Nottingham University Hospitals NHS Trust

The CALYPSO study demonstrated activity of savolitinib and durvalumab in MET-driven papillary renal cancer (PRC). We report final efficacy outcomes and exploratory circulating tumor DNA (ctDNA) biomarker analysis. This single-arm phase II study evaluated savolitinib and durvalumab in treatment-naïve or pretreated PRC. End points included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). FoundationOne CDx assessed DNA alterations and MET/PD-L1 or MET/tumor mutational burden (TMB) copositivity. ctDNA collected at baseline and on treatment was correlated with outcomes. At 41-months median follow-up, ORR was 34% (95% CI, 20.0 to 51.0) in the intention-to-treat (ITT) population (N = 41) and 53% (95% CI, 28.0 to 77.0) in MET-driven patients (n = 17). Median PFS was 6.5 (95% CI, 2.7 to 12.0) versus 13.9 months (95% CI, 2.9 to 23.8), and OS was 18.3 (95% CI, 7.3 to 30.7) versus 27.4 months (95% CI, 9.3 to 37.4), in the ITT population and the MET-driven population, respectively. PD-L1 (66% positive) and TMB (median 2.5 mut/Mb) status did not correlate with response. Baseline ctDNA positivity (10/21) correlated with shorter OS (median 7.3 v 33.3 months), while ctDNA clearance and mean variant allele frequency reduction correlated with improved OS (median 31.3 v 7.2 and 31.3 v 15.5 months, respectively). Savolitinib plus durvalumab shows OS in MET-driven PRC, supporting the ongoing SAMETA RIII trial (ClinicalTrials.gov identifier: NCT05043090). ctDNA may be a useful predictive biomarker.

Adrenal insufficiency (AI) is a common complication following glucocorticoid (GC) therapy. However, reliable predictors of AI and GC regimens that mitigate this risk remain unclear. Previous systematic reviews (SRs) have included many observational studies with imprecise reporting of GC dose and duration. We conducted a systematic review focusing exclusively on studies with well-defined GC exposure. We searched Embase, Web of Science, and MEDLINE for original studies published since 2000 that investigated adults receiving protocolised systemic GC regimens and assessed all participants for AI using the adrenocorticotropic hormone (ACTH) stimulation test. Data extracted included AI prevalence, diagnosis, administration route, GC dose and tapering, treatment duration and timing of outcome assessment. Risk of bias was assessed using an adapted Newcastle-Ottawa Scale. Meta-analysis was performed using random-effects models in R. Of 1340 unique records identified, 12 studies (1170 participants) met inclusion criteria. AI was present in 423 individuals, with a pooled prevalence of 30% (95% CI: 19-45%) at the earliest time point tested. Reported prevalence ranged from 0 to 70%, and was not consistently associated with diagnosis, administration route, treatment duration, or study quality. AI was significantly less common in studies that included tapering (p < 0.01) and in those assessing AI ≥15 days after stopping GCs (15%, 95% CI: 8-26%) compared to testing at cessation (48%, 95% CI: 35-62%). AI is frequent following systemic GC use, with considerable variability. Tapering regimens and delayed testing post-cessation appear to reduce the observed prevalence. No specific GC regimen reliably prevents AI.

Renin-angiotensin-aldosterone system inhibitor (RAASi) therapies are a cornerstone of guideline-directed medical therapy in the management of cardiorenal disease, including chronic kidney disease and heart failure. Management guidelines state that these therapies should be prescribed at the maximum licensed or tolerated dose in order to prevent disease progression and adverse events. However, both cardiorenal disease and RAASi therapies increase the risk of hyperkalaemia. When hyperkalaemia occurs, clinicians often down-titrate or discontinue these important RAASi therapies, leaving patients at risk of adverse cardiorenal outcomes. Eleven cardiorenal experts considered how hyperkalaemia can act as a barrier to optimised RAASi therapy in patients with cardiorenal disease and how these issues could be mitigated. Four key areas of suboptimal and variable clinical practice were identified: optimisation of RAASi therapy; definition and management of acute hyperkalaemia; secondary to primary care communications; and patient education. In this podcast article, two of the experts discuss the clinical challenges and principles of optimal care for each of the four areas identified. The experts agreed that hyperkalaemia should be considered a predictable and manageable condition, requiring a pre-emptive and long-term approach. When hyperkalaemia occurs, down-titrating or discontinuing RAASi therapy should be a last resort, after all other management approaches have been employed. Healthcare professionals in secondary and primary care must communicate and collaborate to ensure effective, consistent management of patients with cardiorenal disease. Finally, patients should be educated to understand their cardiorenal disease and its management and the importance of optimal RAASi therapy. Supplementary file1 (MP4 173853 KB).

Abstract Purpose Surgical site infections (SSIs) are a major complication in spinal surgery, especially with instrumentation, leading to higher morbidity, longer hospital stays, and increased costs. Intraoperative wound irrigation (IWI) with povidone-iodine (PI) has been suggested as a preventive measure. This systematic review and meta-analysis assessed the effectiveness of PI irrigation versus control (saline or no irrigation) in reducing SSIs and its impact on spinal fusion. Methods Following PRISMA guidelines, we searched Ovid MEDLINE, EMBASE, Web of Science, and Cochrane Library through March 2025. Eligible studies were randomized controlled trials (RCTs) comparing PI irrigation with control in adult spinal surgery. The primary outcome was overall SSI rate; secondary outcomes included superficial and deep SSIs, fusion rates, and adverse events. Data were pooled with a random-effects model, and heterogeneity was evaluated using I². Results Six RCTs with 1804 patients (901 PI, 903 control) were included. PI irrigation significantly reduced overall SSI risk (0.77% versus 6.0%; RR = 0.16, 95% c.i.: 0.08–0.34; P &amp;lt; 0.00001; I² = 0%). Subgroup analyses showed lower superficial (RR = 0.19; 95% c.i.: 0.07–0.52; P &amp;lt; 0.001) and deep SSI rates (RR = 0.21; 95% c.i.: 0.08–0.52; P = 0.0009), with absolute rates reduced from 2.9% to 0.33% and 3.2% to 0.4%, respectively. Fusion outcomes were comparable (RD = 0.03; 95% c.i.: 0.00–0.06; P = 0.10). Conclusions PI irrigation markedly reduces superficial and deep SSIs without compromising fusion, supporting its use as a safe, cost-effective adjunct in spinal surgery infection prevention.

Abstract Aims Free tissue transfer is a common plastic surgical procedure with a wide array of applications. There is limited consensus on how free flap ischaemia time impacts flap survival. This systematic review aims to evaluate the association between free flap ischaemia time and acute flap failure rate. Methods A systematic review and meta-analysis in compliance with PRISMA statement standards was conducted following registration on the PROSPERO Register (CRD420251052841). A search strategy was developed and the search conducted in September 2024. Studies eligible for inclusion reported length of ischaemia time for free flap surgery and acute flap failure rate. 78 articles were eligible for inclusion and were published between 1997 and 2024. Study populations ranged from 7 to 3926 patients, with a pooled total of 26 374 free flaps in 23 615 patients. The meta-analysis showed overall risk of flap failure was 3.5% (95% c.i. 3%–4.1%). Meta-regression using ischaemia time as a continuous variable showed an increasing risk of acute flap failure from 3% (2.3%–3.9%) at 30 min ischaemia time to 7.5% (4.4%–12.5%) at 240 min. The variables study type, flap type, indication and risk of bias did not account for between study heterogeneity which was substantial. Conclusions This study has systematically assessed existing literature to show a significant association between prolonged ischaemia time and acute free flap loss. This association can guide microsurgical training as carrying out microsurgery in a time efficient manner has a positive impact on free flap survival.

Abstract Objectives To assess how often adult spinal deformity (ASD) surgery achieves preoperative sagittal alignment goals, whether corrections are durable, and the impact of planning frameworks and enabling technologies. Methods A PRISMA-guided search of MEDLINE, EMBASE, Web of Science, Cochrane Library, and Scopus through June 2025 identified studies of adults undergoing ASD surgery where alignment targets were defined by numeric thresholds (for example SVA, PI–LL, PT), algorithmic frameworks (for example Roussouly, GAP), or technology-assisted modalities (for example virtual planning, patient-specific rods, robotics, custom implants). Outcomes included plan-to-achieved fidelity, durability, complications, and PROMs. Random-effects meta-analyses were performed when data were sufficiently homogeneous (SVA &amp;lt; 5 cm, PI–LL ≤10°, PT ≤20°). Results Fifteen studies (2006–2025) with ∼1980 patients were included. Cohort sizes ranged 15–608; mean age was 65 years (58–72) and 68% female. Mean follow-up was 20 months (immediate to 5 years). Most patients met early postoperative targets for SVA, PI–LL, and/or PT, though durability attenuated at longer follow-up. Algorithm-driven planning—especially restoration to a Roussouly-consistent profile—was associated with fewer mechanical complications. Technology-assisted approaches improved plan-to-achieved fidelity but showed inconsistent PROM gains. Study quality varied: small single-center series were higher risk, while larger prospective cohorts showed lower but heterogeneous risk. Conclusions ASD surgery often achieves sagittal targets initially, but long-term durability is variable. Algorithmic frameworks predict fewer complications, and enabling technologies improve fidelity without consistent PROM gains. Future studies should standardize goals, assess durability beyond two years, and link alignment fidelity to patient-centered outcomes and cost.

Abstract Introduction Classically, the common bile duct (CBD) is believed to have a variable presence of scattered smooth muscle within the muscularis mucosae. The prevalence and organisation of these fibres remain poorly defined. This study aimed to qualitatively and quantitatively assess smooth muscle in CBD resections from patients with biliary obstruction and examine correlations with peak preoperative bilirubin levels. Methods CBD specimens from 81 surgeries, between January 2019 and January 2025, were retrieved from Queen’s Medical Centre, Nottingham, and stained for desmin, smooth muscle actin (SMA), and calretinin. Qualitative analysis classified smooth muscle banding around the lumen. Quantitative analysis was conducted using QuPath, employing a semi-automated approach, with manual annotation where required. Independent reviewers resolved discrepancies &amp;gt;10% by consensus. Additionally, bilirubin concentrations were correlated with quantitative smooth muscle measurements. Results Smooth muscle was present in all samples. Interrupted muscle bands were observed in 74.07% of cases, focal muscle fibres in 23.46%, and concentric bands in only 2.47%. Quantitative analysis of samples demonstrated mean tissue staining of 2.54% ± 2.44 (0.26–17.30) for Desmin, 32.86% ± 12.58 (3.74–66.25) for SMA and 2.27% ± 2.25 (0.27–18.24) for Calretinin. A weak positive correlation was observed between SMA expression and peak bilirubin (ρ = 0.241, P = 0.0312); correlations with desmin and calretinin were not significant. Conclusions This study introduces a novel semi-automated method for assessing smooth muscle in the CBD. The consistent presence of smooth muscle across all specimens challenges traditional assumptions and may have implications for understanding biliary physiology, pathology, and surgical planning.

Abstract Background In this paper, we describe the role of Copy Number Variation (CNV) detection applications in Genome Sequencing data in the diagnosis of Loeys-Dietz syndrome type 4 in a large family, bringing a 30-year diagnostic odyssey to an end. Initially, a 38-year-old man was referred for clinical assessment due to a family history of Marfan syndrome. He had several clinical features indicative of Marfan's syndome. Linkage analysis performed in the family in 1990s was considered informative within a 4.3Mb locus on chromosome 15 including FBN1, supporting the clinical suspicion of Marfan syndrome. Methods A range of genomic tests in the next two decades, initially DHPLC and later sequencing and MLPA of FBN1, failed to identify a pathogenic variant in the family. Genome sequencing (GS) through the UK 100,000 Genomes Project (100kGP) was performed in the patient and his affected maternal aunt using 150bp paired-end reads. Results Reanalysis of the GS data using the SVRare application (1) identified a heterozygous 19,256bp deletion encompassing the last exon of TGFB2 with TCC microhomology seen at breakpoints. This finding, one of the smallest deletions involving TGFB2 described to date (2,3,4), was consistent with a diagnosis of Loeys-Dietz syndrome in the patient and his affected aunt. There have been a range of clinical benefits from a precise molecular diagnosis in this family. The aortic phenotype in this family was significant, with history of aortic surgery or dissection in at least five relatives. Predictive genetic testing has resulted in Loeys-Dietz syndrome type 4 being diagnosed in five further patients in this family. Conclusions Heterozygous loss-of-function variants in TGFB2 cause Loeys-Dietz syndrome type 4 (2) and there are overlapping features between this condition and Marfan syndrome. Precise molecular diagnosis of connective tissue disorders is crucial in appropriate management and surveillance, with a range of clinical benefits seen within this family.

Hypertension remains a leading contributor to cardiovascular morbidity and premature mortality worldwide, with increasing prevalence observed among younger populations. Although avoidable lifestyle factors account for a substantial proportion of hypertension risk, prevention efforts depend heavily on adequate awareness and understanding of these factors. This study examines the level of knowledge of avoidable risk factors of hypertension among university students in England and evaluates the relationship between these factors and hypertension status. A cross-sectional quantitative design was employed using a structured questionnaire administered to students at a large English university. Descriptive statistics, chi-square analysis, and multinomial logistic regression were used to analyse the data. Findings indicate a high level of knowledge of avoidable risk factors, including alcohol consumption, obesity, high salt intake, and junk food consumption. Despite this, significant associations were observed between several avoidable risk factors and hypertension status, particularly alcohol use, body mass index, salt intake, and frequent consumption of junk food. The results highlight a clear disjunction between knowledge and health behaviour, suggesting that awareness alone is insufficient to reduce hypertension risk among university students. The study underscores the need for prevention strategies that extend beyond information provision to address behavioural, social, and environmental drivers of risk.