Objective To explore how parents of children with de novo retinoblastoma (RB) experience the diagnostic process and acute treatment phase, and to identify factors that may support parental coping and adaptation.Design A qualitative interview study using reflexive thematic analysis.Setting National Retinoblastoma Unit at Aarhus University Hospital, Denmark.Participants Thirty-one parents (21 mothers, 10 fathers) of 21 children diagnosed with de novo RB were recruited via hospital follow-up clinics and a support group day.Results For most parents, the diagnostic process was short. In cases of diagnostic delay, parents described frustration and guilt due to missed symptoms. Receiving the RB diagnosis was described as a surreal experience, accompanied by feelings of shock, grief and loss of control. Parents faced challenges in adapting to rapid medical decisions and the unfamiliar demands of hospital protocols. However, meeting the clinical experts was a relief, as parents felt they were in capable hands, experiencing empathetic communication and a clearly framed treatment plan. Parents emphasised the importance of support systems, including family, healthcare professionals and the child’s resilience, as crucial for coping with and managing the diagnosis.Conclusions Parents faced a sudden and disruptive transition from symptom recognition to life-altering diagnosis and treatment. While professional care and communication were experienced as supportive, they did not eliminate the emotional impact. Clinical pathways should prioritise early validation of parental concerns and provide transparent communication, both prior to referral and throughout treatment. Future research should examine longer-term parental adjustment and identify interventions that support emotional resilience beyond the acute phase.

Childhood cancer outcomes in low- and middle-income countries are impacted by the presentation of advanced disease and limited diagnostic and treatment resources. Papua New Guinea is highly populated with significant health coverage and workforce difficulties, in addition to unique geographical and political challenges affecting childhood cancer care. With improvements in communicable disease management, childhood cancer care has become an emerging need, managed by a dedicated service in Port Moresby General Hospital (PMGH). A longstanding partnership between PMGH and the International Society of Paediatric Oncology Oceania has facilitated the development of a cancer registry, education/training, research, and technical support. We describe an in-country visit comprising a tailored childhood cancer workshop for health care workers, with advocacy and collaboration efforts. Goals included education, childhood cancer registry implementation, clinical support, stakeholder engagement and supply of practical resources. Outcomes include enhanced nursing capacity with the establishment of a national oncology nurses association for peer support and ongoing educational opportunities. Key learnings include identifying palliative care as an unmet need, unique cultural aspects allowing for future targeted education, further collaboration on adapted treatment regimens, and formalised multidisciplinary meetings for enhanced practice. This partnership demonstrates the positive effect of strong local champions partnering with supportive peer relationships in global oncology.

To evaluate the clinical presentation, pathological features and outcomes of retinoblastoma based on the race of origin in a global cohort of patients. Retrospective collaborative study of 1426 patients who underwent primary enucleation for retinoblastoma. Patients were grouped into Caucasians ( n  = 231, 16%), Asians ( n  = 841, 59%), Hispanics ( n  = 226, 16%), Arabs ( n  = 96, 7%) and Others (Africans, African Americans, Indigenous Australians; n  = 32, 2%) cohorts. On histopathology, massive choroidal invasion was higher in Asians (30%) and Hispanics (26%) than Caucasians (15%, p  < 0.001). Post-laminar optic nerve invasion was higher in Asians (28%), Hispanics (20%) and Others (9%) than Caucasians (11%, p  < 0.001). At a mean follow-up of 41 months (median, 35 months; range, < 1–149 months), tumour recurrence and metastasis-related death was higher in Hispanics (9% and 12%, respectively), Asians (4% and 13%, respectively) and Others (6% and 6%, respectively). Multivariate Cox proportional hazards analysis of outcomes based on race with 8th edition AJCC pT stage and adjuvant therapy as covariates revealed 6.8 times greater risk for orbital tumour recurrence in Hispanics compared to Caucasians ( p  = 0.010) and 3.2 times risk hazards for metastasis-related death in Hispanics and Asians compared to Caucasians ( p  = 0.028 and p  = 0.038, respectively). The histopathological features in primarily enucleated eyes with retinoblastoma vary with race. Despite adjusting for tumour staging and adjuvant treatment, race remains an independent predictor of outcomes, including orbital tumour recurrence and metastasis-related death. A stringent follow-up and a more aggressive treatment approach is recommended in Asians and Hispanics who manifest high-risk histopathological features.

OBJECTIVE:Diabetic retinopathy (DR) in pregnancy can cause blindness. National guidelines recommend at least one eye examination in early pregnancy, then ideally 3-monthly, through to the postpartum for pregnant women with pregestational diabetes. Here we examined adherence rates, barriers and enablers to recommended DR screening guidelines. DESIGN:Cross-sectional survey study, as part of a larger prospective cohort study. SETTING:Participants were recruited from two tertiary maternity hospitals in Melbourne, Australia. PARTICIPANTS:Of the 173 pregnant women with type 1 (T1D) or type 2 diabetes (T2D) in the main cohort study, with an additional four who participated solely in this survey study, 130 (74.3%) completed the survey. PRIMARY AND SECONDARY OUTCOME MEASURES:This study calculated rates of adherence to guideline-recommended DR screening schedules and collected data on the enablers and barriers to attendance using a modified Compliance with Annual Diabetic Eye Exams Survey. Each of the 5-point Likert-scale survey items was compared between adherent and non-adherent participants using the Wilcoxon rank-sum test and logistic regression models were constructed to quantify associations as ORs. RESULTS:A retinal assessment was undertaken at least once during pregnancy in 86.3% of participants, but only 40.9% attended during their first trimester and only 21.2% attended the recommended number of examinations. Competing priorities were the main barriers to adherence, with eye examinations ranked as the fourth priority (IQR 4th-5th) among other health appointments during pregnancy. Meanwhile, knowledge of the benefits of eye screening examinations, eye-check reminders and support from relatives was identified as enablers. CONCLUSIONS:Despite the risk of worsening DR during pregnancy, less than half of the participants adhered to recommended screening guidelines, suggesting that eye health is not a priority. Proactive measures to integrate care are needed to prevent visual loss in this growing population.

With the increased availability of genetic testing and the addition of mitochondrial genetic variants on disease panels, accurate genetic counselling for individuals and families affected by, or at risk of, Leber hereditary optic neuropathy (LHON) is becoming increasingly relevant. Challenges in providing genetic counselling for LHON include its mitochondrial inheritance pattern, different haplogroups, incomplete penetrance and that it predominantly affects males. Accurate genetic counselling aims to avoid incorrect disease-risk assessment and delays in either diagnosis or implementation of psychosocial support. Families are also empowered to make autonomous health decisions regarding potential trigger factors for LHON vision loss and informed reproductive choices. Using clinical vignettes, this review demonstrates that an increased awareness of LHON amongst eye care, general and genetic health professionals can address challenges and misconceptions.

Purpose:To assess histopathology and outcomes after primary enucleation of eyes with retinoblastoma presenting with neovascular glaucoma (NVG). Methods:This was an international multicenter case series study across five continents. A retrospective review of patient charts was performed for all patients undergoing primary enucleation for retinoblastoma (n = 1,420) using a standardized data-collection spreadsheet. Clinical features, pathologic grade, and outcomes were compared between NVG patients and those with an American Joint Commission on Cancer eighth edition clinical stage of cT2. High-risk histopathology was defined as American Joint Commission on Cancer eighth edition pathologic stage >= pT2b. Results:Neovascular glaucoma was seen in 224/1,420 (16%) patients. The mean age at presentation of those with NVG was 30 months (median 25, range 0-120 months), and 131 (58%) patients had high-risk histopathology. The univariate logistic regression odds ratio for NVG predicting high-risk histopathology was 1.73 (95% confidence interval: 1.3-2.31) and from multivariate logistic regression was 1.77 (95% confidence interval: 1.23-2.56). Patients with a longer duration of symptoms (P = 0.03), buphthalmos (P = 0.02), and ectropion uveae (P < 0.01) were more likely to have high-risk histopathology. Patients with NVG were more likely to develop metastasis than cT2 patients (P = 0.04). Conclusion:There is a significant association between NVG at presentation, high-risk histopathology, and metastatic risk.

AIM:Leber hereditary optic neuropathy (LHON) predominantly manifests during adolescence or young adulthood, resulting in sudden and profound vision loss in individuals who previously had normal vision. This abrupt change significantly impacts daily life, necessitating emotional support, counseling and low-vision rehabilitative services to help affected individuals cope with the shock and adapt to their residual vision. The psychosocial burden of dealing with vision loss extends beyond the individuals directly affected by LHON, affecting matrilineal relatives who face the dual challenges of grieving for their loved one's vision loss and managing their own uncertainty about potential vision loss and its familial implications. METHOD:We reviewed key information that needs to be obtained prior to genetic counseling for LHON. We reviewed key counseling issues within LHON-affected families and the issues pending several subgroups of family members with distinct and varying genetic counseling needs. RESULTS:Family subgroups requiring specific counseling issues include the individuals affected by LHON, their mother, siblings, father, partner, and children. Genetic counseling plays an integral part of clinical care in families affected by LHON, providing tailored support and information to each subgroup. CONCLUSION:To provide accurate information to families and guide them toward potential supports, treatments and preventive measures, health professionals need to be aware of the factors influencing visual recovery and individual risk of vision loss.

PRÉCIS:As additional glaucoma genes are identified and classified, polygenic risk scores will be refined, facilitating early diagnosis and treatment. Ensuring genetic research is equitable to prevent glaucoma blindness worldwide is crucial. PURPOSE:To review the progress in glaucoma genetics over the past 25 years, including the identification of genes with varying contributions to the disease and the development of polygenic risk scores. METHODS/RESULTS:Over the last 2 and a half decades, glaucoma genetics has evolved from identifying genes with Mendelian inheritance patterns, such as myocilin and CYP1B1, to the discovery of hundreds of genes associated with the disease. Polygenic risk scores have been developed, primarily based on research in Northern European populations, and efforts to refine these scores are ongoing. However, there is a question regarding their applicability to other ethnic groups, especially those at higher risk of primary open angle glaucoma, like individuals of African ancestry. Glaucoma is highly heritable and family history can be used for cascade clinical screening programs, but these will not be feasible in all populations. Thus, cascade genetic testing using well-established genes such as myocilin may help improve glaucoma diagnosis. In addition, ongoing investigations seek to identify pathogenic genetic variants within genes like myocilin. CONCLUSIONS:The expanding availability of genetic testing for various diseases and early access to genetic risk information necessitates further research to determine when and how to act on specific genetic results. Polygenic risk scores involving multiple genes with subtle effects will require continuous refinement to improve clinical utility. This is crucial for effectively interpreting an individual's risk of developing glaucoma and preventing blindness.

Intraocular lacrimal gland choristoma - IJOOO- Print ISSN No: - 2581-5024 Online ISSN No:- 2581-5016 Article DOI No:- 10.18231/j.ijooo.2024.008, IP International Journal of Ocular Oncology and Oculoplasty-IP Int J Ocul Oncol Oculoplasty

Retinoblastoma (RB) represents one of the most prevalent intraocular cancers in children. Understanding the tumor heterogeneity in RB is important to design better targeted therapies. Here we used spatial transcriptomic to profile human retina and RB tumor to comprehensively dissect the spatial cell-cell communication networks. We found high intratumoral heterogeneity in RB, consisting of 10 transcriptionally distinct subpopulations with varying levels of proliferation capacity. Our results uncovered a complex architecture of the tumor microenvironment that predominantly consisted of cone precursors, as well as glial cells and cancer-associated fibroblasts. We delineated the cell trajectory underlying malignant progression of RB, and identified key signaling pathways driving genetic regulation across RB progression. We also explored the signaling pathways mediating cell-cell communications in RB subpopulations, and mapped the spatial networks of RB subpopulations and region neighbors. Altogether, we constructed the first spatial gene atlas for RB, which allowed us to characterize the transcriptomic landscape in spatially-resolved RB subpopulations, providing novel insights into the complex spatial communications involved in RB progression.### Competing Interest StatementThe authors have declared no competing interest.

Although the blinding eye disease glaucoma is more common in people of African ancestry, previous genetic studies predominantly involved European subjects. In this issue of Cell, O'Brien et al. report a genome-wide association study for glaucoma in individuals of African ancestry, showing overlap with European studies and refining an African polygenic risk score.

Background: Intra-arterial chemotherapy (IAC) is increasingly used in managing patients with retinoblastoma. In Australia, IAC is primarily used as a globe-salvage treatment when primary treatment has failed. Methods: A retrospective, single-institution study conducted on consecutive children treated with IAC at the Royal Children’s Hospital, Victoria, Australia between September 2009 to January 2021. Results: Using the Intraocular Classification of Retinoblastoma (ICRB), 16 eyes of 14 children classified as group A (n=1), Group B (n=3), Group D (n=10), or Group E (n=2) were treated with IAC. All but one child received IAC as secondary treatment for relapsed or refractory disease. Successful catheterisation of the ophthalmic artery was achieved in 37/46 (80.4%) procedures. A systemic complication occurred in one child (n=1): radiological evidence of a watershed infarct. Local complications of IAC included conjunctival injection (n=1), forehead rash (n=1), sixth cranial nerve palsy (n=2), ptosis (n=2), hemi-retinal ischaemia (n=1), choroidal ischaemia (n=1), retinal detachment (n=2), and choroidal neovascularisation (n=1). Regional extra-ocular disease occurred in one child. No child had distant metastatic disease and no child died. The overall globe salvage rate was 8/16 (50%): Group A (n=1, 100%), group B (n=2, 66.6%), Group D (n=5, 50%), group E (n=0, 0%). Kaplan Meier analysis of ocular survival following treatment with IAC was 75%, 68% and 53% for 6 months, 1 year and 2 years, respectively. Conclusions: Our experience demonstrates that IAC can be a useful treatment modality for refractory retinoblastoma in globe salvage, with an acceptable side-effect profile.

center dot PURPOSE: To compare the clinical outcomes of children with unilateral retinoblastoma (Rb) and high-risk histopathology features (HRHF) following upfront enucleation with/without adjuvant chemotherapy, and investigate cases locally considered non-HRHF but converted to a standardized HRHF definition. center dot DESIGN: Retrospective multinational clinical cohort study. center dot METHODS: Children with Rb who presented to 21 centers from 12 countries between 2011-2020, and underwent primary enucleation were recruited. Centers retrieved clinical data and were asked to report detailed histopathology findings, as well as indicate cases defined locally as high-risk. For analysis, only unilateral cases with standardized HRHF, defined as retrolaminar optic nerve invasion, massive choroidal invasion, scleral invasion, anterior-segment involvement, and/or combined nonmassive choroidal and prelaminar/laminar optic nerve invasion, were included. Main outcome measures included orbital tumor recurrence, systemic metastasis, survival and number, and outcome of cases converted to standardized HRHF. center dot RESULTS: A total of 600 children presenting to 14 centers in 9 countries were included. Of these, 505 (84.2%) were considered locally as HRHF and received adjuvant chemotherapy. After a median follow-up period of 39.2 +/- 1.6 months (range: 0.8-60.0 months), 36 (6.0%) had orbital tumor recurrence, 49 (8.2%) metastasis, and 72 (12.0%) children died. Children not receiving adjuvant chemotherapy were at significantly increased risk of orbital tumor recurrence, metastasis, and death ( P <= .002). Of the study children, 63/600 (10.5%) were considered locally non-HRHF, but converted to standardized HRHF and included in the analysis. Of these, 6/63 (9.5%) had orbital tumor recurrence, 5/63 (7.9%) metastasis, and 6/63 (9.5%) children died. Isolated minor choroidal invasion with prelaminar/laminar optic nerve invasion was reported in 114 (19.0%) children, but considered locally as HRHF only in 68/114 (59.6%). Of these, 6/114 (5.3%) children developed metastasis and subsequently died, yielding a number needed to treat of 15. center dot CONCLUSION: Based on this multinational cohort of children with Rb, we recommend the use of adjuvant chemotherapy following upfront enucleation and diagnosis of HRHF. Variation exists worldwide among centers when defining HRHF, resulting in adverse patient outcomes, warranting standardization. (Am J Ophthalmol 2024;268: 399-408. (c) 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Purpose: To evaluate high-risk histopathological features following primary enucleation of eyes with retinoblastoma and assess the patient outcomes across continents. Methods: A retrospective study of 1,426 primarily enucleated retinoblastoma eyes from five continents. Results: Of all, 923 (65%) were from Asia (AS), 27 (2%) from Australia (AUS), 120 (8%) from Europe (EUR), 162 (11%) from North America (NA), and 194 (14%) from South America (SA). Based on the continent (AS vs. AUS vs. EUR vs. NA vs. SA), the histopathological features included massive choroidal invasion (31% vs. 7% vs. 13% vs. 19% vs. 27%, P = 0.001), postlaminar optic nerve invasion (27% vs. 0% vs. 16% vs. 21% vs. 19%, P = 0.0006), scleral infiltration (5% vs. 0% vs. 4% vs. 2% vs. 7%, P = 0.13), and microscopic extrascleral infiltration (4% vs. 0% vs. <1% vs. <1% vs. 4%, P = 0.68). Adjuvant chemotherapy with/without orbital radiotherapy was given to 761 (53%) patients. Based on Kaplan-Meier estimates in different continents (AS vs. AUS vs. EUR vs. NA vs. SA), the 6-year risk of orbital tumor recurrence was 5% versus 2% versus 0% versus 0% versus 12% (P < 0.001), systemic metastasis was reported in 8% versus 5% versus 2% versus 0% versus 13% (P = 0.001), and death in 10% versus 3% versus 2% versus 0% versus 11% (P < 0.001) patients. Conclusion: There is a wide variation in the infiltrative histopathological features of retinoblastoma across continents, resulting in variable outcomes. SA and AS had a higher risk of orbital tumor recurrence, systemic metastasis, and death compared to AUS, EUR, and NA.

BACKGROUND:To evaluate the clinical presentation, pathological features and outcomes of retinoblastoma based on the race of origin in a global cohort of patients. METHODS:Retrospective collaborative study of 1426 patients who underwent primary enucleation for retinoblastoma. RESULTS:Patients were grouped into Caucasians (n = 231, 16%), Asians (n = 841, 59%), Hispanics (n = 226, 16%), Arabs (n = 96, 7%) and Others (Africans, African Americans, Indigenous Australians; n = 32, 2%) cohorts. On histopathology, massive choroidal invasion was higher in Asians (30%) and Hispanics (26%) than Caucasians (15%, p < 0.001). Post-laminar optic nerve invasion was higher in Asians (28%), Hispanics (20%) and Others (9%) than Caucasians (11%, p < 0.001). At a mean follow-up of 41 months (median, 35 months; range, < 1-149 months), tumour recurrence and metastasis-related death was higher in Hispanics (9% and 12%, respectively), Asians (4% and 13%, respectively) and Others (6% and 6%, respectively). Multivariate Cox proportional hazards analysis of outcomes based on race with 8th edition AJCC pT stage and adjuvant therapy as covariates revealed 6.8 times greater risk for orbital tumour recurrence in Hispanics compared to Caucasians (p = 0.010) and 3.2 times risk hazards for metastasis-related death in Hispanics and Asians compared to Caucasians (p = 0.028 and p = 0.038, respectively). CONCLUSION:The histopathological features in primarily enucleated eyes with retinoblastoma vary with race. Despite adjusting for tumour staging and adjuvant treatment, race remains an independent predictor of outcomes, including orbital tumour recurrence and metastasis-related death. A stringent follow-up and a more aggressive treatment approach is recommended in Asians and Hispanics who manifest high-risk histopathological features.

Hereditary congenital facial paresis type 1 (HCFP1) is an autosomal dominant disorder of absent or limited facial movement that maps to chromosome 3q21-q22 and is hypothesized to result from facial branchial motor neuron (FBMN) maldevelopment. In the present study, we report that HCFP1 results from heterozygous duplications within a neuron-specific GATA2 regulatory region that includes two enhancers and one silencer, and from noncoding single-nucleotide variants (SNVs) within the silencer. Some SNVs impair binding of NR2F1 to the silencer in vitro and in vivo and attenuate in vivo enhancer reporter expression in FBMNs. Gata2 and its effector Gata3 are essential for inner-ear efferent neuron (IEE) but not FBMN development. A humanized HCFP1 mouse model extends Gata2 expression, favors the formation of IEEs over FBMNs and is rescued by conditional loss of Gata3 . These findings highlight the importance of temporal gene regulation in development and of noncoding variation in rare mendelian disease.

Purpose: To conduct a costing study comparing orthoptist-led with consultant-led clinics screening for optic pathway gliomas (OPGs) in children with neurofibromatosis Type 1 (NF1) attending the Royal Children’s Hospital (RCH), Melbourne. Methods: Patients with NF1 examined in the orthoptist-led NF1 screening clinic and/or consultant-led clinics during the study period were identified. The workflow management software Q-Flow 6® provided data documenting patient’s time spent with the orthoptist, nurse, and ophthalmologist. Time points were converted into minutes and multiplied by the cost-per-minute for each profession. A bottom-up micro-costing approach was used to estimate appointment level costs. Bootstrap simulations with 1000 replications were used to estimate 95% confidence intervals (CIs) for the difference in mean appointment time and cost between clinics. Results: Data for 130 consultant-led clinic appointments and 234 orthoptist-led clinic appointments were extracted for analysis. The mean time per appointment for the consultant-led clinic was 45.11 minutes, and the mean time per appointment for the orthoptist-led clinic was 25.85 minutes. The mean cost per appointment for the consultant-led clinic was A $84.15 (GBP £39.60) compared to the orthoptist-led clinic at A $20.40 (GBP £9.60). This represents a mean reduction of 19.25 minutes per appointment (95% CI, –24.85 to –13.66) and a mean reduction of A $63.75 (GBP £30.00) per appointment (95% CI, (A $-75.40 to $-52.10 [GBP £ -35.48 to £ -24.52]). Conclusion: An orthoptist-led clinic screening for OPGs in patients with NF1 can be a more cost-efficient model of care for ophthalmic screening in this patient group.

Background Retinoblastoma is the most common intraocular cancer worldwide. There is some evidence to suggest that major differences exist in treatment outcomes for children with retinoblastoma from different regions, but these differences have not been assessed on a global scale. We aimed to report 3-year outcomes for children with retinoblastoma globally and to investigate factors associated with survival. Methods We did a prospective cluster-based analysis of treatment-naive patients with retinoblastoma who were diagnosed between Jan 1,2017, and Dec 31,2017, then treated and followed up for 3 years. Patients were recruited from 260 specialised treatment centres worldwide. Data were obtained from participating centres on primary and additional treatments, duration of follow-up, metastasis, eye globe salvage, and survival outcome. We analysed time to death and time to enucleation with Cox regression models. Findings The cohort included 4064 children from 149 countries. The median age at diagnosis was 23.2 months (IQR 11.0-36.5). Extraocular tumour spread (cT4 of the cTNMH classification) at diagnosis was reported in five (0.8%) of 636 children from high-income countries, 55 (5.4%) of 1027 children from upper-middle-income countries, 342 (19. 7%) of 1738 children from lower-middle-income countries, and 196 (42.9%) of 457 children from low-income countries. Enudeation surgery was available for all children and intravenous chemotherapy was available for 4014 (98.8%) of 4064 children. The 3-year survival rate was 99.5% (95% CI 98.8-100.0) for children from high-income countries, 91.2% (89.5-93.0) for children from upper-middle-income countries, 80.3% (78.3-82.3) for children from lower-middle-income countries, and 57.3% (524-63-0) for children from low-income countries. On analysis, independent factors for worse survival were residence in low-income countries compared to high-income countries (hazard ratio 16.67; 95% CI 4.76-50.00), cT4 advanced tumour compared to cT1 (8.98; 4.44-18.18), and older age at diagnosis in children up to 3 years (1.38 per year; 1.23-1.56). For children aged 3-7 years, the mortality risk decreased slightly (p=0.0104 for the change in slope). Interpretation This study, estimated to include approximately half of all new retinoblastoma cases worldwide in 2017, shows profound inequity in survival of children depending on the national income level of their country of residence. In high-income countries, death from retinoblastoma is rare, whereas in low-income countries estimated 3-year survival is just over 50%. Although essential treatments are available in nearly all countries, early diagnosis and treatment in low-income countries are key to improving survival outcomes. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd.