Salisbury District Hospital

Multicystic mesothelioma (MCM) is a rare disease and there is debate about it's neoplastic nature with a spectrum of disease behaviour and little known about the genomic profile. In contrast, the genomic profile of malignant peritoneal mesothelioma (MPeM) is characterised. We characterized 24 MCM and 18 MPeM cases across a panel of cancer related regions and expanded to whole-exome sequencing for 11 MCMs. Validation by amplicon sequencing and functional assessment by molecular dynamic simulation were carried out. Kaplan-Meier analysis was carried out to assess recurrence-free survival. Few mutations were identified in MCMs across the panel. Exome sequencing revealed 28 genes mutated in >1 MCM case. We saw significant overrepresentation of mutations in the cohesin complex in SMC3, SMC1A, and STAG3. Multiple mutations in SMC3 at codon p.E1144 indicated a mutational hotspot. Molecular dynamics simulations showed mutation at this site impacts the protein function. Amplicon sequencing confirmed hotspot mutations in further MCMs. We observed a significant association (p = 0.0302) of mutation in SMC3 or SMC1A with disease recurrence. We see recurrent somatic mutations in MCMs particularly at a novel mutational hotspot in SMC3, consistent with a neoplastic process. Mutations in cohesin complex genes are associated with disease recurrence.

Inflammation plays an essential role in the pathogenesis of cardiovascular diseases (CVDs), and despite advances in treatments, challenges still exist. Recent studies have explored the use of colchicine in reducing the risk of CVDs. Therefore, the present systematic review aimed to evaluate the impact of colchicine in terms of efficacy, safety, and therapeutic role in managing CVD patients. A comprehensive literature search was performed from different electronic databases, such as PubMed, Scopus, and the Cochrane Library, using keywords associated with the aim of the study, using Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). Methodological quality assessment was performed using the Cochrane risk of bias-2.0 (RoB-2.0) and the Risk of Bias in Non-Randomized Studies-Intervention (ROBINS-I) tools for randomized controlled trials (RCTs) and non-RCTs, respectively. For the meta-analysis, RevMan 5.4 was used to construct forest plots. Finally, 19 studies were included for qualitative and quantitative analyses. Both male and female patients were included in the studies; however, studies were more skewed toward male patients reported with different types of CVDs, including acute pericarditis, coronary artery disease (CAD), heart failure, and myocardial infarction, and also reported comorbidities, like hypertension (HTN), diabetes, and dyslipidemia. Overall, a low dose of 0.5 mg/daily of colchicine was used. A high adherence rate (>85%) was observed in the studies, with few cases of discontinuation of medications. Numerous studies have reported that colchicine successfully benefits in reducing the inflammatory and other biomarkers, such as C-reactive protein (CRP), Interleukin (IL)-6, and IL-1β. The pooled estimate size for comorbidities, like diabetes, was 0.94, odds ratio (OR) (95% CI, 0.86-1.02, p = 0.13, I2 = 0%). For hypertension and dyslipidemia, it was 1, OR (95% CI, 0.93-1.07, p = 0.95, I2 = 9%) and 0.89, OR (95% CI, 0.66-1.2, p = 0.46, I2 = 0%), respectively. Meanwhile, the overall effect size was 0.97, OR (95% CI, 0.92-1.02, p = 0.29, I2 = 0%). The pooled estimate size for major adverse cardiovascular events (MACEs) and all complications was 0.68, OR (95% CI, 0.36-1.26, p = 0.22, I2 = 47%) and 1.60, OR (95% CI, 1.11-2.31, p = 0.01, I2 = 65%). The overall effect size was 1.26, OR (95% CI, 0.92-1.72, p = 0.16, I2 = 63%). Furthermore, the pooled estimate size for mortality associated with CVDs and all-cause mortality was 0.77, OR (95% CI, 0.56-1.06, p = 0.11, I2 = 17%) and 1.11, OR (95% CI, 0.72-1.71, p = 0.65, I2 = 48%), with the overall effect size of 0.89, OR (95% CI, 0.70-1.12, p = 0.32, I2 = 40%). These outcomes suggest that colchicine offers potential anti-inflammatory benefits in CVD patients, but its clinical impact on outcomes, like MACE and mortality, remains uncertain due to the non-significant difference, warranting further large-scale, high-quality multicenter studies.

<bold>Background:</bold> Some, but not all, pathogenic hemizygous variants in <italic>RPGR</italic> (exons 1-14) have been shown to cause X-linked PCD with concurrent retinitis pigmentosa (RP). Due to rarity of cases little is known about the phenotypic variation in the airway cilia of these patients. <bold>Methods:</bold> Patients referred for PCD diagnostics underwent functional testing of nasal epithelium: high-speed video microscopy analysis of cilia beat pattern pre and post air-liquid interface culture, axonemal ultrastructure quantification by transmission electron microscopy (TEM) and immunofluorescence (IF) localisation of cilia proteins, with PCD gene panel or whole genome sequencing analysis. <bold>Results:</bold> Five male patients with clinical history and functional tests consistent with PCD diagnosis were identified with pathogenic variants (stop gain 4/5, missense 1/5) in <italic>RPGR</italic> exons 6&7. Nasal cilia presented as dyskinetic, stiff and of variable (often short) length before (5/5) and post-culture (3/3), with either normal ultrastructure (3/5) or 46-48% microtubule disorganisation, a class 2 TEM defect (2/5). RPGR localisation by IF was reduced compared to controls (2/2). All presented with <italic>situs solitus</italic> and early onset respiratory symptoms, nasal nitric oxide levels ranged from 19.7-100.2 nL/min. One patient was previously diagnosed with RP, 3 were diagnosed with PCD in childhood before onset of RP symptoms and received counselling. One adult has no reported vision loss. <bold>Conclusion:</bold> We provide evidence that presence of shortened dyskinetic cilia is a common feature of <italic>RPGR</italic> PCD patients. Our cases, all with variants in <italic>RPGR</italic> exons 6&7, present with either normal ultrastructure or with microtubule disorganisation, supporting previously published observations.

Post-polypectomy syndrome (PPS) is a rare yet significant complication of endoscopic polypectomy that can clinically mimic intestinal perforation. This report presents the case of an 85-year-old female who developed PPS following an elective endoscopic mucosal resection (EMR) of a 3 cm mid-rectal polyp. Her past medical history included asthma and epilepsy. The EMR was performed in a piecemeal fashion using snare tip soft coagulation, and the defect was closed with eleven endoclips. The patient initially remained stable post-procedure but developed pyrexia, drowsiness, and a Glasgow Coma Scale (GCS) score of 3/15 later that evening. Laboratory results revealed severe metabolic acidosis, elevated lactate, markedly raised inflammatory markers, and significant leukocytosis. A contrast-enhanced CT scan of the abdomen and pelvis showed no evidence of perforation or obstruction but did reveal rectal wall edema, fat stranding, and a small-to-moderate volume of pelvic free fluid. These findings, in conjunction with her recent procedure and clinical deterioration, led to a diagnosis of PPS. She was managed conservatively with intravenous fluids and piperacillin-tazobactam; she made a full recovery and was discharged within 72 hours. This report underscores the importance of early recognition and differentiation of PPS from true bowel perforation. PPS is typically self-limiting and can be managed non-surgically with close monitoring. A thorough awareness of the risk factors-such as large polyp size, use of thermal coagulation, and rectal location-can assist in early diagnosis and prevent unnecessary surgical intervention. This report highlights the need for high clinical suspicion, timely imaging, and prompt supportive treatment in patients who deteriorate following endoscopic interventions.