentation.Results: Results showed a significant improvement in adherence to inpatient monitoring requirements, from a baseline median of 50.9%-86.8% after the second PDSA cycle. From baseline, the completion of nutritional status assessment (+52.6%), daily 12-lead ECG (+63.2%) and fluid status monitoring (+52.6%) saw the largest improvements. Run-chart analysis revealed that monitoring adherence stabilised by Cycle 2.Conclusion: This QIP demonstrates that cost-effective, low-resource, bundle-based interventions can enhance inpatient CHF monitoring, while showcasing the valuable role medical students can play in advancing sustainability initiatives within the NHS. Sustainability was supported by minimal reliance on additional infrastructure, enabling it to continue beyond the students’ placement period.

Nonmetastatic (M0) clear cell renal cell carcinoma (ccRCC) recurs in ∼20% of patients within 5yr after surgery. With no biomarkers available, recurrence detection relies on radiological imaging. Urine glycosaminoglycan profiles (GAGomes) were previously associated with M0 ccRCC recurrence. We conducted an observational prospective multicentre diagnostic test cohort study to evaluate GAGomes for postsurgery recurrence detection in M0 ccRCC. Postsurgical M0 ccRCC patients with a Leibovich score of ≥5 points were included. Follow-up imaging up to 18mo assessed radiological recurrence (reference standard). Urine GAGomes were measured every 3mo to compute a GAGome score (index test). Sensitivity and specificity to radiological recurrence were calculated. The lead time between the first positive GAGome score and radiological recurrence was estimated. Bayesian joint modelling estimated recurrence-free survival hazard ratio (HR). Of the 393 patients screened (January 2020 to November 2021), 134 met the inclusion criteria. The median follow-up was 16mo (interquartile range [IQR]: 12-18) for those without recurrence. At the last follow-up visit, 16% had recurred. The GAGome score had 90% sensitivity (95% confidence interval [CI]: 62-100%) and 51% specificity (95% CI: 30-71%) to radiological recurrence. The positive and negative predictive values were 26% (95%CI: 4-46%) and 97% (95% CI: 87-100%), respectively. The median lead time was 4.2mo (IQR: 1.6-6.4). A 10-point GAGome score increase was associated with an HR of 1.62 (95% high density interval: 1.11-2.30) for recurrence. The main limitation was short follow-up time. GAGome score had very high sensitivity to ccRCC recurrence, resulting in a negative predictive value of 97%. External validation foreseen in the study design aims to confirm its utility to personalise follow-up for M0 ccRCC patients.