The Fight Tumour Blindness Registry: Efficient capture of high-quality real-world data in uveal melanoma.

OBJECTIVE: To describe the development of a web-based data collection tool to track the management and outcomes of uveal melanoma patients. DESIGN: Description of a clinical registry. PARTICIPANTS: Patients with uveal melanoma. METHODS: A panel of expert ocular oncologists, with input from other relevant specialties and individuals with expertise in registry development, collaborated to formulate a minimum data set to be collected to track patient centred, real-world outcomes in uveal melanoma. This data set was used to create the Fight Tumour Blindness! (FTB!) registry within Save Sight Registries. RESULTS: The data set to be collected includes patient demographics and medical history, baseline visit, follow-up visit including tumour treatment, metastatic staging and surveillance, pathology, and patient-reported questionnaires. The inbuilt mechanisms to ensure efficient and complete data collection are described. CONCLUSIONS: The FTB! registry can be used to monitor outcomes for patients with uveal melanoma. It allows benchmarking of outcomes and comparisons between different clinics and countries.

A direct aorta to segmental artery bypass for prevention of spinal cord ischemia after endovascular aortic repair.

Spinal cord ischemia remains a persistent challenge after endovascular aortic aneurysm repair. We present a novel direct aorta to segmental artery bypass before aneurysm repair in a 64-year-old woman presenting with an enlarging aneurysm following dissection. Through an eighth intercostal incision, a polyester graft was sewn into the aorta using pledgeted sutures. An entry needle was used to directly access the previously treated aortic segment, and the opening was stented and angioplasty was performed to create inflow. Anastomoses were performed to a prominent left T10 segmental artery with a harvested saphenous vein. The patient remained neurologically intact postoperatively and the 1-month follow-up angiography demonstrated bypass patency.

Lapatinib dysregulates HER2 signaling and impairs the viability of human uveal melanoma cells.

Uveal melanoma (UM) is the principal type of intraocular malignancy in adults. Up to 50% of UM patients develop metastatic disease with very poor survival. There are few drugs available to treat the primary or metastatic UM. This study was undertaken to evaluate the anti-cancer effect of lapatinib and corroborate the potential of HER2 inhibition in the treatment of UM. The anti-UM activity of lapatinib was assessed using cell viability, cell death and cell cycle analysis, and its anti-metastatic actions were evaluated using would healing, invasion and colony formation assays. Immunoblotting was used to substantiate the actions of lapatinib on apoptotic and HER2 signaling. The anti-UM activity of lapatinib was further evaluated in a UM xenograft mouse model. Lapatinib decreased the viability of four UM cell lines (IC50: 3.67-6.53 µM). The antiproliferative activity of lapatinib was corroborated in three primary cell lines isolated from UM patient tumors. In UM cell lines, lapatinib promoted apoptosis and cell cycle arrest, and strongly inhibited cell migration, invasion and reproductive cell growth. Lapatinib dysregulated HER2-AKT/ERK/PI3K signalling leading to the altered expression of apoptotic factors and cell cycle mediators in UM cell lines. Importantly, lapatinib suppressed tumourigenesis in mice carrying UM cell xenografts. Together the present findings are consistent with the assertion that HER2 is a viable therapeutic target in UM. Lapatinib is active in primary and metastatic UM as a clinically approved HER2 inhibitor. The activity of lapatinib in UM patients could be evaluated in future clinical trials.

Short- and long-term mortality following acute medical admission.

BACKGROUND: Short-term in-hospital mortality following acute medical admission has been widely investigated. Longer term mortality, particularly out-of-hospital mortality, has been less well studied. AIM: The aim of this study is to evaluate short- and long-term mortality, and predictors of such, following acute medical admission. DESIGN: Retrospective database study. METHODS: We evaluated all acute medical admissions to our institution over 10 years (2002-11) with a minimum of a further 10 years follow-up to 2021 using the Irish National Death Register. Predictors of 30-day in-hospital and long-term mortality were analysed with logistic and Cox regression, with loss of life years estimated. RESULTS: The 2002-11 cohort consisted of 62 184 admissions in 35 140 patients. 30-Day in hospital mortality (n = 3646) per patient was 10.4% and per admission was 5.9%. There were an additional 11 440 longer-term deaths by 2021-total mortality was 15 086 (42.9%). Deaths post hospital discharge had median age at admission of 75.4 years [interquartile range (IQR) 63.7, 82.8] and died at median age of 80 years (IQR 69, 87). The half-life of survival following admission was 195 months-representing a short fall of 8 life years (32.9%) compared with the projected population reference of 24.3 years. Age [odds ratio (OR) 1.73 (95% confidence interval (CI) 1.64, 1.81)], acute illness severity score [OR 1.39 (95% CI 1.36, 1.43)] and comorbidity score [OR 1.09 (95% CI 1.08, 1.10)] predicted long-term mortality. CONCLUSION: Similar factors influence both short- and long-term mortality following acute medical admission, the magnitude of effect is attenuated over time.

The multifunctional human ocular melanocortin system.

Immune privilege in the eye involves physical barriers, immune regulation and secreted proteins that together limit the damaging effects of intraocular immune responses and inflammation. The neuropeptide alpha-melanocyte stimulating hormone (α-MSH) normally circulates in the aqueous humour of the anterior chamber and the vitreous fluid, secreted by iris and ciliary epithelium, and retinal pigment epithelium (RPE). α-MSH plays an important role in maintaining ocular immune privilege by helping the development of suppressor immune cells and by activating regulatory T-cells. α-MSH functions by binding to and activating melanocortin receptors (MC1R to MC5R) and receptor accessory proteins (MRAPs) that work in concert with antagonists, otherwise known as the melanocortin system. As well as controlling immune responses and inflammation, a broad range of biological functions is increasingly recognised to be orchestrated by the melanocortin system within ocular tissues. This includes maintaining corneal transparency and immune privilege by limiting corneal (lymph)angiogenesis, sustaining corneal epithelial integrity, protecting corneal endothelium and potentially enhancing corneal graft survival, regulating aqueous tear secretion with implications for dry eye disease, facilitating retinal homeostasis via maintaining blood-retinal barriers, providing neuroprotection in the retina, and controlling abnormal new vessel growth in the choroid and retina. The role of melanocortin signalling in uveal melanocyte melanogenesis however remains unclear compared to its established role in skin melanogenesis. The early application of a melanocortin agonist to downregulate systemic inflammation used adrenocorticotropic hormone (ACTH)-based repository cortisone injection (RCI), but adverse side effects including hypertension, edema, and weight gain, related to increased adrenal gland corticosteroid production, impacted clinical uptake. Compared to ACTH, melanocortin peptides that target MC1R, MC3R, MC4R and/or MC5R, but not adrenal gland MC2R, induce minimal corticosteroid production with fewer adverse systemic effects. Pharmacological advances in synthesising MCR-specific targeted peptides provide further opportunities for treating ocular (and systemic) inflammatory diseases. Following from these observations and a renewed clinical and pharmacological interest in the diverse biological roles of the melanocortin system, this review highlights the physiological and disease-related involvement of this system within human eye tissues. We also review the emerging benefits and versatility of melanocortin receptor targeted peptides as non-steroidal alternatives for inflammatory eye diseases such as non-infectious uveitis and dry eye disease, and translational applications in promoting ocular homeostasis, for example, in corneal transplantation and diabetic retinopathy.

Outcomes for Emergency Department Final Diagnosis of Non-specific Complaint compared to Dyspnoea and Pain.

AIM: To compare outcomes in Emergency Department (ED) final diagnoses of (non-specific complaint) NSC, dyspnoea and pain. METHODS: We studied all ED final diagnoses of NSC, dyspnoea, and pain over 6 years (2015-2020). Multivariable logistic regression was performed. RESULTS: There were 49,965 admissions. 30-day in-hospital mortality was significantly lower for pain, 3.0% (95%CI 2.4%, 3.6%), compared to NSC, 4.2% (95%CI 3.8%, 4.7%), and dyspnoea, 4.6% (95%CI 4.2%, 5.0%). NSC did not predict 30-day in-hospital mortality- univariate OR 1.05 (95%CI 0.93, 1.19), multivariable OR 1.07 (95%CI 0.93, 1.23). Comorbidity and Acute Illness Severity Scores demonstrated a curvilinear relationship with 30-day in-hospital mortality. CONCLUSION: An ED final diagnosis of NSC did not predict 30-day in-hospital mortality.

The multi-kinase inhibitor afatinib serves as a novel candidate for the treatment of human uveal melanoma.

PURPOSE: Uveal melanoma (UM) is the most common intraocular malignancy in adults with a poor prognosis and a high recurrence rate. Currently there is no effective treatment for UM. Multi-kinase inhibitors targeting dysregulated pro-tumorigenic signalling pathways have revolutionised anti-cancer treatment but, as yet, their efficacy in UM has not been established. Here, we identified the multi-kinase inhibitor afatinib as a highly effective agent that exerts anti-UM effects in in vitro, ex vivo and in vivo models. METHODS: We assessed the anti-cancer effects of afatinib using cell viability, cell death and cell cycle assays in in vitro and ex vivo UM models. The signaling pathways involved in the anti-UM effects of afatinib were evaluated by Western blotting. The in vivo activity of afatinib was evaluated in UM xenograft models using tumour mass measurement, PET scan, immunohistochemical staining and TUNEL assays. RESULTS: We found that afatinib reduced cell viability and activated apoptosis and cell cycle arrest in multiple established UM cell lines and in patient tumour-derived primary cell lines. Afatinib impaired cell migration and enhanced reproductive death in these UM cell models. Afatinib-induced cell death was accompanied by activation of STAT1 expression and downregulation of Bcl-xL and cyclin D1 expression, which control cell survival and cell cycle progression. Afatinib attenuated HER2-AKT/ERK/PI3K signalling in UM cell lines. Consistent with these observations, we found that afatinib suppressed tumour growth in UM xenografted mice. CONCLUSION: Our data indicate that afatinib activates UM cell death and targets the HER2-mediated cascade, which modulates STAT1-Bcl-xL/cyclin D1 signalling. Thus, targeting HER2 with agents like afatinib may be a novel therapeutic strategy to treat UM and to prevent metastasis.

The application of natural compounds in uveal melanoma drug discovery.

OBJECTIVES: Uveal melanoma (UM) is the most common primary intraocular tumour in adults. UM has a poor overall prognosis and ~50% of patients progress to metastatic disease that has a median survival of 5.2 months. There are currently no proven pharmacological treatments for primary or metastatic UM. Research efforts continue to seek new agents. Many natural compounds have shown promising anti-UM activity in in-vitro and/or in-vivo studies. This review summarises the current findings for natural compounds that may be potentially useful in treating UM. KEY FINDINGS: Literature suggests that natural compounds, such as pristimerin, picropodophyllin, oridonin, zeaxanthin, withaferin and FR-900359, may be promising candidate compounds to treat UM. Most of these compounds have demonstrated satisfactory efficacy in inhibiting in-vitro UM cell growth. SUMMARY: The evidence regarding the anti-UM effects of natural compounds is mainly limited to in-vitro studies; to date, only a small number of these agents have been evaluated in vivo. The molecular mechanisms underpinning the anti-UM properties of these compounds remain largely undefined. Further studies are required to evaluate the in-vivo anticancer activity, appropriate dosage regimen and safety of natural compounds that could be developed for use in UM.

The 'Unwell' clinical presentation- an opportunity for admission avoidance?

BACKGROUND: An 'unwell' patient is a common presentation. METHODS: We studied all ED 'unwell' admissions over 6 years, assessing factors influencing mortality with logistic regression. RESULTS: From 49,965 admissions, the ED diagnosis was 'unwell' in 3650 (7.3%). 'Unwell' presentations were older and had longer length of stay. Mortality was not different 4.2% vs 4.6 % (p=0.28). Respiratory patients and those >=70 years had increased mortality, 8.3% (95%CI: 5.9%, 10.6%) and 7.1% (5.7%, 8.4%) respectively. Being unwell predicted a better outcome - univariate OR 0.35 (95%CI: 0.24, 0.52), multivariable OR 0.68 (95%CI: 0.44, 1.03). CONCLUSION: A diagnosis of 'unwell' applied to a heterogenous group; clinical trajectories and outcomes were sufficiently different to preclude targeted admission avoidance as a strategy.

Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE) as a Screening Marker for Familial Adenomatous Polyposis (FAP): Systematic Literature Review and Screening Recommendations.

Purpose: Familial adenomatous polyposis (FAP) has an almost 100% colorectal cancer risk warranting early detection in gene carriers. This study presents congenital hypertrophy of the retinal pigment epithelium (CHRPE) as a highly specific phenotypical marker for FAP that can be used in screening at-risk individuals. Screening recommendations including morphological subclassification were formulated with supporting literature. Methods: A systematic literature review with a comprehensive search strategy was conducted using online databases. Manual searches of bibliographies and reference lists were also performed. Studies meeting inclusion criteria were graded with respect to their hierarchy of evidence and strength of recommendations according to the National Health and Medical Research Council (NHMRC) guidelines of Australia. Results: Almost 4500 participants were analysed across 28 included studies. The mean specificity of CHRPE as a phenotypical screening marker of FAP was 89% (standard deviation (SD); 14) with a mean sensitivity of 79% (SD; 8). The mean prevalence of CHRPE amongst FAP participants; at-risk participants were found to be 76% (SD; 24) and 37% (SD; 21) respectively. Bilateralism and multiple lesion number ≥3 are features highly specific for FAP. Conclusion: CHRPE was found to be a non-invasive, rapid, early phenotypical screening marker of FAP. Clinical recognition further allows increased gene analysis efficiency. The absence of CHRPE alone cannot exclude FAP. Our screening recommendations provide guidance to clinicians on evidence based CHRPE assessment. We would advocate inclusion of ocular examinations as part of a three-pronged approach, along with endoscopy and genetic testing, for efficient, timely FAP assessment in at-risk individuals.

The unfolded protein response and the biology of uveal melanoma.

Uveal melanoma (UM) is a highly metastatic ocular cancer that arises from the melanocytes of the uveal tract (the choroid, ciliary body and iris). Despite a growing understanding of UM biology, effective systemic treatments are currently lacking and the cancer has an extremely poor prognosis. Therefore, identifying novel agents that act by new tumorigenic mechanisms in UM is essential to address this unmet clinical need. Endoplasmic reticulum (ER) stress occurs when misfolded proteins accumulate in the organelle, and the unfolded protein response (UPR) is the cellular mechanism that is activated so that cells may adapt to the situation. Dysregulated UPR signalling has been detected in UM tumors and has been associated with an increase in immune evasion and metastatic activity. A number of established and novel oncology drugs act in part by modulating ER stress and the UPR. The induction of protein-folding stress and the UPR could be a novel approach for the development of new therapeutics in UM. Further studies are now warranted to understand the mechanisms and consequences of UPR signalling in UM.

Blood Culture and Troponin Testing in Suspected Bacteraemic Admissions - Example of Risk Stratification Based on Clinical Testing.

AIM: To investigate the clinical predictive value of troponin (hscTnT) and blood culture testing. METHODS: We examined all medical admissions from 2011-2020. Prediction of 30-day in-hospital mortality, dependent on blood culture and hscTnT requests/results, was evaluated using multiple variable logistic regression. Length of stay was related to utilization of procedures/services with truncated Poisson regression. RESULTS: There were 77,566 admissions in 42,325 patients. With both blood cultures and hscTnT requested, 30-day in-hospital mortality increased to 20.9% (95%CI: 19.7, 22.1) vs 8.9% (95%CI: 8.5, 9.4) for blood cultures alone and 2.3% (95%CI: 2.2, 2.4) with neither. Blood culture 3.93 (95%CI: 3.50, 4.42) or hsTnT requests 4.58 (95%CI: 4.10, 5.14) were prognostic. CONCLUSION: Blood culture and hscTnT requests and results predict worse outcomes.

Analysis of Circulating Tumour Cells in Early-Stage Uveal Melanoma: Evaluation of Tumour Marker Expression to Increase Capture.

(1) Background: The stratification of uveal melanoma (UM) patients into prognostic groups is critical for patient management and for directing patients towards clinical trials. Current classification is based on clinicopathological and molecular features of the tumour. Analysis of circulating tumour cells (CTCs) has been proposed as a tool to avoid invasive biopsy of the primary tumour. However, the clinical utility of such liquid biopsy depends on the detection rate of CTCs. (2) Methods: The expression of melanoma, melanocyte, and stem cell markers was tested in a primary tissue microarray (TMA) and UM cell lines. Markers found to be highly expressed in primary UM were used to either immunomagnetically isolate or immunostain UM CTCs prior to treatment of the primary lesion. (3) Results: TMA and cell lines had heterogeneous expression of common melanoma, melanocyte, and stem cell markers. A multi-marker panel of immunomagnetic beads enabled isolation of CTCs in 37/43 (86%) patients with UM. Detection of three or more CTCs using the multi-marker panel, but not MCSP alone, was a significant predictor of shorter progression free (p = 0.040) and overall (p = 0.022) survival. (4) Conclusions: The multi-marker immunomagnetic isolation protocol enabled the detection of CTCs in most primary UM patients. Overall, our results suggest that a multi-marker approach could be a powerful tool for CTC separation for non-invasive prognostication of UM.

Development of new therapeutic options for the treatment of uveal melanoma.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Important cytogenetic and genetic risk factors for the development of UM include chromosome 3 monosomy, mutations in the guanine nucleotide-binding proteins GNAQ/GNA11, and loss of the BRACA1-associated protein 1 (BAP 1). Most primary UMs are treated conservatively with radiotherapy, but enucleation is necessary for large tumours. Despite the effectiveness of local control, up to 50% of UM patients develop metastasis for which there are no effective therapies. Attempts to utilise the targeted therapies that have been developed for the treatment of other cancers, including a range of signal transduction pathway inhibitors, have rarely produced significant outcomes in UM. Similarly, the application of immunotherapies that are effective in cutaneous melanoma to treat UM have also been disappointing. Other approaches that have been initiated involve proteasomal inhibitors and histone deacetylase inhibitors which are approved for the treatment of other cancers. Nevertheless, there have been occasional positive outcomes from these treatments in UM. Moreover, combination approaches in UM have also yielded some positive developments. It would be valuable to identify how to apply such therapies efficiently in UM, potentially via individualised tumour profiling. It would also be important to characterise UM tumours to differentiate the potential drivers of progression from those in other types of cancers. The recent identification of novel kinases and metastatic genes in UM tumours makes the development of new UM-specific treatments feasible.

The role of melanocytes in the human choroidal microenvironment and inflammation: Insights from the transcriptome.

The choroid within the human eye contains a rich milieu of cells including melanocytes. Human choroidal melanocytes (HCMs) absorb light, regulate free radical production, and were recently shown to modulate inflammation. This study aimed to identify key genes and pathways involved in the inflammatory response of HCMs through the use of RNA-seq. Primary HCMs were cultured from donor choroids, RNA was extracted from control and lipopolysaccharide (LPS)-treated HCMs, and mRNA was sequenced. Functional annotation and pathway analysis were performed using gene ontology and gene set enrichment analyses. Representative RNA-seq results were verified with RT-qPCR and protein measurements. We detected 100 differentially expressed genes including an array of CCL and CXCL cytokines and mediators of cell-cell and cell-matrix adhesion, such as ICAM1, CLDN1, CCN3, ITGA1 and ITGA11. Functional annotation showed that these gene sets control inflammatory pathways, immune cell trafficking, cell-cell adhesion, interactions with the extracellular matrix and blood vessels, angiogenesis and epithelial-to-mesenchymal transitions. Our study provides insights into the transcriptional regulation of primary HCMs in response to inflammatory stimuli and identifies novel melanocyte-driven mechanisms potentially involved in choroidal homeostasis and inflammation.

Routine testing of close contacts of confirmed COVID-19 cases - National COVID-19 Contact Management Programme, Ireland, May to August 2020.

OBJECTIVES: The objective of this study was to inform public health practitioners who are designing, adapting and implementing testing and tracing strategies for Coronavirus disease (COVID-19) control. STUDY DESIGN: The study design is monitoring and evaluation of a national public health protection programme. METHODS: All close contacts of laboratory-confirmed cases of COVID-19 identified between the 19th May and 2nd August were included; secondary attack rates and numbers needed to test were estimated. RESULTS: Four thousand five hundred eighty six of 7272 (63%) close contacts of cases were tested with at least one test. The secondary attack rate in close contacts who were tested was 7% (95% Confidence Interval [CI]: 6.3 - 7.8%). At the 'day 0' test, 14.6% (95% CI: 11.6-17.6%) of symptomatic close contacts tested positive compared with 5.2% (95% CI: 4.4-5.9%) of asymptomatic close contacts. CONCLUSIONS: The application of additional symptom-based criteria for testing in this high-incidence population (close contacts) is of limited utility because of the low negative predictive value of absence of symptoms.

Limited Prognostic Utility of a Simplified Vital Sign Based Risk Calculator in Acute Medical Admissions.

BACKGROUND: Accurate efficient prognostication in acute medical admissions remains challenging. METHODS: We constructed a Vital Sign based Risk Calculator using vital parameters and Major Disease Categories to predict 30-day in-hospital mortality using a multivariable fractional polynomial model. RESULTS: We evaluated 113,807 admissions in 58,126 patients. The Vital Sign based Risk Calculator predicted 30-day inhospital mortality to increase from 2 points - 3.6% (95%CI 3.4, 3.7) to 12 points - 14.8% (95%CI 14.0, 15.7). AUROC was 0.74 (95%CI 0.72, 0.74). The addition of illness severity and comorbidity data improved AUROC to 0.90 (95%CI 0.89, 0.90). CONCLUSION: The Vital Sign based Risk Calculator is limited by its simplicity; inclusion of illness severity and comorbidity data improve prediction.

Prognostic Value Of Blood Cultures as an Illness Severity Marker In Emergency Medical Admissions.

BACKGROUND: Positive blood cultures predict mortality. The prognostic value of blood culture performance itself has not been fully defined. METHODS: We evaluated medical admissions from 2002-2017. We defined blood culture category as 1) no culture 2) negative culture 3) positive culture. We employed a multivariable logistic regression model to evaluate outcomes. RESULTS: We evaluated 78,568 blood cultures in 106,586 admissions. 30-day in-hospital mortality for no culture was 2.8% (95%CI 2.7, 2.9), culture negative 8.9% (95%CI 8.5, 9.3) and culture positive 16.7% (95%CI 15.5, 17.9). There was significant interaction between blood culture category and illness severity, OR 1.06 (95%CI 1.05, 1.08), and comorbidity, OR 1.09 (95%CI 1.09, 1.10). CONCLUSION: Performance and results of blood cultures are independently associated with increased mortality.