Objective Radiotherapy modalities such as iodine-125 (I125) and ruthenium-106 (Ru106) brachytherapy and proton beam radiotherapy (PBR) are well established for the treatment of choroidal melanoma. This study aimed to evaluate the rates of local tumour control, globe retention and visual acuity (VA) outcomes in patients with choroidal melanoma treated with I125 or Ru106 brachytherapy or PBR.Methods and analysis A review was conducted of all cases of choroidal melanoma treated with Ru106 or I125 brachytherapy or PBR over a 10-year period. Patient demographics, comorbidities, tumour characteristics, treatment parameters and VA outcomes were analysed. A predictive nomogram was developed to estimate final VA based on baseline clinical, tumour and radiation parameters.Results A total of 310 eyes from 310 patients were included, comprising 175 patients (56.5%) treated with Ru106, 72 (23.2%) treated with I125 brachytherapy and 63 (20.3%) treated with PBR. Local tumour control was achieved in 95.8% of cases. The recurrence rates were 4.0%, 4.2% and 4.8% for Ru106, I125 and PBR, respectively. Retention rates were 96.0% for Ru106, 94.4% for I125 and 95.2% for PBR. LogMAR VA of 1.0 or better was maintained in 50.9% of Ru106patients, 27.8% of I125patients and 39.7% of those treated with PBR. Baseline LogMAR VA, tumour volume, radiation dose to the fovea, radiotherapy modality and follow-up duration were significant predictors of final VA and were incorporated into the nomogram.Conclusions Each radiotherapy modality demonstrated high rates of local tumour control and globe retention. The predictive nomogram may serve as a practical tool to support individualised visual prognostication and patient counselling in the management of choroidal melanoma.

Background: This study evaluated a patellar tendon shortening (PTS) surgical procedure that uses an overlapping repair combined with an additional Tycron non-absorbable suture to support the shortening in children with Cerebral Palsy (CP). This study aimed to outline this surgical technique and to evaluate its effectiveness in restoring the knee extensor mechanism. Methods: The sagittal plane lower limb kinematics, peak knee extensor moment, gait deviation index (GDI), localised movement deviation profile (MDP), temporospatial parameters, passive knee extension ROM, quadriceps lag, and knee extensor strength were calculated pre- and postoperatively. To determine significant differences a robust linear regression model with high breakdown point and high efficiency was fitted to the data. Results: In this retrospective cohort study, a total of 41 patients with CP who were treated with unilateral or bilateral PTS in isolation or as part of single event multilevel surgery (SEMLS), with a mean age of 11.1 years were included. The knee extension angle improved at initial contact (p < 0.0001), and during stance phase (p < 0.0001). The peak internal knee extensor moment decreased during early (p = 0.0014) and late stance phase (p < 0.0001). The quadriceps lag decreased (p < 0.0001) and knee extensor strength increased (p < 0.0001). The GDI improved (p < 0.0001), as well as the localised MDP for sagittal angles (p <0.0001) and moments (p = 0.0001). Walking speed (p = 1.0) remained unchanged, but the cadence decreased (p = 0.024) and step length increased (p = 0.0001). Conclusions: The knee extension angle and moment during stance phase improved significantly. The children with CP in this study showed improvements in knee extensor strength and quadriceps lag. Thereby it can be concluded that the PTS procedure was able to restore the knee extensor mechanism effectively.

Purpose:To predict monosomy 3 (M3) in uveal melanoma with clinical and histopathological features, including nuclear BRCA1-associated protein 1 immunohistochemistry (nBAP1-IHC), and to evaluate its prognostication performance in the Liverpool Uveal Melanoma Prognosticator Online (LUMPO3) algorithm. Methods:Patients with uveal melanoma excluding iris melanoma were included. Clinical, genetic, and histopathological features, including nBAP1-IHC, were obtained and used to construct an M3 prediction model. Two simplified models mimicking the scenario where only histology or cytology specimens are available were obtained by simplification of the full model; the M3 status predicted by these models was introduced into LUMPO3 to evaluate the performance against the standard LUMPO3 with genetic testing-based M3 status. Results:Data from 2521 patients were used to construct the M3-prediction model. nBAP1-IHC was the most significant predictor (χ2 = 128, P < 0.0001). The simplified M3-prediction models maintained the area under the receiver operating curve at 88%, with Youden sensitivity at 79% and specificity at 82%. Predicted-M3-based LUMPO3 showed that 83% (cytology-based) and 87% (histology-based) of the prognostications fell within ±10% on the metastatic mortality scale of the genetic-based LUMPO3. The designations of metastatic surveillance group, using 3%, 5%, or 10% metastatic mortality prognostication as thresholds, were identical in 96.9%, 95.8%, and 92.5%, respectively (cytology-based), and 97.1%, 95.9%, and 93.8%, respectively (histology-based), using either the genetic-M3-based LUMPO3 or the predicted-M3-based LUMPO3. Conclusions:M3 can be accurately predicted using clinical and histopathological features, of which nBAP1-IHC is the most significant predictor. The predicted-M3-based LUMPO3 and the genetic-M3-based LUMPO3 are highly consistent in terms of survival prognostication and surveillance planning.

Background and aim Alkaptonuria (AKU) is a rare metabolic disorder characterised by the accumulation of homogentisic acid (HGA). Deposition of HGA in the aortic valve leading to progressive aortic stenosis is a serious complication. Nitisinone has been shown to improve morbidity and slow disease progression in AKU, but the effects of this treatment on aortic stenosis progression have not yet been described. The objective of this study was to evaluate whether treatment with nitisinone attenuated the progression of aortic stenosis, as assessed by peak trans-aortic valve pressure (Pmax), in patients with AKU. This post-hoc analysis used longitudinal echocardiographic data from the Suitability of Nitisinone in Alkaptonuria (SONIA) 2, a four-year multicenter randomised controlled trial, to examine aortic stenosis disease progression. Methods Data were obtained from echocardiograms performed on 138 patients over 48 months of follow-up. A linear mixed-effects regression model was used to ascertain the difference in the maximal trans-aortic valve pressure gradient (Pmax) at baseline and 48 months between the treatment and control groups, adjusting for baseline Pmax and other covariates. Results At baseline, 18/138 patients (13.0%) had aortic stenosis of varying degrees of severity, and 25/138 (18.1%) had aortic sclerosis. The difference in Pmax between the control (N=69) and treatment (N=69) groups at baseline was 0.063 mmHg [95% CI: -0.054 mmHg to 0.18 mmHg) and did not reach statistical significance (p=0.23). At the end of the four-year treatment period, the difference in Pmax was 0.10 mmHg (95% CI: -0.0007 mmHg to 0.20 mmHg) (p = 0.05), representing a modest but statistically significant between-group treatment effect. Conclusion Nitisinone may attenuate the progression of aortic stenosis in patients with AKU. Given the small absolute effect size and post-hoc nature of the analysis, these findings should be interpreted as exploratory and hypothesis-generating rather than clinically definitive. Additional research is needed to determine whether nitisinone produces clinically meaningful outcomes for aortic stenosis in this population.

BACKGROUND/OBJECTIVES:Neoadjuvant systemic therapy may enhance ocular and visual preservation, also prolonging life in patients with choroidal melanoma. We investigated how many choroidal melanomas would be eligible for such treatment to enable Ruthenium-106 brachytherapy. METHODS:The cohort comprised 5859 patients treated for choroidal melanoma at the Liverpool Ocular Oncology Centre between 1993 and 2023. RESULTS:If the objective is ocular conservation, then, after excluding tumors > 16 mm in diameter, involving disc and/or more than two clock hours of angle or iris, and/or extending extraocularly, approximately 60.5%, 65.1%, and 67.6% of patients would remain eligible for neoadjuvant systemic therapy, according to whether the maximum allowable tumor thickness is 8 mm, 10 mm or 12 mm, respectively. If the objective is preservation of 20/80 vision, and if exclusion criteria also include vision worse than 20/80 and tumor extension to within 3 mm of optic disc and/or fovea, then 31.0%, 33.2% and 34.1% of tumors would remain in the three tumor-thickness groups, respectively. Chromosome 3 loss would be found in approximately 33%, 52% and 56% of tumors measuring 11-12 mm, 13-14 mm and >14 mm, respectively. CONCLUSIONS:Based on the provided data and with effective neoadjuvant treatment, approximately two thirds of subjects with choroidal melanoma requiring enucleation could potentially become candidates for ruthenium-106 brachytherapy and as many as one third could also have the potential for preservation of useful vision.

PURPOSE:To investigate the prevalence of aggressive traits in small posterior uveal melanomas (UM). METHODS:This retrospective, multicentre cohort study included 804 patients with small posterior UM (≤9 mm in largest basal diameter, ≤3 mm in thickness) from centres in the UK, Germany, and Sweden. Chromosomal aberrations, cytomorphology, nuclear BAP1 expression and circulating tumour cells (CTC) were analysed. RESULTS:Markers of poor prognosis, including monosomy 3, 8q gain, loss of BAP1 expression, and the presence of CTC, were detected in tumours as small as 3-4 mm in diameter and 1-1.5 mm in thickness. In the cytogenetically analysed subset, monosomy 3 was observed in 23% (41/175), 8q gain in 32% (23/72) and 6q aberrations in 13% (9/71); loss of nuclear BAP1 was seen in 22% (19/88); and CTC were detected in 50% (22/44). There was a strong association between tumour size and the number of clinical risk factors for lesion growth, such as subretinal fluid, orange pigment and acoustic hollowness on ultrasound, whereas these clinical features did not correlate with markers for poor prognosis. Monosomy of chromosome 3, gain of 8q, loss of 1p, gain or loss of 6q, gain or loss of 8p, loss of BAP1 expression, and cytomorphology were associated with worse survival. CONCLUSION:Aggressive traits are common in small UM, including those <10 mm3 in volume. Clinical risk factors traditionally used for assessing nevus growth appear more closely related to lesion size than metastatic potential. These findings underscore the importance of identifying novel clinical markers for metastatic risk.

(1) Background: Globe-sparing radiotherapy is widely utilised in the treatment of uveal melanoma, but often results in complications requiring vitreoretinal intervention. The outcomes of secondary vitrectomy remain unclear. A multidisciplinary approach involving vitreoretinal and ocular oncology specialists is essential to managing complications. (2) Methods: We reviewed 1794 patients treated with radiotherapy for uveal melanoma between 2012 and 2022. In total, 70 patients underwent secondary vitrectomy after primary radiotherapy treatment. The outcomes included overall tumour control and visual outcome. (3) Results: Complications requiring vitrectomy were more common after proton-beam radiotherapy than plaque brachytherapy (5.4% versus 3.0%). Common indications included vitreous haemorrhage (39%) and retinal detachment/toxic tumour syndrome (31%). The affected tumours were larger, more often ciliary body in origin, and associated with a worse prognosis. Vitrectomy patients had higher rates of enucleation (9% versus 3%), metastasis (16% versus 6%), and visual decline (average 0.60 LogMAR), with limited visual improvement (≥3-line gain in 13%). Proton-beam patients had worse outcomes than plaque brachytherapy patients. (4) Conclusions: Vitreoretinal complications after uveal melanoma radiotherapy are rare, but timely treatment by those with experience may enable patients to keep their eye in situations where enucleation would be the only alternative. Patients and clinicians must understand the risks of complications to make informed decisions about treatment plans, with vitreoretinal surgeons and ocular oncologists key to outcomes.

PURPOSE:Peripapillary choroidal melanoma provides a unique challenge; proximity to visually important structures, such as the optic disc and fovea, confers a high risk for the development of maculopathy and optic neuropathy, leading to poorer visual outcomes with most forms of radiotherapy. Ocular proton therapy (OPT) requires an aperture to shape the beam to the tumour. An aperture 'notch' may minimise damage to the optic disc and/or the fovea. This study aims to explore if there are any additional advantages to incorporating a notch over the optic nerve beam area. DESIGN:Retrospective audit (cohort study). PARTICIPANTS:Participants included eighty-three patients treated at Liverpool with proton beam therapy from January 2012 to March 2020 for their peripapillary choroidal melanoma. All had a minimum of two and a half years of follow-up vision data; this was to ensure there was enough visual acuity assessment data to perform sufficient analysis. Patients excluded had choroidal melanoma situated over 3 mm from the optic disc, as these were unlikely to have an aperture notch. METHODS:A retrospective audit was undertaken in accordance with the Declaration of Helsinki, and registered with the Royal Liverpool Hospitals audit department (audit reference number: Ophth/SE/2024-25/25). Data was collated from the Liverpool Ocular Oncology database, clinic letters and the individual proton beam 3D plans. Robust statistical analysis using a mixed effects model was used to explore associations between notched beams and vision loss and complications. MAIN OUTCOME MEASURES:The primary outcome measure is visual acuity loss post-proton beam therapy. Secondary outcome measures were enucleation and other complication rates. RESULTS:Analysis shows that at 10 years post-OPT, there would be an expected 0.058 (p = 0.077) logMAR of vision saved using a notch for the optic disc compared to no notch (normal apertures); this is considered clinically significant. This cohort also loses vision at a slower rate than other cases. No other predictors were found to be statistically significant for loss of vision, and notched beams showed no advantage in reducing rates of complications. CONCLUSIONS:There is some evidence of a trend that utilising a notch for optic disc does show long-term vision benefit; it demonstrates a clinically significant benefit in patients with peripapillary choroidal melanoma.

PURPOSE:The objective of this investigation was to conduct a randomized controlled trial to evaluate whether KiActiv Heart alongside usual care (UC) promotes positive physical activity (PA) change versus UC alone. METHODS:Patients in cardiac rehabilitation (n = 130) undertook an 8-wk intervention with follow-up at wk 8. Both groups attended UC and wore a PA monitor during the intervention. The intervention group accessed the digital service and received weekly one-to-one remote mentor sessions. The primary outcome was change in PA to achieve the Association of Certified Physiotherapists in Cardiac Rehabilitation (ACPICR) recommendations. The secondary outcome was cardiorespiratory fitness (CRF) change, measured using incremental shuttle walk test (ISWT). RESULTS:The probability of meeting ACPICR "Daily Activity" recommendation was statistically significantly greater in the intervention group versus control at wk 8 ( P < .05). No statistically significant differences between groups were found for mean ISWT change (intervention 89 ± 116 m; control 44 ± 124 m). CONCLUSION:Participation in KiActiv Heart alongside UC was associated with statistically significant improvement in probability of meeting ACPICR recommendation and non-statistically significant but potentially clinically important increases in CRF versus UC alone. This builds on existing evidence for effectiveness.

Background: We estimated metastatic-death risk when the treatment of small choroidal melanomas is deferred until growth is observed. Methods: In 24 patients with choroidal melanoma (median diameter 5.85 mm), the exponential growth rate estimated by a mixed-effects model was 4.3% per year. Using the Liverpool Uveal Melanoma Prognosticator Online v.3 (LUMPO3), we measured changes in 15-year metastatic and non-metastatic death risks according to whether the tumor is treated immediately or after observing growth 4 or 12 months later, considering age, sex, and metastasis predictors. Results: In 40-year-old females with 10 mm, disomy 3 and monosomy 3 choroidal melanomas (prevalence 16%), the 15-year absolute risks of metastatic death are 4.2% and 76.6%, respectively, increasing after a 4-month delay by 0.0% and 0.2% and by 3.0% and 2.3% with tumor growth rates of 5.0% and 20.0%, respectively. With 12-month delays, these risks increase by 0.0% and 0.5% and by 1.0% and 7.1%, respectively. Increases in metastatic-death risk are less with smaller tumors and with a higher risk of non-metastatic death. Conclusions: Deferring treatment of choroidal melanomas until documentation of growth may delay iatrogenic visual loss by months or years and is associated with minimal increase in metastatic mortality, at least with small tumors with usual growth rates of up to 40% per year.

Abstract Background/introduction Alkaptonuria (AKU) is a rare metabolic disorder caused by a defective enzyme, resulting in deposition of unmetabolised homogentisic acid in various connective tissues throughout the body (also termed "ochronosis"). Ochronosis of the aortic valve leading to progressive aortic stenosis is a rare but serious complication. Nitisinone decreases urinary and serum homogentisic acid levels and has been shown to improve morbidity and slow disease progression in AKU but the effects of this treatment on the progression of aortic stenosis have not yet been described. This review extrapolated from the data set of the SONIA 2 study, a 4-year multi-centre, randomised controlled trial investigating the effect of nitisinone on a composite clinical measure of AKU disease activity, but looked more specifically at measures of aortic stenosis disease progression. Methods Data was obtained from echocardiograms performed on 138 patients at baseline, 12, 24, 36 and 48 months of follow-up. In measuring the degree of aortic stenosis, the peak trans-aortic velocity (Vmax) was examined. A linear mixed effects regression model was used to assess the association between treatment and Vmax and to ascertain the difference in this measure at baseline and 48 months between the treatment and control groups. The mixed effects model incorporated both fixed effects for population parameters (age, sex, baseline Vmax, follow-up time) and treatment; and random effects, to account for intra-subject correlation of longitudinal observations of Vmax, inter-subject variability of baseline measurements of Vmax, and centre. Results At baseline, 19/138 patients (13.8%) had aortic stenosis, as classified by echocardiogram findings in accordance with the European Society of Cardiology (ESC) guidance on valvular heart disease, with 9/19 having mild aortic stenosis, 6/19 having moderate aortic stenosis and 4/19 having severe aortic stenosis. 25/138 had aortic sclerosis (see figure 1). The prevalence of aortic valve disease increased with age. From the 4-year follow-up period, 613 longitudinal observations of 138 subjects across all sites were obtained. At baseline, the difference in Vmax between the control and treatment groups was 0.063 m/s [95% CI: -0.054 m/s to 0.18 m/s] and did not reach statistical significance (p=0.23). At the end of the 4-year treatment period, the difference in Vmax was 0.10 m/s [95% CI: -0.0007 m/s to 0.20 m/s] and was statistically significant (p=0.05) (see figure 2). Conclusion Nitisinone slowed progression of aortic stenosis in patients with AKU. This may be grounds for timely initiation of nitisinone in those deemed to be at high risk, as identified by echocardiography. Of note, this is the first time that any medical therapy has ever been shown to affect the natural history of aortic stenosis.

Uveal melanoma (UM) metastasises in ~50% of patients, most frequently to the liver. Surveillance imaging can provide early detection of hepatic metastases; however, guidance regarding UM patient risk stratification for surveillance is unclear. This study compared sensitivity and specificity of four current prognostic systems, when used for risk stratification for surveillance, on patients treated at the Liverpool Ocular Oncology Centre (LOOC) between 2007–2016 (n = 1047). It found that the Liverpool Uveal Melanoma Prognosticator Online III (LUMPOIII) or Liverpool Parsimonious Model (LPM) offered greater specificity at equal levels of sensitivity than the American Joint Committee on Cancer (AJCC) system or monosomy 3 alone, and suggests guidance to achieve 95% sensitivity and 51% specificity (i.e., how to detect the same number of patients with metastases, while reducing the number of negative scans). For example, 180 scans could be safely avoided over 5 years in 200 patients using the most specific approach. LUMPOIII also offered high sensitivity and improved specificity over the AJCC in the absence of genetic information, making the result relevant to centres that do not perform genetic testing, or where such testing is inappropriate or fails. This study provides valuable information for clinical guidelines for risk stratification for surveillance in UM.

Background Systematic annual screening for sight-threatening diabetic retinopathy is established in several countries but is resource intensive. Personalised (individualised) medicine offers the opportunity to extend screening intervals for people at low risk of progression and to target high-risk groups. However, significant concern exists among all stakeholders around the safety of changing programmes. Evidence to guide decisions is limited, with, to the best of our knowledge, no randomised controlled trials to date. Objectives To develop an individualised approach to screening for sight-threatening diabetic retinopathy and test its acceptability, safety, efficacy and cost-effectiveness. To estimate the changing incidence of patient-centred outcomes. Design A risk calculation engine; a randomised controlled trial, including a within-trial cost-effectiveness study; a qualitative acceptability study; and an observational epidemiological cohort study were developed. A patient and public group was involved in design and interpretation. Setting A screening programme in an English health district of around 450,000 people. Participants People with diabetes aged ≥ 12 years registered with primary care practices in Liverpool. Interventions The risk calculation engine estimated each participant’s risk at each visit of progression to screen-positive diabetic retinopathy (individualised intervention group) and allocated their next appointment at 6, 12 or 24 months (high, medium or low risk, respectively). Main outcome measures The randomised controlled trial primary outcome was attendance at first follow-up assessing the safety of individualised compared with usual screening. Secondary outcomes were overall attendance, rates of screen-positive and sight-threatening diabetic retinopathy, and measures of visual impairment. Cost-effectiveness outcomes were cost/quality-adjusted life year and incremental cost savings. Cohort study outcomes were rates of screen-positive diabetic retinopathy and sight-threatening diabetic retinopathy. Data sources Local screening programme (retinopathy), primary care (demographic, clinical) and hospital outcomes. Methods A seven-person patient and public involvement group was recruited. Data were linked into a purpose-built dynamic data warehouse. In the risk assessment, the risk calculation engine used patient-embedded covariate data, a continuous Markov model, 5-year historical local population data, and most recent individual demographic, retina and clinical data to predict risk of future progression to screen-positive. The randomised controlled trial was a masked, two-arm, parallel assignment, equivalence randomised controlled trial, with an independent trials unit and 1 : 1 allocation to individualised screening (6, 12 or 24 months, determined by risk calculation engine at each visit) or annual screening (control). Cost-effectiveness was assessed using a within-trial analysis over a 2-year time horizon, including NHS and societal perspectives and costs directly observed within the randomised controlled trial. Acceptability was assessed by purposive sampling of 60 people with diabetes and 21 healthcare professionals with semistructured interviews analysed thematically; this was a constant comparative method until saturation. The cohort was an 11-year retrospective/prospective screening population data set. Results In the randomised controlled trial, 4534 participants were randomised: 2097 out of 2265 in the individualised arm (92.6%) and 2224 out of 2269 in the control arm (98.0%) remained after withdrawals. Attendance rates at first follow-up were equivalent (individualised 83.6%, control 84.7%) (difference –1.0%, 95% confidence interval –3.2% to 1.2%). Sight-threatening diabetic retinopathy detection rates were non-inferior: individualised 1.4%, control 1.7% (difference –0.3%, 95% confidence interval –1.1% to 0.5%). In the cost-effectiveness analysis, the mean differences in complete-case quality-adjusted life years (EuroQol-5 Dimensions, five-level version, and Health Utilities Index Mark 3) did not significantly differ from zero. Incremental cost savings per person not including treatment costs were from the NHS perspective £17.34 (confidence interval £17.02 to £17.67) and the societal perspective £23.11 (confidence interval £22.73 to £23.53). In the individualised arm, 43.2% fewer screening appointments were required. In terms of acceptability, changing to variable intervals was acceptable for the majority of people with diabetes and health-care professionals. Annual screening was perceived as unsustainable and an inefficient use of resources. Many people with diabetes and healthcare professionals expressed concerns that 2-year screening intervals may detect referable eye disease too late and might have a negative effect on perceptions about the importance of attendance and diabetes care. The 6-month interval was perceived positively. Among people with dementia, there was considerable misunderstanding about eye-related appointments and care. In the cohort study, the numbers of participants (total 28,384) rose over the 11 years (2006/7, n = 6637; 2016/17, n = 14,864). Annual incidences ranged as follows: screen-positive 4.4–10.6%, due to diabetic retinopathy 2.3–4.6% and sight-threatening diabetic retinopathy 1.3–2.2%. The proportions of screen-positive fell steadily but sight-threatening diabetic retinopathy rates remained stable. Limitations Our findings apply to a single city-wide established English screening programme of mostly white people with diabetes. The cost-effectiveness analysis was over a short timeline for a long-standing disease; the study, however, was designed to test the safety and effectiveness of the screening regimen, not the cost-effectiveness of screening compared with no screening. Cohort data collection was partly retrospective: data were unavailable on people who had developed sight-threatening diabetic retinopathy or died prior to 2013. Conclusions Our randomised controlled trial can reassure stakeholders involved in diabetes care that extended intervals and personalised screening is feasible, where data linkage is possible, and can be safely introduced in established screening programmes with potential cost savings compared with annual screening. Rates of screen-positive diabetic retinopathy and sight-threatening diabetic retinopathy are low and show consistent falls over time. Involvement of patients in research is crucial to success. Future work Future work could include external validation with other programmes followed by scale-up of individualised screening outside a research setting and economic modelling beyond the 2-year time horizon. Trial registration This trial is registered as ISRCTN87561257. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research ; Vol. 11, No. 6. See the NIHR Journals Library website for further project information.

Purpose: To determine liver screening frequency and modality in UM patients following primary treatment, and the characteristics of detected metastases. Methods: A 10-year retrospective study of 615 UM patients undergoing liver surveillance in Liverpool. Information was collected from liver scan reports of these patients. Results: Of 615 UM patients analyzed, there were 337 men (55%) and 278 women (45%). Median age at primary treatment was 61 years (range, 22–94). At study end, median follow-up was 5.1 years, with 375 patients (61%) alive and 240 deceased (39%). Of the deceased patients, 187 (78%) died due to metastatic UM; 24 (10%) deaths were due to other causes; and 29 (12%) patients died of unknown conditions. In total, 3854 liver scans were performed in the 615 UM patients, with a median of 6.2 scans per patient (range, 1–40). Liver MRI was most frequently performed (62.8%). In total, 229 (37%) UM patients developed metastases during the study period: 150 were detected via liver surveillance and 79 were observed post-mortem. Conclusions: Metastatic UM onset is related to the size and genetic profiles of the primary UM, and can be predicted using the model LUMPO3. Regular liver surveillance allowed for timely detection of metastases, and through metastasectomy can lead to prolongation of life in some patients.

Summary: Background: Large lung nodules (≥15 mm) have the highest risk of malignancy, and may exhibit important differences in phenotypic or clinical characteristics to their smaller counterparts. Existing risk models do not stratify large nodules well. We aimed to develop and validate an integrated segmentation and classification pipeline, incorporating deep-learning and traditional radiomics, to classify large lung nodules according to cancer risk. Methods: 502 patients from five U.K. centres were recruited to the large-nodule arm of the retrospective LIBRA study between July 2020 and April 2022. 838 CT scans were used for model development, split into training and test sets (70% and 30% respectively). An nnUNet model was trained to automate lung nodule segmentation. A radiomics signature was developed to classify nodules according to malignancy risk. Performance of the radiomics model, termed the large-nodule radiomics predictive vector (LN-RPV), was compared to three radiologists and the Brock and Herder scores. Findings: 499 patients had technically evaluable scans (mean age 69 ± 11, 257 men, 242 women). In the test set of 252 scans, the nnUNet achieved a DICE score of 0.86, and the LN-RPV achieved an AUC of 0.83 (95% CI 0.77–0.88) for malignancy classification. Performance was higher than the median radiologist (AUC 0.75 [95% CI 0.70–0.81], DeLong p = 0.03). LN-RPV was robust to auto-segmentation (ICC 0.94). For baseline solid nodules in the test set (117 patients), LN-RPV had an AUC of 0.87 (95% CI 0.80–0.93) compared to 0.67 (95% CI 0.55–0.76, DeLong p = 0.002) for the Brock score and 0.83 (95% CI 0.75–0.90, DeLong p = 0.4) for the Herder score. In the international external test set (n = 151), LN-RPV maintained an AUC of 0.75 (95% CI 0.63–0.85). 18 out of 22 (82%) malignant nodules in the Herder 10–70% category in the test set were identified as high risk by the decision-support tool, and may have been referred for earlier intervention. Interpretation: The model accurately segments and classifies large lung nodules, and may improve upon existing clinical models. Funding: This project represents independent research funded by: 1) Royal Marsden Partners Cancer Alliance, 2) the Royal Marsden Cancer Charity, 3) the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, 4) the National Institute for Health Research (NIHR) Biomedical Research Centre at Imperial College London, 5) Cancer Research UK (C309/A31316).

Our aim was to determine whether size impacts on the difference in metastatic mortality of genetically high-risk (monosomy 3) uveal melanomas (UM). We undertook a retrospective analysis of data from a patient cohort with genetically characterized UM. All patients treated for UM in the Liverpool Ocular Oncology Centre between 2007 and 2014, who had a prognostic genetic tumor analysis. Patients were subdivided into those with small (≤2.5 mm thickness) and large (>2.5 mm thickness) tumors. Survival analyses were performed using Gray rank statistics to calculate absolute probabilities of dying as a result of metastatic UM. The 5-year absolute risk of metastatic mortality of those with small monosomy 3 UM was significantly lower (23%) compared to the larger tumor group (50%) (p = 0.003). Small disomy 3 UM also had a lower absolute risk of metastatic mortality (0.8%) than large disomy 3 UM (6.4%) (p = 0.007). Hazard rates showed similar differences even with lead time bias correction estimates. We therefore conclude that earlier treatment of all small UM, particularly monosomy 3 UM, reduces the risk of metastatic disease and death. Our results would support molecular studies of even small UM, rather than ‘watch-and-wait strategies’.

This paper outlines a method for cost-utility analysis of liver screening for metastases in patients with posterior uveal melanoma (UM). A semiparametric model of the cumulative incidence of onset of liver metastases was fitted to a retrospective data set of 615 subjects with clinical follow-up with respect to liver surveillance imaging and outcome. The model was internally validated via bootstrap resampling in terms of its discrimination and calibration performance. Receiver operating characteristics (ROC) were derived at different time points. The discrimination performances are consistent across time. The area under the ROC curve at 5 years post treatment was 0.85 [95% CI: 0.81–0.88]. A goodness-of-fit test gives χ2(10)=5.3,p=0.9 demonstrating no evidence against the null hypothesis of zero difference between observed and expected onset of metastatic events. Results showed that at 80% sensitivity, 87% of UM patients will avoid unnecessary radiological scans. This provides potential cost savings of between £46,000 and £97,000 per year to the National Health Service assuming 600 new cases per year.