Western General Hospital

Higher-risk MDS (HR-MDS) with RARA gene overexpression is a subset of HR-MDS patients (pts) with an actionable target for tamibarotene, an oral and selective RARα agonist. Tamibarotene in combination with azacitidine (AZA) showed high complete remission (CR) rates in AML. SELECT-MDS-1 (NCT04797780) was a Phase 3 study comparing the activity of tamibarotene/ azacitidine (AZA) to placebo/AZA in newly diagnosed (ND) HR-MDS pts with RARA overexpression. Eligible patients had confirmed RARA overexpression by blood-based assay, untreated MDS with higher-risk features by IPSS-R and a bone marrow blast count >5%. Patients were randomized 2:1 to receive either tamibarotene/AZA or placebo/AZA, respectively. A total of 246 participants with HR-MDS and RARA overexpression were randomized with 164 and 82 in the tamibarotene/azacitidine and placebo/azacitidine groups, respectively. Baseline characteristics included: 69.9% male; median age 75 (38-93); primary MDS 89.8%; WHO 2016 classification MDS-EB-1 48%, MDS-EB-2 52%; median bone marrow blasts 9.0%; IPSS-R risk category intermediate (25.5%), high (35.7%), very high (38.9%). The study did not meet the primary endpoint of CR, with a p-value of 0.2084 for the treatment effect in the tamibarotene/AZA group compared to the placebo/AZA group. The CR rates were 23.81% and 18.75% in the tamibarotene/AZA and placebo/AZA groups, respectively. The use of tamibarotene-based therapy to target RARα as a novel approach in HR-MDS pts with RARA gene overexpression is not a paradigm which can augment response rates beyond HMA monotherapy. Further explorations of alternative approaches, including those with a biomarker, to alter the natural history of this disease are warranted.

During the twentieth century, inflammatory bowel disease (IBD) was considered a disease of early industrialized regions in North America, Europe and Oceania¹. At the turn of the twenty-first century, IBD incidence increased in newly industrialized and emerging regions in Africa, Asia and Latin America, while the prevalence in early industrialized regions continued to grow steadily2, 3–4. Changes in the incidence and prevalence denote the evolution of IBD across four epidemiologic stages: stage 1 (emergence), characterized by low incidence and prevalence; stage 2 (acceleration in incidence), marked by rapidly rising incidence and low prevalence; and stage 3 (compounding prevalence), where the incidence decelerates, plateaus or declines while the prevalence steadily increases. A fourth stage (prevalence equilibrium) has been proposed in which the prevalence slope plateaus due to demographic shifts in an ageing IBD population, but it has not yet been evidenced. To date, these stages have remained theoretical, lacking specific numerical indicators to define transition points. Here, using real-world data from 522 population-based studies encompassing 82 global regions and spanning more than a century (1920–2024), we show spatiotemporal transitions across stages 1–3 and model stage 4 progression. Understanding the evolution of IBD across epidemiologic stages enables healthcare systems to better anticipate the future worldwide burden of IBD.

Patients with inflammatory bowel disease (IBD) remain at increased risk for colorectal cancer and death from colorectal cancer compared with the general population despite improvements in inflammation control with advanced therapies, colonoscopic surveillance and reductions in environmental risk factors. This guideline update from 2010 for colorectal surveillance of patients over 16 years with colonic inflammatory bowel disease was developed by stakeholders representing UK physicians, endoscopists, surgeons, specialist nurses and patients with GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodological support. An a priori protocol was published describing the approach to three levels of statement: GRADE recommendations, good practice statements or expert opinion statements. A systematic review of 7599 publications, with appraisal and GRADE analysis of trials and network meta-analysis, where appropriate, was performed. Risk thresholding guided GRADE judgements. We made 73 statements for the delivery of an IBD colorectal surveillance service, including outcome standards for service and endoscopist audit, and the importance of shared decision-making with patients. Core areas include: risk of colorectal cancer, IBD-related post-colonoscopy colorectal cancer; service organisation and supporting patient concordance; starting and stopping surveillance, who should or should not receive surveillance; risk stratification, including web-based multivariate risk calculation of surveillance intervals; colonoscopic modalities, bowel preparation, biomarkers and artificial intelligence aided detection; chemoprevention; the role of non-conventional dysplasia, serrated lesions and non-targeted biopsies; management of dysplasia, both endoscopic and surgical, and the structure and role of the multidisciplinary team in IBD dysplasia management; training in IBD colonoscopic surveillance, sustainability (green endoscopy), cost-effectiveness and patient experience. Sixteen research priorities are suggested.

Urinary catheters are used extensively in hospitals and long-term care and they are highly prone to infection. Understanding the pathways by which bacteria colonise a urinary catheter could guide strategies to mitigate infection, but quantitative models for this colonisation process are lacking. Here we present a mathematical model for bacterial colonisation of a urinary catheter that integrates population dynamics and fluid dynamics. The model describes bacteria migrating up the outside surface of the catheter, spreading into the bladder and being swept through the catheter lumen. Computer simulations of the model reveal that clinical outcomes for long-term versus short-term catheterisation are controlled by different factors: the rate of urine production by the kidneys as opposed to urethral length, catheter surface properties and bacterial motility. Our work may help explain variable susceptibility to catheter-associated urinary tract infection (CAUTI) among individuals and the mixed success of antimicrobial surface coatings. Our model suggests that for long-term catheterised patients, increasing fluid intake or reducing residual urine volume in the bladder may help prevent infection, while antimicrobial surface coatings are predicted to be effective only for short-term catheterised patients. Therefore, different catheter management strategies could be rationally targeted to long-term vs short-term catheterised patients.

This report provides guidance for users of linear accelerator (linac) manufacturer integrated quality control (MIQC) tools. MIQC tools have been developed and introduced by radiotherapy linac vendors, and have the potential to improve both the quality and efficiency of linac quality control (QC). They usually utilise the Electronic Portal Imaging Device (EPID), but may acquire data from other sources, and automatically perform and analyse tests of various treatment machine QC parameters. The currently available systems meeting this definition are Varian machine performance check, CyberKnife automated quality assurance /end-to-end, TomoTherapy Quality Assurance, and Elekta machine QA (also known as AQUA). This guidance report covers the commissioning and implementation of MIQC. The guidance has been developed by a radiotherapy special interest group working party on behalf of the Institute of Physics and Engineering in Medicine. Recommendations within the report are derived from the experience of the working party members, existing guidance, literature, and a United Kingdom survey conducted in 2022 (Pearson et al 2023 Phys. Med. Biol. 68 245018). Topics covered include developing an understanding of the QC system, independence review of MIQC, commissioning, implementation, ongoing QC and calibration, software upgrades and periodic review. The commissioning section covers detector commissioning, repeatability and reproducibility, baseline and tolerance setting, concordance with existing QC, sensitivity testing, cost-benefits analysis, and risk assessment methods. In order to offer practical guidance, case studies covering each aspect of commissioning are included. They are real-world examples or experiences from early adopters, each applied to a different example MIQC system. The examples will be directly applicable to users of that specific MIQC system, but also provide practical guidance on clinical implementation to users of the other systems.

The authors present a compelling case of a man in his 50s whose long-standing congenital cervical haemangioma became symptomatic after adopting a more physically active lifestyle. Imaging revealed notable findings, with ENT assessment uncovering deep airway extension of the hemangioma, triggering neck discomfort after strenuous activity. The patient had previously been advised to avoid general anaesthesia due to anticipated difficulties with intubation. Subsequent flexible laryngoscopy and CT imaging revealed a greater degree of airway involvement than initially suspected. The article explores the range of management options available for this condition. Remarkably, despite the potential complications, the patient continues to enjoy a good quality of life without requiring medical or surgical intervention.

On 6 November 2024, the Royal College of Physicians of Edinburgh (RCPE) hosted its annual gastroenterology symposium, marking the first collaboration with the American College of Gastroenterology (ACG) and the Scottish Society of Gastroenterology (SSG). The event addressed key global challenges in gastroenterology, including obesity, liver disease, inflammatory bowel disease (IBD), the gut microbiome, endoscopy quality and artificial intelligence (AI) applications. Discussions emphasised the growing burden of metabolic dysfunction-associated steatotic liver disease (MASLD), with promising pharmacologic and endoscopic interventions emerging. Advances in microbiome-targeted therapies, including faecal microbiota transplantation (FMT), were explored for recurrent Clostridium difficile infection and IBD. Professor David Rubin delivered the esteemed Sir Stanley Davidson lecture, highlighting the era of disease modification in IBD, emphasising early intervention and personalised treatment strategies. The symposium also addressed the role of AI in improving endoscopic detection rates and optimising resource allocation. This international collaboration underscored the importance of a multidisciplinary approach to tackling global digestive diseases, integrating clinical innovation, policy interventions and technological advancements. The event fostered knowledge exchange among global experts, aiming to advance patient care and improve long-term outcomes in gastroenterology.

Cell number is a major determinant of organism size in mammals. In humans, gene mutations in cell cycle components result in restricted growth through reduced cell numbers. Here we identified biallelic mutations in CDK4 as a cause of microcephaly and short stature. CDK4 encodes a key cell cycle kinase that associates with D-type cyclins during G1 of the cell cycle to promote S-phase entry and cell proliferation through retinoblastoma (RB) phosphorylation. CDK4 and CDK6 are believed to be functionally redundant and are targeted jointly by chemotherapeutic CDK4/6 inhibitors. Using molecular and cell biology approaches, we show that functional CDK4 protein is not detectable in cells with CDK4 mutations. Cells display impaired RB phosphorylation in G1, leading to G1/S-phase transition defects and reduced cell proliferation, consistent with complete loss of cellular CDK4 enzymatic activity. Together, these findings demonstrate that CDK4 is itself required for cell proliferation, human growth, and brain size determination during development.

A systematic review and meta-analysis of the presentation, risk factors and treatment response of pregnancy-associated osteoporosis was conducted involving 35 studies and 943 patients. Vertebral fractures, back pain and family history of osteoporosis were common features. Analysis of treatment response was inconclusive due to limited availability of data. Pregnancy-associated osteoporosis (PAO) is a rare disorder most often presenting with vertebral fractures during pregnancy or postpartum. This meta-analysis aimed to evaluate the presenting features of PAO, its risk factors and the effectiveness of various treatments at improving bone mineral density (BMD) and preventing further fractures. A systematic search of PubMed, EMBASE and Web of Science identified 35 studies comprising 943 cases of PAO. A meta-analysis was conducted to evaluate the effect of treatment on change in BMD at the lumbar spine, femoral neck and total hip. Vertebral fractures and back pain occurred in 89.2% and 90.2% of cases, respectively. The diagnosis was predominantly made postpartum. The most common risk factor was a family history of osteoporosis (40.5%). Calcium and vitamin D supplements (31.8%) and teriparatide (30.8%) were the most commonly used treatments. The meta-analysis of BMD response was inconclusive due to limited availability of data. The BMD change at the lumbar spine was greater with teriparatide compared with calcium/vitamin D and bisphosphonates but this was based on only two studies. There was no difference in BMD response at the femoral neck. Recurrent fractures were reported in 12.9% with no difference between treatment groups. While this review can assist clinicians with the diagnosis and management of PAO, it highlights some key knowledge gaps that may inform conduct of a Delphi process on the diagnosis and management of this disorder, pending conduct of randomised controlled trials.

Introduction Mammographic screening identifies many women with small breast cancers with favourable biological features, which have an excellent prognosis. Some of these may never have become clinically apparent without screening and are commonly described as ‘overdiagnosed’ cancers. Despite this, all patients with screen-detected cancers are currently treated with surgical excision and sentinel lymph node biopsy, although this may represent overtreatment. There is, therefore, a need for less invasive approaches to reduce treatment burden for patients while maintaining current excellent oncological outcomes. Vacuum-assisted excision (VAE) may represent such an alternative treatment approach, and the SMALL ( Open Surgery versus Minimally invasive-vacuum Assisted excision for smaLL screen-detected breast cancer ) trial aims to investigate the use of VAE for the safe de-escalation of surgical treatment for such excellent prognosis invasive breast cancers. Methods SMALL is a prospective, multicentre, randomised phase III trial of VAE versus surgery in patients with small, biologically favourable screen-detected invasive breast cancer. SMALL has an innovative hybrid design with coprimary endpoints. These include a randomised non-inferiority comparison of surgical re-excision rates following initial treatment, and a single-arm analysis of local recurrence at 5 years following VAE. Secondary outcomes include complication rates, overall survival, quality of life and a health economic analysis. The trial includes a QuinteT Recruitment Intervention to support recruitment. Ethics and dissemination Ethical approval was obtained from the Office for Research Ethics (Northern Ireland) for all UK sites. Results will be submitted for publication in a peer-reviewed journal, presented, shared with patient partners and with relevant professional organisations to inform future guideline development for the management of screen-detected breast cancer. Trial registration number ISRCTN12240119 .

Objective To determine whether any children in the UK had variant Creutzfeldt-Jakob disease (vCJD). Design This active prospective epidemiological study used the British Paediatric Surveillance Unit, asking UK paediatricians to notify all childhood cases of progressive intellectual and neurological deterioration (PIND), a group that would include all cases of vCJD. Clinical data were obtained by questionnaire or via a site visit. An independent expert group classified the cases. If vCJD was suspected, referral to the National Creutzfeldt-Jakob Disease Research and Surveillance Unit was recommended. Results Between May 1997 and April 2024 (27 years), 5222 children were notified. There were four groups. (1) 2540 were ‘not cases’—they did not meet the case definition or there were notification errors. (2) 2367 had a known underlying diagnosis other than vCJD; the group contained more than 220 different diseases. (3) 309 had no diagnosis to explain their deterioration; there was evidence that none of these cases had vCJD. (4) There were six cases of vCJD: two males and four females. They developed symptoms between 1998 and 2000, aged 12–15 years, and the last two died in 2003. Their clinical features were similar to those of adults. Four were classified as definite vCJD and two as probable vCJD. Conclusions This study has provided unique data about neurodegenerative diseases in UK children. There is no reliable vCJD screening test; so for 27 years, the PIND study has provided reassurance that childhood vCJD cases were not missed. New vCJD cases with the methionine/valine genotype could appear.

Aim Microscopically positive resection margins (R1) are associated with poorer outcomes in colon cancer. While the sequalae of a positive margin related to the primary tumour (R1Tumour) are relatively well known, comparatively less is known when the positive margin pertains to a metastatic lymph node (R1LNM). The aim of this study is to confirm the significance and impact of R1LNM margins in colon cancer patients. Method A retrospective, observational study of patients treated for American Joint Committee on Cancer Stage 3 colon cancer with potentially curative surgical intervention during a 10‐year study period was performed. Patients were stratified into three groups (R0, R1Tumour, R1LNM). Outcomes measured were disease‐specific survival (DSS), local recurrence‐free survival (LRFS) and systemic recurrence‐free survival (SRFS). Cox multivariable analysis and sensitivity analyses (time‐stratified, competing‐risk and propensity‐matched analyses) were performed to determine the independent importance of R1LNM. Results A total of 801 patients were included. The R1 resection rate was 6.6% and the R1LNM resection rate was 4.7%. Compared with R0 resection, R1LNM margins had significantly lower 5‐year DSS [R1LNM 53.8% (95% CI 37.4%–77.3%) vs. R0 74.2%], LRFS [R1LNM 61% (95% CI 41.7%–89.1%) vs. R0 80.5%] and SRFS [R1LNM 39.5% (95% CI 24.2%–63.8%) vs. R0 70%]. R1LNM was not independently associated with the above outcomes following traditional, time‐stratified and competing‐risk multivariable analyses, nor following propensity matching. Conclusion R1LNM positivity may reflect other poor‐prognosis variables, which themselves play a more substantial role in determining disease outcomes.

Background Localised renal cell carcinoma (RCC) is usually treated surgically, with post‐operative imaging‐based surveillance to monitor for recurrence. However, surveillance practices vary widely, and patients often lack a clear understanding of their risk of recurrence and follow‐up care. The PREDICT Kidney tool has been developed to enhance risk communication by providing individualised recurrence and mortality risk estimates. The tool uses the Leibovich score augmented with English national data to provide a personalised risk assessment of cancer recurrence and death from other causes, presented in both numerical and visual formats. Study Design A multicentre, prospective feasibility study of incorporating the PREDICT Kidney risk communication tool into the first follow‐up consultation for localised RCC patients post‐surgery. Endpoints Patient uptake into the study, completeness of data collection, consultation duration, the acceptability of the tool to both patients and clinicians, clinician adherence to the study “best‐practice” guide, variability in tool usage across clinicians and sites and patient‐level clinical outcomes including subjective and objective comprehension of risk of recurrence and follow‐up, perceived risk of cancer recurrence, risk conviction, satisfaction with the information provided on risk of recurrence and follow‐up, and fear of cancer recurrence. Patients and Methods We aim to recruit 60 patients from three hospitals in England and Scotland. Patients treated with surgery for primary localised clear‐cell RCC awaiting their first follow‐up appointment will be invited to take part. Participants will be allocated into two groups: standard care and standard care supplemented with the use of the PREDICT Kidney tool. Data will be collected through questionnaires, audio/video recordings of consultations and interviews with a subset of patients and clinicians. The study period is planned from September 2024 to July 2025. The findings will guide the design of a future randomised controlled trial to evaluate the tool's efficacy in clinical settings.

High-quality radiotherapy depends upon accurate definition of both disease and normal healthy tissue, and it therefore depends upon high-quality imaging. Image registration is a process that geometrically links two images together and in so doing aligns the anatomical and biological information in these images. Image registration tools are used to incorporate information from other imaging modalities such as MRI, and PET/CT into the radiotherapy planning process, and are now widely used for radiotherapy planning in most tumour sites. Because image registration is a crucial step in the radiotherapy workflow, it is important to understand the limitations of the process, how to assess the quality of an image registration, and to communicate well within teams. Powerful deformable image registration tools are increasingly used in applications such as adaptive radiotherapy and radiotherapy retreatment, and whilst they permit more accurate alignment of anatomical changes over time, the process contains some uncertainties and should be used carefully.