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Abstract Millions of people require custom ocular prostheses due to eye loss or congenital defects. The current fully manual manufacturing processes used by highly skilled ocularists are time-consuming with varying quality. Additive manufacturing technology has the potential to simplify the manufacture of ocular prosthetics, but existing approaches just replace to various degrees craftsmanship by manual digital design and still require substantial expertise and time. Here we present an automatic digital end-to-end process for producing custom ocular prostheses that uses image data from an anterior segment optical coherence tomography device and considers both shape and appearance. Our approach uses a statistical shape model to predict, based on incomplete surface information of the eye socket, a best fitting prosthesis shape. We use a colour characterized image of the healthy fellow eye to determine and procedurally generate the prosthesis’s appearance that matches the fellow eye. The prosthesis is manufactured using a multi-material full-colour 3D printer and postprocessed to satisfy regulatory compliance. We demonstrate the effectiveness of our approach by presenting results for 10 clinic patients who received a 3D printed prosthesis. Compared to a current manual process, our approach requires five times less labour of the ocularist and produces reproducible output.

(1) Background: We reviewed a stem cell-derived therapeutic strategy for advanced neovascular age-related macular degeneration (nAMD) using a human embryonic stem cell-derived retinal pigment epithelium (hESC-RPE) monolayer delivered on a coated, synthetic basement membrane (BM)—the patch—and assessed the presence and distribution of hESC-RPE over 5 years following transplantation, as well as functional outcomes. (2) Methods: Two subjects with acute vision loss due to sub-macular haemorrhage in advanced nAMD received the hESC-RPE patch. Systematic immunosuppression was used peri-operatively followed by local depot immunosuppression. The subjects were monitored for five years with observation of RPE patch pigmentation, extension beyond the patch boundary into surrounding retina, thickness of hESC-RPE and synthetic BM and review for migration and proliferation of hESC-RPE. Visual function was also assessed. (3) Results: The two study participants showed clear RPE characteristics of the patch, preservation of some retinal ultrastructure with signs of remodelling, fibrosis and thinning on optical coherence tomography over the 5-year period. For both participants, there was evidence of pigment extension beyond the patch continuing until 12 months post-operatively, which stabilised and was preserved until 5 years post-operatively. Measurement of hESC-RPE and BM thickness over time for both cases were consistent with predefined histological measurements of these two layers. There was no evidence of distant RPE migration or proliferation in either case beyond the monolayer. Sustained visual acuity improvement was apparent for 2 years in both subjects, with one subject maintaining the improvement for 5 years. Both subjects demonstrated initial improvement in fixation and microperimetry compared to baseline, at year 1, although only one maintained this at 4 years post-intervention. (4) Conclusions: hESC-RPE patches show evidence of continued pigmentation, with extension, to cover bare host basement membrane for up to 5 years post-implantation. There is evidence that this represents functional RPE on the patch and at the patch border where host RPE is absent. The measurements for thickness of hESC-RPE and BM suggest persistence of both layers at 5 years. No safety concerns were raised for the hypothetical risk of RPE migration, proliferation or tumour formation. Visual function also showed sustained improvement for 2 years in one subject and 5 years in the other subject.

Introduction: Proline/arginine-rich end leucine-rich repeat protein (PRELP), is a small secreted proteoglycan expressed by pericytes and vascular smooth muscle cells surrounding the brain vasculature of adult mouse.Methods: We utilised a Prelp knockout (Prelp−/−) mouse model to interrogate vasculature integrity in the brain alongside performing in vitro assays to characterise PRELP application to endothelial cells lines. Our findings were supplemented with RNA expression profiling to elucidate the mechanism of how PRELP maintains neurovasculature function.Results:Prelp−/− mice presented with neuroinflammation and reducedneurovasculature integrity, resulting in IgG and dextran leakage in the cerebellum and cortex. Histological analysis of Prelp−/− mice revealed reducedcell-cell integrity of the blood brain barrier, capillary attachment of pericytes andastrocyte end-feet. RNA-sequencing analysis found that cell-cell adhesion andinflammation are affected in Prelp−/− mice and gene ontology analysis as well as gene set enrichment analysis demonstrated that inflammation related processes and adhesion related processes such as epithelial-mesenchymal transition and apical junctions were significantly affected, suggesting PRELP is a regulator of cell-cell adhesion. Immunofluorescence analysis showed that adhesion junction protein expression levels of cadherin, claudin-5, and ZO-1, was suppressed in Prelp−/− mice neurovasculature. Additionally, in vitro studies revealed that PRELP application to endothelial cells enhances cell-cell integrity, induces mesenchymal-endothelial transition and inhibits TGF-β mediated damage to cell-cell adhesion.Discussion: Our study indicates that PRELP is a novel endogenous secreted regulator of neurovasculature integrity and that PRELP application may be a potential treatment for diseases associated with neurovascular damage.

Retinoblastoma (RB) is the most common intraocular pediatric cancer. Nearly all cases of RB are associated with mutations compromising the function of the RB1 tumor suppressor gene. We previously demonstrated that PRELP is widely downregulated in various cancers and our in vivo and in vitro analysis revealed PRELP as a novel tumor suppressor and regulator of EMT. In addition, PRELP is located at chromosome 1q31.1, around a region hypothesized to be associated with the initiation of malignancy in RB. Therefore, in this study, we investigated the role of PRELP in RB through in vitro analysis and next-generation sequencing. Immunostaining revealed that PRELP is expressed in Müller glial cells in the retina. mRNA expression profiling of PRELP−/− mouse retina and PRELP-treated RB cells found that PRELP contributes to RB progression via regulation of the cancer microenvironment, in which loss of PRELP reduces cell–cell adhesion and facilitates EMT. Our observations suggest that PRELP may have potential as a new strategy for RB treatment.

Uveal melanoma (UM) is an uncommon but highly aggressive ocular malignancy. Poor overall survival is associated with deleterious BAP1 alterations, which frequently occur with monosomy 3 (LOH3) and a characteristic gene expression profile. Tumor DNA from a cohort of 100 UM patients from Moorfields Biobank (UK) that had undergone enucleation were sequenced for known UM driver genes (BAP1, SF3B1, EIF1AX, GNAQ, and GNA11). Immunohistochemical staining of BAP1 and interphase FISH for chromosomes 3 and 8 was performed, and cellular localization of BAP1 was correlated with BAP1 mutations. Wildtype (WT) BAP1 staining was characterized by nBAP1 expression with GNA11 and 48% harbored mutations in GNAQ at residues 209 or 183. Of the secondary drivers, 39% of mutations were in BAP1, 11% were in EIF1AX, and 20% were in the SF3B1 R625 hotspot. Most tumors with SF3B1 or EIF1AX mutations retained nuclear BAP1 (nBAP1). The majority of tumor samples with likely pathogenic BAP1 mutations, regardless of mutation class, displayed ≥25% loss of nBAP1. This included all tumors with truncating mutations and 80% of tumors with missense mutations. In addition, 60% of tumors with truncating mutations and 82% of tumors with missense mutations expressed >10% cBAP1.

Purpose: Intra-arterial chemotherapy (IAC), delivered directly to the globe via the internal carotid artery is now an established treatment for retinoblastoma. We report a case of anterior segment ischaemia following treatment with multiple intra-arterial chemotherapy (IAC) infusions. Observations: A 5 month old female presented with bilateral retinoblastoma and was treated with 12 infusions of IAC. Her right eye was enucleated at diagnosis. After her seventh IAC treatment, she developed ipsilateral sixth and third cranial nerve palsies. After the twelfth IAC, she developed an area of conjunctival and scleral ischaemia between 12 and 3 o'clock meridians in her left eye. However, she maintained visual acuity of LogMAR 0.34. Conclusions and Importance: The median number of IAC treatments in large studies is three. It is possible that repeated doses of IAC have an accumulative negative effect on the ocular blood supply, risking anterior segment and neurologic sequelae. This case highlights the significant challenge of balancing the salvage of eyes and vision with the potentially significant morbidity associated with IAC.

Prompt detection and treatment of local treatment failure after radiotherapy for choroidal melanoma optimises any opportunities for conserving vision and the eye, possibly reducing an increased risk of metastatic disease. Long-term surveillance is therefore required but is hampered by the perceived need to perform ultrasonography, which may not be available at a patient’s local hospital. The aim of this study was to determine whether local treatment failure can reliably be detected with colour fundus photography alone, and, if so, in which patients. Patients were included in the study if diagnosed with local treatment failure between April 2016 and February 2021 after eye-conserving therapy for choroidal melanoma. Wide-field colour and fundal autofluorescence (FAF) images, optical coherence tomography (OCT), and ultrasonography (US) were analysed by two of the authors (GN and UH). The cohort included 87 patients with local treatment failure. In 75 patients with clear media, tumour progression was detected by colour photography alone in 74 (98.7%) patients. Sensitivity was not increased by the addition of either OCT or AF. One patient with clear media developed extraocular extension detected with US without visible change in the intraocular part of the tumour. In the other 12 patients, US was required because of opaque media and a consequently poor fundal view. Local treatment failure after radiotherapy for choroidal melanoma is detected in 98.7% of cases with colour photography when the media are clear. Ultrasonography is useful when photography is prevented by opaque media or tumours having locations in the far periphery.

The protective effects of breastfeeding on various childhood malignancies have been established but an association has not yet been determined for retinoblastoma (RB). We aimed to further investigate the role of breastfeeding in the severity of nonhereditary RB development, assessing relationship to (1) age at diagnosis, (2) ocular prognosis, measured by International Intraocular RB Classification (IIRC) or Intraocular Classification of RB (ICRB) group and success of eye salvage, and (3) extraocular involvement. Analyses were performed on a global dataset subgroup of 344 RB patients whose legal guardian(s) consented to answer a neonatal questionnaire. Patients with undetermined or mixed feeding history, family history of RB, or sporadic bilateral RB were excluded. There was no statistically significant difference between breastfed and formula-fed groups in (1) age at diagnosis (p = 0.20), (2) ocular prognosis measures of IIRC/ICRB group (p = 0.62) and success of eye salvage (p = 0.16), or (3) extraocular involvement shown by International Retinoblastoma Staging System (IRSS) at presentation (p = 0.74), lymph node involvement (p = 0.20), and distant metastases (p = 0.37). This study suggests that breastfeeding neither impacts the sporadic development nor is associated with a decrease in the severity of nonhereditary RB as measured by age at diagnosis, stage of disease, ocular prognosis, and extraocular spread. A further exploration into the impact of diet on children who develop RB is warranted.

Abstract Background In Africa, accessing eye health services is a major challenge. Ocular surface squamous neoplasia (OSSN) is a substantial ocular health problem in Africa related to solar UV light exposure and HIV infection among other risk factors. The disease causes visual loss and even death in advanced cases. This study was conducted to assess referral pathway and treatment delay for patients with OSSN in Kenya. Methods Adults with conjunctival lesions presenting to four eye centres were asked about their occupations, when they noticed the growth, health facilities visited in seeking care, cost of consultation, surgery, medicines and histopathology and dates at each step. The time-to-presentation was divided into quartiles and correlates analysed using ordinal logistic regression. Results We evaluated 158 first-time presenters with OSSN. Most were women (102 [65%]), living with HIV (78/110 tested [71%]), with low to medium income (127 [80%]). Most of the HIV patients (49/78 [63%]) were in antiretroviral care programs. About half (88/158, [56%]) presented directly to the study centres while the rest were referred. Indirect presenters sought care earlier than direct presenters (median 2.0 months vs 5.5 months) and travelled a shorter distance to the first health facility (median 20 km vs 30 km) but had surgery later (median 12.5 months vs 5.5 months). Visits beyond the first health facility for indirect presenters markedly increased delay (median 7.3, 29.0, 37.9, and 32.0 months for 1–4 facilities, respectively). Delay was associated with number of health facilities visited (adjusted ordered OR = 9.12; 95%CI 2.83–29.4, p

Melanoma of the eye is rare, but can mimic a range of disorders. This report highlights 2 cases of choroidal melanoma with vision loss mimicking neurological diagnoses. The first patient is a 41-year-old white male with a known history of multiple sclerosis and a previous episode of optic neuritis in the right eye, who presented with a 6-month history of decreased vision in the same eye, and occasional photopsiae. He was treated with 2 courses of oral steroids for presumed recurrent optic neuritis. After a temporary improvement in his symptoms, his vision worsened, following which he had a head MRI, which revealed a solid intraocular mass. He was subsequently diagnosed with a choroidal melanoma for which he was treated successfully with ruthenium-106 plaque brachytherapy. The second patient is a 57-year-old female, who presented with a progressive cerebellar syndrome under investigation by the neurology service, as well as decreased vision in the right eye. Her visual acuity gradually deteriorated and her neurological assessment, which included a PET-CT, revealed uptake in the right eye. The diagnosis of a choroidal melanoma was made, and following conservative treatment with proton beam radiotherapy, she had an enucleation of the eye. Intraocular tumours can masquerade as many different entities. Unexplained unilateral visual loss, especially if it is atypical for a neurological syndrome, should prompt dilated fundoscopy and referral to an ophthalmologist.

Background: The relationship between lag time and outcomes in retinoblastoma (RB) is unclear. In this study, we aimed to study the effect of lag time between onset of symptoms and diagnosis of retinoblastoma (RB) in countries based on their national-income and analyse its effect on the outcomes. Methods: We performed a prospective study of 692 patients from 11 RB centres in 10 countries from 1 January 2019 to 31 December 2019. Results: The following factors were significantly different among different countries based on national-income level: age at diagnosis of RB (p = 0.001), distance from home to nearest primary healthcare centre (p = 0.03) and mean lag time between detection of first symptom to visit to RB treatment centre (p = 0.0007). After adjusting for country income, increased lag time between onset of symptoms and diagnosis of RB was associated with higher chances of an advanced tumour at presentation (p < 0.001), higher chances of high-risk histopathology features (p = 0.003), regional lymph node metastasis (p < 0.001), systemic metastasis (p < 0.001) and death (p < 0.001). Conclusions: There is a significant difference in the lag time between onset of signs and symptoms and referral to an RB treatment centre among countries based on national income resulting in significant differences in the presenting features and clinical outcomes.

We thank Capasso et al [...]

The development of retinoblastoma is thought to require pathological genetic changes in both alleles of the RB1 gene. However, cases exist where RB1 mutations are undetectable, suggesting alternative pathways to malignancy. We used whole-genome sequencing (WGS) and transcriptomics to investigate the landscape of sporadic retinoblastomas derived from twenty patients, sought RB1 and other driver mutations and investigated mutational signatures. At least one RB1 mutation was identified in all retinoblastomas, including new mutations in addition to those previously identified by clinical screening. Ten tumours carried structural rearrangements involving RB1 ranging from relatively simple to extremely complex rearrangement patterns, including a chromothripsis-like pattern in one tumour. Bilateral tumours obtained from one patient harboured conserved germline but divergent somatic RB1 mutations, indicating independent evolution. Mutational signature analysis showed predominance of signatures associated with cell division, an absence of ultraviolet-related DNA damage and a profound platinum-related mutational signature in a chemotherapy-exposed tumour. Most RB1 mutations are identifiable by clinical screening. However, the increased resolution and ability to detect otherwise elusive rearrangements by WGS have important repercussions on clinical management and advice on recurrence risks.

Osteomodulin (OMD) and proline/arginine-rich end leucine repeat protein (PRELP) are secreted extracellular matrix proteins belonging to the small leucine-rich proteoglycans family. We found that OMD and PRELP were specifically expressed in umbrella cells in bladder epithelia, and their expression levels were dramatically downregulated in all bladder cancers from very early stages and various epithelial cancers. Our in vitro studies including gene expression profiling using bladder cancer cell lines revealed that OMD or PRELP application suppressed the cancer progression by inhibiting TGF-β and EGF pathways, which reversed epithelial–mesenchymal transition (EMT), activated cell–cell adhesion, and inhibited various oncogenic pathways. Furthermore, the overexpression of OMD in bladder cancer cells strongly inhibited the anchorage-independent growth and tumorigenicity in mouse xenograft studies. On the other hand, we found that in the bladder epithelia, the knockout mice of OMD and/or PRELP gene caused partial EMT and a loss of tight junctions of the umbrella cells and resulted in formation of a bladder carcinoma in situ-like structure by spontaneous breakdowns of the umbrella cell layer. Furthermore, the ontological analysis of the expression profiling of an OMD knockout mouse bladder demonstrated very high similarity with those obtained from human bladder cancers. Our data indicate that OMD and PRELP are endogenous inhibitors of cancer initiation and progression by controlling EMT. OMD and/or PRELP may have potential for the treatment of bladder cancer.

Purpose: To determine if ultrasonography is necessary to detect progression of choroidal melanocytic tumors undergoing sequential multi-modal imaging with color photography, autofluorescence (AF) and optical coherence tomography (OCT). Methods: All patients with choroidal melanoma undergoing treatment at Moorfields Eye Hospital between January 2016 and March 2020 were reviewed to identify those with treatment deferred by ≥2 months. Tumors that showed progression prior to treatment, defined as an increase in (a) basal dimensions (b) thickness (c) orange pigment and/or (d) sub-retinal fluid, were included. Mushroom shape, Orange pigment, Large size, Enlargement and Sub-retinal fluid (MOLES) scores were assigned to all tumors at earliest date and date of treatment. Results: A total of 99 patients with a mean age of 66 years (range: 26–90) were included. The initial MOLES score was 1 in 2 cases, 2 in 23 cases, and ≥3 in 74 cases. Progression was detected with sequential color photography alone in 100% of MOLES 1/2 and 97% of lesions with a MOLES score of ≥3. When findings on AF and OCT were included, sensitivity for detecting subtle change without ultrasonography improved to 100% for MOLES 3 and 97% for MOLES 4/5. Only one patient included in this study had an isolated increase in thickness that may have been missed had sequential ultrasonography not been performed. Overall, the sensitivity for detecting progression with color photographs alone was 97% (95% CI 93–100%) and increased to 99% (95% CI 97–100%) by including autofluorescence and OCT. Conclusions: Monitoring of choroidal nevi, particularly those classified as MOLES 1 or 2 (i.e., low-risk or high-risk naevi), can be accomplished safely without the need for ultrasonography. The findings of this study may remove barriers to the implementation of tele-oncology clinics for the monitoring of choroidal melanocytic tumors.

Purpose: To evaluate the MOLES system for identifying malignancy in melanocytic choroidal tumors in patients treated for choroidal melanoma. Methods: Records of 615 patients treated for choroidal melanoma between January 2017 and December 2019 were reviewed. Patients were excluded if iris and/or ciliary body involvement (106 patients), inadequate fundus photography (26 patients), no images available for review (21 patients) and/or treatment was not primary (11 patients). Demographic data and AJCC TNM Stage were collected. Color fundus and autofluorescence photographs (FAF), optical coherence tomography (OCT) and B-scan ultrasounds were prospectively reviewed. MOLES scores were assigned according to five criteria: mushroom shape, orange pigment, large size, enlarging tumor and subretinal fluid. Results: A total of 451 patients (mean age, 63.9 ± 13.9 years) were included. At treatment, mean largest basal tumor diameter (LBD) and thickness were 10.3 ± 2.8 mm (range, 3.0–23.0) and 4.3 mm (range, 1.0–17.0). All but one (0.2%) had MOLES scores of ≥3. Eighty-two patients were treated after surveillance lasting a mean of 1.5 years. Initially, most (63/82; 76.8%) had a MOLES score ≥ 3. Importantly, none of the 451 tumors had a score of

Background The relationship between the ethnic background or socioeconomic status (SES) and late retinoblastoma (Rb) presentation in the UK is unclear. We aimed to investigate if such correlations exist in a cohort of non-familial Rb cases.Methods A cross-sectional study based at the two centres providing Rb care in the UK. Included were non-familial Rb cases that presented from January 2006 to December 2011. Epidemiological and clinical data were retrieved from medical charts, as well as patients’ postcodes used to obtain the Index of Multiple Deprivation (IMD) score. A postal questionnaire was sent to participants’ parents to collect further, person-level, information on languages spoken and household socioeconomic position. Statistical correlations to advanced Rb at presentation as well as to treatment by enucleation and need for adjuvant chemotherapy were investigated.Results The cohort included 189 cases, 98 (51.8%) of which were males. The median age at diagnosis was 16 months (IQR 8–34 months). Of the study patients, 153 (81%) presented with advanced Rb; 78 (41%) with group D and 75 (40%) with group E Rb. A total of 134 (72%) patients were treated with enucleation. South Asian ethnicity and being in the most deprived IMD quintile were associated with a higher likelihood of presentation with advanced disease, but these estimates did not reach statistical significance. Older age at presentation was associated with enucleation and bilateral disease with adjuvant chemotherapy.Conclusions In this national UK study of patients with non-familial Rb, there was no evidence of an association of ethnicity or SES and the risk of presenting with advanced disease. These findings may reflect equality in access of healthcare in the UK.

Background Large genomic databases enable genetic evaluation in terms of haploinsufficiency and prevalence of missense and synonymous variants. We explored these parameters in ocular tumour-associated genes.Methods A curated list of ocular tumour-associated genes was assessed using the genomic databases Genome Aggregation Database (gnomAD) and DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) and compared with breast and lung cancer-associated gene lists. Haploinsufficiency was determined based on specific criteria: probability of loss of function index ≥0.9 in gnomAD, upper CI O/E limit

Classifying and staging retinoblastoma is an essential first step when planning how to manage a child with the condition; it also gives important information about prognosis.

We report the clinical findings and imaging in an 11-month-old male referred to the pediatric ocular oncology service for leukocoria. The diagnosis of concomitant myelinated nerve fibers and retinoblastoma group O/C was established. In this case, the association of these two conditions led to early diagnosis of retinoblastoma with successful treatment and good visual outcome.

Even when a diagnosis of germline retinoblastoma cannot be confirmed by genetic testing, the risk to family can still be estimated and used to plan follow-up eye examinations.

Squamous cell carcinoma of the conjunctiva is the end-stage of a spectrum of disease referred to as ocular surface squamous neoplasia (OSSN). OSSN is a malignant disease of the eyes that can lead to loss of vision and, in severe cases, death. The main risk factors for both are exposure to solar ultraviolet radiation outdoors, HIV/AIDS, human papilloma virus and allergic conjunctivitis. The limbal epithelial cells appear to be the progenitors of this disease.

Retinoblastoma is usually initiated by a random mutation of a gene in a retinal cell. It is important to try and recognise if the child has germline retinoblastoma, as this may affect both eyes of the child. Siblings and future children of the child with retinoblastoma are at greater risk of developing this cancer.