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.

Differences in Childhood Growth Parameters Between Patients With Somatic and Heritable Retinoblastoma.

Purpose: Little is known regarding differences in childhood growth between somatic and heritable retinoblastoma (Rb) populations. We aimed to compare childhood growth parameters between somatic and heritable Rb cohorts at birth and at time of diagnosis with Rb. Methods: A multinational, longitudinal cohort study was conducted with patients from 11 centers in 10 countries who presented with treatment naïve Rb from January to December 2019. Variables of interest included age, sex, and size characteristics at birth and at time of presentation, as well as germline mutation status. After Bonferroni correction, results were statistically significant if the P value was less than 0.005. Results: We enrolled 696 patients, with 253 analyzed after exclusion criteria applied. Between somatic (n = 39) and heritable (n = 214) Rb cohorts, with males and females analyzed separately, there was no significant difference in birth weight percentile, weight percentile at time of diagnosis, length percentile at time of diagnosis, weight-for-length percentile at time of diagnosis, or change of weight percentile from birth to time of diagnosis. Patients with heritable Rb had a smaller mean weight percentile at birth and smaller mean weight and length percentiles at time of diagnosis with Rb, although this difference was not statistically significant. All cohorts experienced a slight negative change of weight percentile from birth to time of diagnosis. No cohort mean percentiles met criteria for failure to thrive, defined as less than the 5th percentile. Conclusions: Children with Rb seem to have normal birth and childhood growth patterns. There is no definitive evidence that somatic or heritable Rb has a biological or environmental impact on childhood growth parameters.

Success rates of lateral canthotomy and cantholysis for treatment of orbital compartment syndrome.

PURPOSE: Vision loss after facial trauma can occur from orbital compartment syndrome (OCS). Orbital compartment syndrome is commonly treated surgically with a lateral canthotomy and cantholysis (C&C). Our study investigates success rates of lateral C&C for the treatment of OCS amongst emergency medicine (EM) and ophthalmology providers. METHODS: A retrospective cohort study was performed. Cases were identified and the electronic medical record of patients was interrogated for clinical and procedural information. Success of a lateral C&C was defined as a decrease in intraocular pressure (IOP) to <30 mmHg after the first attempt at the procedure. Inclusion criteria included documentation of a procedural attempt, a pre-procedure IOP >30 mmHg and a post-procedure IOP measurement; or alternatively if no pre-procedure IOP was documented but the IOP was >30 on arrival to the level 1 trauma center. Exclusion criteria included periprocedural use of ocular hypotensive medications and comorbid hyphema. RESULTS: The final analysis included 74 eyes from 64 patients. Emergency medicine providers performed the initial lateral C&C in 68% of cases compared to 32% by ophthalmologists, and success rates were comparable - 68% vs 79.2%, respectively (p = 0.413). Poorer visual outcomes were associated with the initial failure of a lateral C&C and head trauma without an orbital fracture. All patients treated with a vertical lid split procedure met the criteria for 'success' as defined by this study. CONCLUSIONS: The success rate of a lateral C&C is comparable amongst EM and ophthalmology providers. Improved training of physicians on the lateral C&C or other simpler procedures, such as the vertical lid split, could improve outcomes in OCS.

A Multicenter Analysis of Nucleic Acid Quantification Using Aqueous Humor Liquid Biopsy in Retinoblastoma: Implications for Clinical Testing.

Purpose: Retinoblastoma (RB) is most often diagnosed with clinical features and not diagnosed with tumor biopsy. This study describes tumor-derived analyte concentrations from aqueous humor (AH) liquid biopsy and its use in clinical assays. Design: Case series study. Participants: Sixty-two RB eyes from 55 children and 14 control eyes from 12 children from 4 medical centers. Methods: This study included 128 RB AH samples including: diagnostic (DX) samples, samples from eyes undergoing treatment (TX), samples after completing treatment (END), and during bevacizumab injection for radiation therapy after completing RB treatment (BEV). Fourteen-control AH were analyzed for unprocessed analytes (double-stranded DNA [dsDNA], single-stranded DNA [ssDNA], micro-RNA [miRNA], RNA, and protein) with Qubit fluorescence assays. Double-stranded DNA from 2 RB AH samples underwent low-pass whole-genome sequencing to detect somatic copy number alterations. Logistic regression was used to predict disease burden given analyte concentrations. Main Outcome Measures: Unprocessed analyte (dsDNA, ssDNA, miRNA, RNA and protein) concentrations. Results: Results revealed dsDNA, ssDNA, miRNA, and proteins, but not RNA, were quantifiable in most samples (up to 98%) with Qubit fluorescence assays. Median dsDNA concentration was significantly higher in DX (3.08 ng/µl) compared to TX (0.18 ng/µl; P < 0.0001) at an order of 17 times greater and 20 times greater than END samples (0.15 ng/µl; P = 0.001). Using logistic regression, nucleic acid concentrations were useful in predicting higher versus lower RB disease burden. Retinoblastoma somatic copy number alterations were identified in a TX, but not in a BEV sample, indicating the correlation with RB activity. Conclusions: Aqueous humor liquid biopsy in RB is a high-yield source of dsDNA, ssDNA, miRNA, and protein. Diagnostic samples are most useful for RB 1 gene mutational analyses. Genomic analysis may be more informative of tumor activity status than quantification alone and can be performed even with smaller analyte concentrations obtained from TX samples. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

Necrotic Eruption of an Inflammatory Melanoma.

This case report describes a vitreous eruption of a choroidal melanoma in a patient aged 64 years who presented with blurry vision.

Diagnostic Confirmation of Choroidal Lymphoma by Anterior Chamber Paracentesis and Aqueous Fluid Flow Cytometry.

PURPOSE: To report the clinical course of patients with diagnostic confirmation of choroidal lymphoma by anterior chamber paracentesis and aqueous fluid flow cytometry. METHODS: Single-center case series. RESULTS: Two patients with choroidal thickening were suspected to have choroidal lymphoma based on clinical findings and ultrasonographic evidence of extrascleral extension. In each case, anterior chamber paracentesis was performed due to the observation of the associated anterior chamber reaction. Flow cytometry detected the presence of a clonal B-cell population consistent with non-Hodgkin's lymphoma. In one case, external beam radiation therapy resulted in a complete therapeutic response. More invasive methods of ocular tissue biopsy were avoided. CONCLUSIONS: Definitive diagnosis in suspected cases of choroidal lymphoma remains challenging. Ocular fluid sampling may be a low morbidity and convenient alternative for confirming a suspected diagnosis in cases associated with cellular infiltration of the intraocular fluids.

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.

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.

Identification of Metastatic Conjunctival Squamous Cell Carcinoma through Neck Palpation.

An 80-year-old male with a distant 10 pack-years smoking history and squamous cell carcinoma (SCCA) of the scalp diagnosed 15 years ago presented with a new right nasal bulbar conjunctival lesion found to be invasive SCCA. The patient was started on interferon alfa-2b for 5 months until there was no evidence of residual disease. During a follow-up visit 10 months after diagnosis and during routine ophthalmic follow-up, an enlarged right submandibular lymph node was found through neck palpation and revealed to be SCCA without extranodal extension. The lesion was likely to have metastasized from his right conjunctival squamous cell carcinoma (CSCCA). Regional lymph nodes are a commonplace of metastasis for CSCCA making neck palpation a reasonable and recommended part of clinical examination to monitor for metastasis. This is the first known case of identifying regional metastasis of CSCCA through neck palpation.

PHOTODYNAMIC THERAPY FOR THE TREATMENT OF CHOROIDAL METASTASES: A Case Series and Meta-analysis.

PURPOSE: To investigate the efficacy and safety of photodynamic therapy (PDT) in the treatment of choroidal metastasis. METHODS: We conducted a systematic review of all reported cases of choroidal metastases treated with PDT in literature, and included the cases from our institution, for a comprehensive meta-analysis. RESULTS: We identified 52 tumors in 40 eyes of 34 patients. The mean age was 60 years (range 28-77). The mean tumor thickness was 1.9 mm (range 0-4.8 mm), whereas the mean largest basal diameter was 8.2 mm (range 1.5-30 mm) on presentation. After an average of 1.4 treatment visit, PDT resulted in decreased tumor thickness (mean 1.9 mm before vs. 1.0 mm after PDT, P < 0.0001) and decreased central macular thickness (mean 454 µm before vs. 289 µm after PDT, P = 0.03). After PDT, 82% of tumors had reduced thickness, and subretinal fluid resolved in 75% of eyes. Photodynamic therapy also resulted in stable or improved vision in 78% of treated eyes (logMAR 0.50 before vs. 0.56 after PDT, P = 0.54). No adverse events were reported, and PDT was effective in treating the most common choroidal metastases (tumor control rate of 94% in 16 lung adenocarcinoma and 92% in 26 breast carcinoma metastasis cases). CONCLUSION: Photodynamic therapy is effective at controlling tumors and preserving vision in patients with some choroidal metastases. Because of its minimal time commitment and good safety profile, PDT should be considered as a potential first-line treatment for small choroidal metastases.

Improved Prognostic Precision in Uveal Melanoma through a Combined Score of Clinical Stage and Molecular Prognostication.

Introduction: Prognosis of uveal melanoma (UM) is assessed using clinical staging or molecular testing. Two modalities often used for prognostication are the American Joint Committee on Cancer (AJCC) staging and a tumor gene expression profile (GEP), the outcomes of which are often discordant. This article discusses a total risk score created to combine the discordant information from both sources. Methods: A retrospective case series was conducted of all patients presenting with UM over 6 years to 2 referral centers. Each tumor was classified using the AJCC and the GEP. A total risk score was calculated for each patient using results from both AJCC and GEP. Kaplan-Meier analysis of metastasis-free survival was used to compare groups. Results: A total of 294 patients were included in the study. Kaplan-Meier estimates showed significant curve separation between individual AJCC and GEP risk groups. The combined total risk score provided an accurate estimate of prognosis that incorporated results from both AJCC and GEP. Conclusions: Clinical staging and molecular prognostication of UM can be discordant. There is important information provided by each system that is not provided by the other. The total risk score provides a simple method to combine information from both AJCC stage and the GEP class in order to provide patients and care teams with a more complete understanding of metastatic risk.

Uveal melanoma incidentally diagnosed with neuroimaging, a case series of 3 patients.

Uveal melanoma is the most common primary intraocular malignancy and can occur in the choroid, the ciliary body, or the iris. It is most often diagnosed based on clinical examination by an ophthalmologist. Nearly all patients present with visual symptoms. Characteristic findings on clinical examination include pigmented or pale choroidal masses with serous retinal detachments and acoustic hollowness seen with ocular ultrasonography. CT and MRI of the orbits are not traditionally utilized for the diagnosis of uveal melanoma. We present 3 cases in which uveal melanoma was an incidental finding on neuroimaging for unrelated conditions in asymptomatic patients. Radiologists should maintain a high suspicion for uveal melanoma when an intraocular mass of greater than 2 mm in thickness is seen on CT or MRI.

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.