Treatment Outcomes and Definition Inconsistencies in High-Risk Unilateral Retinoblastoma: Outcomes and Definition Variances in High-Risk Rb.

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. DESIGN: Retrospective multinational clinical cohort study. 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 non-massive 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. 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 ≤0.002). 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. 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.

Retinoblastoma survival and enucleation outcomes in 41 countries from the African continent.

BACKGROUND: Retinoblastoma is the most common intraocular malignancy in childhood. Despite one-third of cases occurring in Africa, little is known of the outcomes on the continent. This study aims to explore survival and globe salvage outcomes and identify their risk factors across a large cohort of patients from the African continent. METHODS: A 3-year prospective, observational study was conducted. Kaplan-Meier survival analysis was used to investigate the risk of globe loss and death from retinoblastoma in Africa. Cox regression was used to identify risk factors associated with these outcomes. RESULTS: A total of 958 patients from 41 African countries and 66 participating centres were enrolled in the study. The survival rate was 78.2% at 1 year and 66.2% at 3 years after diagnosis. Cox regression showed a higher risk of death with the most advanced clinical stage (cT4, HR=6.29 vs cT2, p<0.001). The risk of losing at least one eye after diagnosis was 50% within 4 months and 72.6% within 3 years. Higher risk of enucleation was associated with a higher clinical stage compared with cT1 (cT3, HR=4.11, p=0.001; cT4, HR=3.77, p=0.005). CONCLUSION: Nearly one in every four children diagnosed with retinoblastoma in African participating centres succumb to retinoblastoma within 1 year. There is also high morbidity associated with the diagnosis as a large majority of patients require eye removal surgery. The outcome of disease in children with retinoblastoma in Africa is poor compared with other continents and requires prompt intervention by increasing efforts to improve survival and eye salvage outcomes.

Orbital Development in Children with Retinoblastoma: An Imaging-Based Study.

PURPOSE: To examine whether children treated for Retinoblastoma (Rb) have impaired orbital development. METHODS: A retrospective case series was performed among children with Rb treated at a single medical center from 2004 to 2020. Orbital volumes and measurements were assessed by 3-dimensional image processing software. The main outcome measures were differences in orbital growth between Rb and non-Rb eyes assessed at last follow-up. RESULTS: Among 44 patients included (mean age 16.09 ± 18.01 months), a positive correlation between age and orbital volume was observed only in the uninvolved, healthy eyes (p = .03). In unilateral cases, orbital growth in the horizontal, vertical, and depth planes was smaller on the affected side compared to the healthy eyes (p < .05). Orbits that underwent enucleation showed decreased growth over time compared to those treated conservatively (p = .017). CONCLUSIONS: Orbital growth rate is slower in the orbits of children treated for Rb compared to healthy orbits. Enucleation negatively affects orbital growth.

Mechanisms of blood-retinal barrier disruption related to intraocular inflammation and malignancy.

Blood-retinal barrier (BRB) disruption is a common accompaniment of intermediate, posterior and panuveitis causing leakage into the retina and macular oedema resulting in vision loss. It is much less common in anterior uveitis or in patients with intraocular lymphoma who may have marked signs of intraocular inflammation. New drugs used for chemotherapy (cytarabine, immune checkpoint inhibitors, BRAF inhibitors, EGFR inhibitors, bispecific anti-EGFR inhibitors, MET receptor inhibitors and Bruton tyrosine kinase inhibitors) can also cause different types of uveitis and BRB disruption. As malignant disease itself can cause uveitis, particularly from breast, lung and gastrointestinal tract cancers, it can be clinically difficult to sort out the cause of BRB disruption. Immunosuppression due to malignant disease and/or chemotherapy can lead to infection which can also cause BRB disruption and intraocular infection. In this paper we address the pathophysiology of BRB disruption related to intraocular inflammation and malignancy, methods for estimating the extent and effect of the disruption and examine why some types of intraocular inflammation and malignancy cause BRB disruption and others do not. Understanding this may help sort and manage these patients, as well as devise future therapeutic approaches.

Retinoblastoma in Asia: Clinical Presentation and Treatment Outcomes in 2112 Patients from 33 Countries.

PURPOSE: To describe the clinical presentation and treatment outcomes of children who received a diagnosis of retinoblastoma in 2017 throughout Asia. DESIGN: Multinational, prospective study including treatment-naïve patients in Asia who received a diagnosis of retinoblastoma in 2017 and were followed up thereafter. PARTICIPANTS: A total of 2112 patients (2797 eyes) from 96 retinoblastoma treatment centers in 33 Asian countries. INTERVENTIONS: Chemotherapy, radiotherapy, enucleation, and orbital exenteration. MAIN OUTCOME MEASURES: Enucleation and death. RESULTS: Within the cohort, 1021 patients (48%) were from South Asia (SA), 503 patients (24%) were from East Asia (EA), 310 patients (15%) were from Southeast Asia (SEA), 218 patients (10%) were from West Asia (WA), and 60 patients (3%) were from Central Asia (CA). Mean age at presentation was 27 months (median, 23 months; range, < 1-261 months). The cohort included 1195 male patients (57%) and 917 female patients (43%). The most common presenting symptoms were leukocoria (72%) and strabismus (13%). Using the American Joint Committee on Cancer Staging Manual, Eighth Edition, classification, tumors were staged as cT1 (n = 441 [16%]), cT2 (n = 951 [34%]), cT3 (n = 1136 [41%]), cT4 (n = 267 [10%]), N1 (n = 48 [2%]), and M1 (n = 129 [6%]) at presentation. Retinoblastoma was treated with intravenous chemotherapy in 1450 eyes (52%) and 857 eyes (31%) underwent primary enucleation. Three-year Kaplan-Meier estimates for enucleation and death were 33% and 13% for CA, 18% and 4% for EA, 27% and 15% for SA, 32% and 22% for SEA, and 20% and 11% for WA (P < 0.0001 and P < 0.0001), respectively. CONCLUSIONS: At the conclusion of this study, significant heterogeneity was found in treatment outcomes of retinoblastoma among the regions of Asia. East Asia displayed better outcomes with higher rates of globe and life salvage, whereas Southeast Asia showed poorer outcomes compared with the rest of Asia. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Retinoblastoma Outcomes in the Americas: A Prospective Analysis of 491 Children With Retinoblastoma From 23 American Countries.

PURPOSE: Globally, disparities exist in retinoblastoma treatment outcomes between high- and low-income countries, but independent analysis of American countries is lacking. We report outcomes of American retinoblastoma patients and explore factors associated with survival and globe salvage. DESIGN: Subanalysis of prospective cohort study data. METHODS: Multicenter analysis at 57 American treatment centers in 23 countries of varying economic levels (low income [LIC], lower-middle income [LMIC], upper-middle income [UMIC], and high income [HIC]) of 491 treatment-naïve retinoblastoma patients diagnosed in 2017 and followed through 2020. Survival and globe salvage rates analyzed with Kaplan-Meier analysis and Cox proportional hazard models. RESULTS: Of patients, 8 (1.6%), 58 (11.8%), 235 (47.9%), and 190 (38.7%) were from LIC, LMIC, UMIC, and HIC groups, respectively. Three-year survival rates in LICs were 60.0% (95% confidence interval [CI] 12.6-88.2) compared with 99.2% (95% CI 94.6%-99.9%) in HICs. Death was less likely in patients >4 years of age (vs ≤4 years, HR = 0.45 [95% CI 0.27-0.78], P = .048). Patients with more advanced tumors (eg, cT3 vs cT1, HR = 4.65 × 109 [95% CI 1.25 × 109-1.72 × 1010], P < .001) and females (vs males, HR = 1.98 [95% CI 1.27-3.10], P = .04) were more likely to die. Three-year globe salvage rates were 13.3% (95% CI 5.1%-25.6%) in LMICs and 46.2% (95% CI 38.8%-53.3%) in HICs. At 3 years, 70.1% of cT1 eyes (95% CI 54.5%-81.2%) vs 8.9% of cT3 eyes (95% CI 5.5%-13.3%) were salvaged. Advanced tumor stage was associated with higher enucleation risk (eg, cT3 vs cT1, subhazard ratio = 4.98 [95% CI 2.36-10.5], P < .001). CONCLUSIONS: Disparities exist in survival and globe salvage in American countries based on economic level and tumor stage demonstrating a need for childhood cancer programs.

Incidental Genetic Finding in a Fetus.

A 37-year-old woman presented with suspected polycystic kidney detected on routine fetal ultrasonography, and an incidental finding of a heterozygous c.501-2 A

Diffuse choroidal hemangioma in pregnancy: Symptomatic diffuse choroidal hemangioma spontaneously resolving postpartum.

We present the case of a pregnant young woman with symptomatic diffuse choroidal hemangioma (CH), diagnosed with Sturge-Weber syndrome (SWS). Three months postpartum, there was full spontaneous resolution of the subretinal fluid and improvement in the visual acuity (VA). A 29-year-old, 31-week pregnant female with a coagulation disorder and enoxaparin (clexane) treatment, complained of a left visual disturbance of 2 weeks duration. On examination, the right eye was normal; left eye VA was 6/12 (20/40) with a left eyelid port-wine stain and on funduscopic examination there was a serous retinal detachment. On ultrasound, there was diffuse thickening of the choroid with a focus superior and nasal to the disc with active vascularization - a diagnosis of diffuse CH was made. Magnetic resonance imaging (MRI) and MR venography studies of the brain and orbit revealed engorged orbital vasculature, and the diagnosis of SWS was made. Three months after Cesarean section with birth of a healthy baby boy, VA returned to 6/9 with full resorption of subretinal fluid. On fundoscopic exam, there were no retinal or vein occlutions but there were tortuous blood vessels with A-V crossing. This is a rare case of newly diagnosed SWS with symptomatic diffuse CH in pregnancy. Postpartum, there was full resolution of the subretinal fluid. A watchful waiting approach can be considered in such cases.

The Most-Cited Articles on Retinoblastoma: A Fifty-Year Perspective.

PURPOSE: To summarize the characteristics and trends of interest in retinoblastoma (Rb) in the last 50 years. METHODS: The Web of Science Database was used to find all studies focused on Rb published from 1970 to 2018. The term "retinoblastoma" was used to search for the 100 most cited records. RESULTS: The mean number of citations was 153.55 ± 88.9. The majority were from the United States (US) (n = 68). Drs. Shields authored 38% of the papers. The number of citations per year was positively correlated with the number of authors, r = 0.26 (p = 0.008). The number of patients was significantly associated with the number of citations per year (p = 0.012). Although papers on radiotherapy were the most common, publications about intra-arterial chemotherapy (IAC) were associated with 88.3% more citations per year (p = 0.031) and papers on intravenous chemotherapy (IVC) were associated with 40.3% more citations per year (p= 0.04). Review and meta-analysis studies had a higher median of citations (10.5) than interventional (6.4) or observational (5.2) studies. CONCLUSIONS: This study compiles a comprehensive analysis of the most-cited articles on Rb. Studies with a higher number of citations per year were associated with IAC, which emphasizes the significance of the advances in Rb treatments that allow for the saving of eyes and vision as well as lives. Review studies had more citations than observational or interventional studies. More citations were associated with a larger number of authors or more reported patients per paper. These findings highlight the importance of collaborations to achieve relevant, high-quality research of Rb.

Evaluating the baseline survival outcomes of the "six Global Initiative for Childhood Cancer index cancers" in Africa.

Limited survival data for the six Global Initiative for Childhood Cancer (GICC) priority cancers are available in Africa. Management of pediatric malignancies in Africa is challenging due to lack of resources, setting-specific comorbidities, high rates of late presentation and treatment abandonment. Reporting of outcome data is problematic due to the lack of registries. With the aim of evaluating the feasibility of baseline outcomes for the six index cancers, we present a descriptive analysis of respective survival rates in Africa. The survival rates were between 18% (lower middle-income countries) to 82.3% (upper middle-income countries) for acute lymphoblastic leukemia, between 26.9% (low-income countries) to 77.9% (upper middle-income countries) for nephroblastoma, between 23% (low-income countries) to 100% (upper middle-income countries), for retinoblastoma, 45% (low-income countries) to 95% (upper middle-income countries) for Hodgkin lymphoma and 28% (low-income countries) to 76% (upper middle-income countries) for Burkitt lymphoma. Solutions to improve survival rates and reported outcomes include establishing and funding sustainable registries, training and to actively include all countries in consortia from different African regions.HighlightsContinental differences in childhood cancer management such lack of resources, setting-specific comorbidities, high rates of late presentation and treatment abandonment, present challenges to the achievement of Global Initiative for Childhood Cancer goals.The available data registries do not adequately inform on the true incidences and outcomes of childhood cancers in Africa.The pathophysiology of some childhood cancers in Africa are associated with high-risk prognostic factors.Outcomes can be improved by greater regional collaboration to manage childhood cancer based on local resources and tumor characteristics.Some individual countries have reached the Global Initiative for Childhood Cancer goals for single cancers and it should be possible for more African countries to follow suit.

Risk factors associated with abandonment of care in retinoblastoma: analysis of 692 patients from 10 countries.

BACKGROUND: Rates of care abandonment for retinoblastoma (RB) demonstrate significant geographical variation; however, other variables that place a patient at risk of abandoning care remain unclear. This study aims to identify the risk factors for care abandonment across a multinational set of patients. METHODS: A prospective, observational study of 692 patients from 11 RB centres in 10 countries was conducted from 1 January 2019 to 31 December 2019. Multivariate logistic regression was used to identify risk factors associated with higher rates of care abandonment. RESULTS: Logistic regression showed a higher risk of abandoning care based on country (high-risk countries include Bangladesh (OR=18.1), Pakistan (OR=45.5) and Peru (OR=9.23), p<0.001), female sex (OR=2.39, p=0.013) and advanced clinical stage (OR=4.22, p<0.001). Enucleation as primary treatment was not associated with a higher risk of care abandonment (OR=0.59, p=0.206). CONCLUSION: Country, advanced disease and female sex were all associated with higher rates of abandonment. In this analysis, enucleation as the primary treatment was not associated with abandonment. Further research investigating cultural barriers can enable the building of targeted retention strategies unique to each country.

The role of maternal age & birth order on the development of unilateral and bilateral retinoblastoma: a multicentre study.

BACKGROUND/OBJECTIVES: Retinoblastoma is a common childhood intraocular malignancy, the bilateral form of which most commonly results from a de novo germline pathogenic variant in the RB1 gene. Both advanced maternal age and decreasing birth order are known to increase the risk of de novo germline pathogenic variants, while the influence of national wealth is understudied. This cohort study aimed to retrospectively observe whether these factors influence the ratio of bilateral retinoblastoma cases compared to unilateral retinoblastoma, thereby inferring an influence on the development of de novo germline pathogenic variants in RB1. SUBJECTS/METHODS: Data from 688 patients from 11 centres in 10 countries were analysed using a series of statistical methods. RESULTS: No associations were found between advanced maternal age, birth order or GDP per capita and the ratio of bilateral to unilateral retinoblastoma cases (p values = 0.534, 0.201, 0.067, respectively), indicating that these factors do not contribute to the development of a de novo pathogenic variant. CONCLUSIONS: Despite a lack of a definitive control group and genetic testing, this study demonstrates that advanced maternal age, birth order or GDP per capita do not influence the risk of developing a bilateral retinoblastoma.

Seasonal Variation in the Diagnosis of Retinoblastoma.

PURPOSE: To determine the seasonal variation in the diagnosis of retinoblastoma in a global sample of children and to investigate predictors of seasonal trends. METHODS: Data were collected through a global, multicenter, 1-year cross-sectional analysis that included all treatment- naïve retinoblastoma patients presenting to participating centers between January 1, 2017, and December 31, 2017. Due to variations in days per month, data were normalized to a 30-day/month calendar. Observed data were compared to a simulation study of expected results using a uniform distribution. RESULTS: Patient-level data were available for 4,351 children from 276 centers in 153 countries, of which 3,966 had a month of presentation recorded. There were relative peaks in disease presentation in January and July, with lower counts in November and December (p = .0015). No covariates were found to be significantly associated with the seasonal trend. Two covariates, patient age at presentation and extraocular tumor spread, showed a moderate association with month of presentation. CONCLUSION: Our findings suggest seasonal trends in the presentation of retinoblastoma across the world. However, these trends do not appear to be related to income level of a country, climate, or other covariates. Any connection between seasonal variation of retinoblastoma presentation and retinoblastoma outcomes remains unclear or not present.

Peripheral Exudative Hemorrhagic Chorioretinopathy with and without treatment-Clinical and multimodal imaging characteristics and prognosis.

PURPOSE: To describe clinical and imaging characteristics of patients with Peripheral Exudative Hemorrhagic Chorioretinopathy (PEHCR), prognosis and treatment response. METHODS: In this retrospective cohort study medical records of patients diagnosed with PEHCR in a tertiary medical center between 2008 and 2018 were reviewed. Collected data included demographics, medical history, ophthalmologic examination and multi-modal imaging including fundus autofluorescence, optical coherence tomography (OCT), ultrasound (US), fluorescein angiography and indocyanine green angiography when available. Bevacizumab treatment results were analyzed when applied. RESULTS: 35 eyes of 32 patients were included, with a female predominance (56.25%) and an average age of 79.0±9.87 years at presentation. Most common OCT and US findings were subretinal mass (68.75%), pigment epithelial detachment (30.00%) and atrophic changes (21.86%). Median follow-up period was 18.00 months (range 0-102). Visual acuity (VA) remained stable (39.29%) or improved (25.00%) in most cases available for follow-up. Treatment with intravitreal bevacizumab induced a statistically significant clinical resolution in 88.89% of eyes available for follow-up (8/9 eyes) (p = 0.02). CONCLUSIONS: PEHCR is presented with high clinical variability and generally good prognosis. This is the first publication demonstrating a statistically significant clinical resolution of disease following intravitreal bevacizumab injections.

Mammalian target of rapamycin inhibitors for the treatment of astrocytic hamartoma in tuberous sclerosis complex (TSC).

PURPOSE: Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder. Fifty percent of patients with TSC will develop retinal astrocytic hamartoma (RAH). The mammalian target of rapamycin (mTOR) inhibitors interferes with the pathological mechanisms of TSC. Treatment of RAH with mTOR inhibitors has been described in only a few isolated case reports. The purpose of this study was to assess the effect of mTOR inhibitors on RAH in a small cohort of patients. METHODS: The medical records of all consecutive patients with ocular manifestations of TSC that were treated with mTOR inhibitors at the Sheba Medical Center from January 2014 to December 2018 were retrospectively reviewed. Data collection included demographics, medical history, ocular presentation, ocular treatment, and treatment outcome. Tumor size was assessed by a masked observer, before and after treatment. Lesion measurements were made with Heidelberg SD-OCT (HRA + OCT SPECTRALIS), and fundus photos were taken with RetCam3® (Natus, USA) and analyzed by "ImageJ" software. RESULTS: Eleven patients with tuberous sclerosis and astrocytic hamartoma were treated with mTOR inhibitors in the study period. Of them, 6 children (11 eyes, 20 tumors) had proper imaging of tumor size before and after treatment. The analysis included these 11 eyes. All six patients had non-ocular manifestations of TSC, including dermatologic (n = 5), neurologic (n = 5), and renal (n = 3) involvement. Ocular involvement included in five eyes (45%) tumors near the optic disc and in four eyes (37%) foveal tumors. The mean follow-up duration was 2.15 ± 1.4 years (range 10 months to 4.5 years). The average tumor base reduction in the treated group was 17.8% ± 15.9. The average maximal thickness at baseline was 414 ± 174 µm (range 152-686 µm). There was a 14% ± 7.1 reduction after treatment. None of the tumors showed evidence of growth at the final follow-up. CONCLUSION: The findings of this study suggest that mTOR inhibitors can reduce tumor size and that they can be considered as an optional treatment in certain conditions. This preliminary report is the first to quantitatively assess pre- and posttreatment tumor size, in young patients.

Thicker macula in asymptomatic APOE Ɛ4 middle-aged adults at high AD risk.

INTRODUCTION: We compared retinal layers' thickness between apolipoprotein E (APOE) Ɛ4 carriers and non-carriers in a cohort of cognitively normal middle-aged adults enriched for Alzheimer's disease (AD) risk. METHODS: Participants (N = 245) underwent spectral domain optical coherence tomography. Multivariate analyses of covariance adjusting for age, sex, education, and best corrected vision acuity was used to compare retinal thickness between APOE groups. RESULTS: Participants' mean age was 59.60 (standard deviation = 6.42) with 66.4% women and 32.2% APOE Ɛ4 carriers. Greater macular full thickness was observed in APOE Ɛ4 carriers compared to non-carriers (P = .017), reaching statistical significance for the inner and outer nasal (P = .009 and P = .005, respectively), inner superior (P = .041), and inner and outer inferior (P = .013 and P = .033, respectively) sectors. The differences between APOE groups were mainly driven by the ganglion cell layer (P < .05) and the inner plexiform layer (P < .05). DISCUSSION: A thicker macula is observed already in midlife asymptomatic APOE Ɛ4 carriers at high AD risk.

Defining High-risk Retinoblastoma: A Multicenter Global Survey.

IMPORTANCE: High-risk histopathologic features of retinoblastoma are useful to assess the risk of systemic metastasis. In this era of globe salvage treatments for retinoblastoma, the definition of high-risk retinoblastoma is evolving. OBJECTIVE: To evaluate variations in the definition of high-risk histopathologic features for metastasis of retinoblastoma in different ocular oncology practices around the world. DESIGN, SETTING, AND PARTICIPANTS: An electronic web-based, nonvalidated 10-question survey was sent in December 2020 to 52 oncologists and pathologists treating retinoblastoma at referral retinoblastoma centers. INTERVENTION: Anonymized survey about the definition of high-risk histopathologic features for metastasis of retinoblastoma. MAIN OUTCOMES AND MEASURES: High-risk histopathologic features that determine further treatment with adjuvant systemic chemotherapy to prevent metastasis. RESULTS: Among the 52 survey recipients, the results are based on the responses from 27 individuals (52%) from 24 different retinoblastoma practices across 16 countries in 6 continents. The following were considered to be high-risk features: postlaminar optic nerve infiltration (27 [100%]), involvement of optic nerve transection (27 [100%]), extrascleral tissue infiltration (27 [100%]), massive (≥3 mm) choroidal invasion (25 [93%]), microscopic scleral infiltration (23 [85%]), ciliary body infiltration (20 [74%]), trabecular meshwork invasion (18 [67%]), iris infiltration (17 [63%]), anterior chamber seeds (14 [52%]), laminar optic nerve infiltration (13 [48%]), combination of prelaminar and laminar optic nerve infiltration and minor choroidal invasion (11 [41%]), minor (<3 mm) choroidal invasion (5 [19%]), and prelaminar optic nerve infiltration (2 [7%]). The other histopathologic features considered high risk included Schlemm canal invasion (4 [15%]) and severe anaplasia (1 [4%]). Four respondents (15%) said that the presence of more than 1 high-risk feature, especially a combination of massive peripapillary choroidal invasion and postlaminar optic nerve infiltration, should be considered very high risk for metastasis. CONCLUSIONS AND RELEVANCE: Responses to this nonvalidated survey conducted in 2020-2021 showed little uniformity in the definition of high-risk retinoblastoma. Postlaminar optic nerve infiltration, involvement of optic nerve transection, and extrascleral tumor extension were the only features uniformly considered as high risk for metastasis across all oncology practices. These findings suggest that the relevance about their value in the current scenario with advanced disease being treated conservatively needs further evaluation; there is also a need to arrive at consensus definitions and conduct prospective multicenter studies to understand their relevance.

Sex, gender, and retinoblastoma: analysis of 4351 patients from 153 countries.

OBJECTIVE: To investigate in a large global sample of patients with retinoblastoma whether sex predilection exists for this childhood eye cancer. METHODS: A cross-sectional analysis including 4351 treatment-naive retinoblastoma patients from 153 countries who presented to 278 treatment centers across the world in 2017. The sex ratio (male/female) in the sample was compared to the sex ratio at birth by means of a two-sided proportions test at global level, country economic grouping, continent, and for selected countries. RESULTS: For the entire sample, the mean retinoblastoma sex ratio, 1.20, was higher than the weighted global sex ratio at birth, 1.07 (p < 0.001). Analysis at economic grouping, continent, and country-level demonstrated differences in the sex ratio in the sample compared to the ratio at birth in lower-middle-income countries (n = 1940), 1.23 vs. 1.07 (p = 0.019); Asia (n = 2276), 1.28 vs. 1.06 (p < 0.001); and India (n = 558), 1.52 vs. 1.11 (p = 0.008). Sensitivity analysis, excluding data from India, showed that differences remained significant for the remaining sample (χ2 = 6.925, corrected p = 0.025) and for Asia (χ2 = 5.084, corrected p = 0.036). Excluding data from Asia, differences for the remaining sample were nonsignificant (χ2 = 2.205, p = 0.14). CONCLUSIONS: No proof of sex predilection in retinoblastoma was found in the present study, which is estimated to include over half of new retinoblastoma patients worldwide in 2017. A high male to female ratio in Asian countries, India in specific, which may have had an impact on global-level analysis, is likely due to gender discrimination in access to care in these countries, rather than a biological difference between sexes.

The Effects of Breastfeeding on Retinoblastoma Development: Results from an International Multicenter Retinoblastoma Survey.

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.

Strabismus as a Presenting Sign in Retinoblastoma.

PURPOSE: To report the presenting signs of retinoblastoma in a large cohort of patients who underwent orthoptic assessment at presentation. METHODS: A retrospective medical chart review was conducted on 131 patients with retinoblastoma who presented consecutively to a single institution during a 6-year period. The main outcome measure was the presenting sign(s) of the disease. RESULTS: Of 131 patients with retinoblastoma, 88 presented with unilateral disease and 43 presented with bilateral disease (mean ages: 22.7 and 14.8 months, respectively). Leukocoria was the presenting sign in 56% of patients, leukocoria and strabismus in 18%, strabismus in 13%, inflammation in 8%, and "other" signs in 5%. The fovea was affected by the retinoblastoma tumor or its sequelae in 75% of patients. Patients who presented with strabismus were significantly more likely to have foveal involvement than patients who presented with leukocoria alone (P = .001). Thirty-one percent of patients had strabismus as a component of their presentation; 63% had exotropia, 23% had esotropia, and 14% had variable strabismus. The percentage of patients with strabismus increased to 66% when small angle and variable strabismus were also considered. Patients with inflammation had worse ocular survival (P < .05). CONCLUSIONS: This study assessed the combination of leukocoria and strabismus as presenting features of retinoblastoma. Foveal involvement is common in patients who have strabismus and may influence decision-making regarding globe salvage. The authors confirmed that exotropia is more common than esotropia in retinoblastoma in the largest cohort to have undergone an orthoptic assessment. [J Pediatr Ophthalmol Strabismus. 2021;58(5):324-330.].