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

Global Retinoblastoma Presentation and Analysis by National Income Level.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs

The global retinoblastoma outcome study : a prospective, cluster-based analysis of 4064 patients from 149 countries

DATA SHARING : The study data will become available online once all analyses are complete.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. Enucleation 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% (52·1-63·0) 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.The Queen Elizabeth Diamond Jubilee Trust and the Wellcome Trust.https://www.thelancet.com/journals/langlo/homeam2023Paediatrics and Child Healt

Retinoblastoma: Etiology, Modeling, and Treatment

Retinoblastoma is a retinal cancer that is initiated in response to biallelic loss of RB1 in almost all cases, together with other genetic/epigenetic changes culminating in the development of cancer. RB1 deficiency makes the retinoblastoma cell-of-origin extremely susceptible to cancerous transformation, and the tumor cell-of-origin appears to depend on the developmental stage and species. These are important to establish reliable preclinical models to study the disease and develop therapies. Although retinoblastoma is the most curable pediatric cancer with a high survival rate, advanced tumors limit globe salvage and are often associated with high-risk histopathological features predictive of dissemination. The advent of chemotherapy has improved treatment outcomes, which is effective for globe preservation with new routes of targeted drug delivery. However, molecularly targeted therapeutics with more effectiveness and less toxicity are needed. Here, we review the current knowledge concerning retinoblastoma genesis with particular attention to the genomic and transcriptomic landscapes with correlations to clinicopathological characteristics, as well as the retinoblastoma cell-of-origin and current disease models. We further discuss current treatments, clinicopathological correlations, which assist in guiding treatment and may facilitate globe preservation, and finally we discuss targeted therapeutics for future treatments

Endogenous panophthalmitis in a patient with COVID-19 during hospitalization in an intensive care unit: A case report

Purpose: To report a case of endogenous panophthalmitis in a patient with COVID-19 during treatment in an Intensive Care Unit. Observation: A 64‐year‐old woman with COVID-19 and Salmonella septicemia presented with decreased visual acuity, ocular pain, and proptosis in her right eye after treatment with favipiravir, intravenous dexamethasone, and ceftriaxone. An ocular examination of her right eye revealed periorbital tenderness, exophthalmos, and corneal haze. The ultrasonography showed a subretinal abscess. Her right eye lost light perception vision and underwent enucleation. Microbiologic evaluation of the enucleated right eye was negative for organisms. Conclusions and importance: Patents with COVID-19 may develop severe ocular involvement after COVID-19 due to a generalized reduction in immunity. Comorbidities and intensive care unit treatments can predispose COVID-19 patients to endogenous panophthalmitis

Chiasmal Migration of Intraocular Silicone Oil

To report a rare neuronal complication of long-term intraocular silicone oil

A three-dimensional organoid model recapitulates tumorigenic aspects and drug responses of advanced human retinoblastoma

Abstract Persistent or recurrent retinoblastoma (RB) is associated with the presence of vitreous or/and subretinal seeds in advanced RB and represents a major cause of therapeutic failure. This necessitates the development of novel therapies and thus requires a model of advanced RB for testing candidate therapeutics. To this aim, we established and characterized a three-dimensional, self-organizing organoid model derived from chemotherapy-naïve tumors. The responses of organoids to drugs were determined and compared to relate organoid model to advanced RB, in terms of drug sensitivities. We found that organoids had histological features resembling retinal tumors and seeds and retained DNA copy-number alterations as well as gene and protein expression of the parental tissue. Cone signal circuitry (M/L+ cells) and glial tumor microenvironment (GFAP+ cells) were primarily present in organoids. Topotecan alone or the combined drug regimen of topotecan and melphalan effectively targeted proliferative tumor cones (RXRγ+ Ki67+) in organoids after 24-h drug exposure, blocking mitotic entry. In contrast, methotrexate showed the least efficacy against tumor cells. The drug responses of organoids were consistent with those of tumor cells in advanced disease. Patient-derived organoids enable the creation of a faithful model to use in examining novel therapeutics for RB

Clinical Presentations and Outcomes of Retinoblastoma Patients in relation to the Advent of New Multimodal Treatments: A 12-Year Report from Single Tertiary Referral Institute in Thailand

Purpose. To investigate the clinical presentations and outcomes of retinoblastoma in relation to the advent of new multimodal treatments in Thailand. Patients and Methods. Retrospective case series. We evaluated the clinical presentation, staging, details of treatment, and treatment outcomes of retinoblastoma patients who were treated at Ramathibodi Hospital, Bangkok, Thailand, between January 1, 2007, and December 31, 2018. The log-rank test was used to explore clinical characteristics and treatment modalities that affected globe salvage and survival curves. Results. This study included 124 eyes of 81 patients with retinoblastoma. Forty-three patients (53.1%) had bilateral retinoblastoma. The median age at diagnosis was 8 months (range, 1–48 months). Of 124 eyes, 9 eyes (7.3%) had extraocular retinoblastoma and 115 eyes (92.7%) had intraocular retinoblastoma, which were classified by the International Classification of Retinoblastoma (ICRB) as group A, 4 eyes (3.5%); group B, 19 eyes (16.5%); group C, 6 eyes (5.2%); group D, 31 eyes (27%); and group E, 56 eyes (47.8%). Treatment included systemic chemotherapy, intra-arterial chemotherapy, ruthenium-106 plaque brachytherapy, external beam radiation therapy, cryotherapy, transpupillary thermotherapy, subtenon chemotherapy, and intravitreal chemotherapy. At the median follow-up period of 38.4 months (range, 0.2–148.2 months), the overall globe salvage rate of intraocular retinoblastoma was 51.7%. For unilateral retinoblastoma, globe salvage rate was 37.5% (group B, 100%; group C, 100%; group D, 50%; and group E, 18.8%). For bilateral intraocular retinoblastoma, the globe salvage rate was 57.8% (group A, 100 %; group B, 94.4%; group C, 100%; group D, 64.7%; and group E, 28.2%). The overall survival rate was 93.8%. Conclusions. Recent advanced treatment modalities have improved the probability of globe salvage. However, enucleation remains an important life-saving intervention in many advanced cases

INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR INJECTIONS FOR EXUDATIVE RETINAL ARTERIAL MACROANEURYSMS

Purpose: There is no established therapy for exudative-hemorrhagic complications in primary retinal arteriolar macroaneurysm (RAM)

The Global Retinoblastoma Outcome Study: a prospective, cluster-based analysis of 4064 patients from 149 countries

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.Y