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.

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.

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.

International travel to obtain medical treatment for primary retinoblastoma: A global cohort study.

Early diagnosis and treatment of retinoblastoma (Rb), the most common intraocular malignancy, can save both the child's life and vision. However, access to services and hence chances for survival and preserving the eye and its vision vary widely across the globe. Some families have to, or make a choice to, leave their home country to seek planned medical treatment abroad. We aimed to investigate how frequently this cross-border travel occurs and the factors associated with it. A total of 278 Rb centres in 153 countries were recruited to participate in a global cross-sectional analysis of newly diagnosed Rb patients in 2017. Number and proportions of children who travelled from their home country for treatment were analysed by country, continent, socioeconomic stratum and clinical and demographic features. The cohort included 4351 new patients of whom 223 [5.1%, 95% confidence interval 4.5-5.8] were taken across country borders for planned medical treatment. Independently significant predictors of travelling across borders included: being from a country with a smaller population, being from a country classified as low socioeconomic status, having bilateral Rb and having intraocular disease without extraocular spread. The factors that determine international travel for Rb treatment are complex and deserve further investigation. We may need to rethink the way services are delivered in the light of the threat of severe curtailment of international travel from pandemics like corona virus disease 2019.

Knowledge, attitude and practice of Ethiopian pediatricians concerning childhood eye diseases.

BACKGROUND: Eye examination and vision assessment are vital for the detection of conditions that result in blindness. Childhood blindness seriously impacts the development, education, and future employment opportunities of affected children. Pediatricians' knowledge of eye diseases is critical for the prevention of blindness through early diagnosis, allowing proper treatment and identification of conditions requiring referral to an ophthalmologist to preserve or restore vision. This study aimed to assess the knowledge, attitude, and practice of Ethiopian pediatricians concerning childhood eye diseases. METHODS: We carried out a cross-sectional descriptive study of pediatricians working in various hospitals and clinics in Ethiopia. Participants were selected via a convenient sampling technique. Data were collected using both closed and open-ended semi-structured questionnaires. Responses were entered into EpiData 3.1 and transferred to SPSS version 21.0 software for analysis. RESULTS: A total of 79 pediatricians participated in the study. Our findings showed that the attitude of all but 2 participants towards improving the management of childhood eye diseases was positive, even though this was not reflected in actual knowledge or practice. Even though attitudes were positive, knowledge was often poor and practice inadequate owing to barriers such as inadequate undergraduate training, lack of ophthalmology options during pediatric residency, and unavailability of ophthalmic equipment. CONCLUSIONS: Participants' attitudes towards improving treatment for childhood eye diseases are positive, but their insufficient knowledge of eye diseases makes their practice poor in this respect.

Number, frequency and time interval of examinations under anesthesia in bilateral retinoblastoma.

PURPOSE: Current practice in retinoblastoma (Rb) has transformed this malignancy into a curable disease. More attention should therefore be given to quality of life considerations, including measures related to examinations under anesthesia (EUAs). We aimed to investigate EUA measures in bilateral Rb patients and compare the findings to EUAs in unilateral Rb. METHODS: A retrospective analysis of bilateral Rb patients that presented to the London Rb service from 2006 to 2013, were treated and had long-term follow-up. RESULTS: A total of 62 Rb patients, 15 (24.2%) of which had International Intraocular Retinoblastoma Classification (IIRC) group A/B/no Rb at presentation, 26 (41.9%) C/D, and 21 (33.9%) were E in at least one eye. The mean number of EUAs was 35.8 ± 21.5, mean time from first to last EUA was 50.6 ± 19.9 months, and mean EUA frequency was 0.715 ± 0.293 EUAs/month. IIRC group was found not to correlate with any of the EUA measures. Age at presentation inversely correlated with time interval from first to last EUA and to EUA frequency (p ≤ 0.029). Rb family history correlated with the latter measure (p = 0.005) and intraophthalmic artery chemotherapy and brachytherapy correlated with all EUA measures (p ≤ 0.029). Mean follow-up time was 80.1 ± 24.3 months. When compared with a previously reported cohort of unilateral Rb, the present group underwent 3× more EUAs (p < 0.001) over nearly double the time (p < 0.001). CONCLUSIONS: Families should be counselled on anticipated EUA burden associated with bilateral Rb. In this respect, age at presentation and family history were found to have a predictive role, whereas IIRC group did not.

[UNUSUAL VITREOUS DETACHMENT].

INTRODUCTION: A 49 years old patient with a history of brachytherapy for choroidal melanoma was referred to the ocular emergency room for suspected recurrence due to pigment in the vitreous cavity. On examination, pigmented vitreous secondary to posterior vitreous detachment with traction from the atrophic tumor was observed with no evidence of recurrence.

[DEVELOPMENT AND CHALLENGES IN TREATMENT OF UVEAL MELANOMA].

INTRODUCTION: Uveal melanoma, the most common primary intraocular malignancy in adults, is potentially a lethal tumour. Since the development of local radiotherapy, tumour control is achieved in the majority of cases and most eyes are salvaged. Despite this, more than 50% of patients develop distant metastatic spread, mainly to the liver, and in the absence of efficient treatments to extend life, die soon after. A great deal of effort has been put into developing prognostic markers for metastatic spread and survival. Novel genetic prognostic tests, recently introduced, are now being clinically used in many ocular oncology centres worldwide. In addition, in most centres, patients are referred for systemic surveillance programs for early detection of liver metastasis. Novel treatment modalities to battle metastatic uveal melanoma are being developed and used in clinical trials. Their efficacy is yet to be proved. This review summarizes the recent developments and current challenges related to uveal melanoma management.

Evicel versus Tisseel versus Sutures for Attaching Conjunctival Autograft in Pterygium Surgery: A Prospective Comparative Clinical Study.

PURPOSE: To evaluate the outcome of pterygium surgery with conjunctival autograft using Vicryl sutures (Ethicon, NJ), Evicel fibrin glue (Omrix Biopharmaceuticals Ltd, Ramat-Gan, Israel), or Tisseel fibrin glue (Baxter Corp., Deerfield, IL). DESIGN: Prospective, randomized study. PARTICIPANTS: Eighty-nine adult patients with primary pterygium. METHODS: Patients undergoing pterygium surgery with conjunctival autografting were randomized into groups receiving 10-0 Vicryl sutures, Evicel fibrin glue, or Tisseel fibrin glue. MAIN OUTCOME MEASURES: Duration of surgery, level of patient discomfort, visual acuity (VA), surgically induced refractive change (SIRC), complications, and pterygium recurrence. RESULTS: Eighty-nine patients participated: 25 in the Vicryl group, 29 in the Evicel group, and 35 in the Tisseel group. The patients' preoperative characteristics were similar in all groups. Fashioning and repositioning of the conjunctival autograft (flap time) was significantly shorter in the fibrin glue groups compared with the Vicryl group: 5.46 minutes for Evicel, 3.6 minutes for Tisseel, and 16.72 minutes for sutures (P < 0.0001). The patient discomfort level during the first postoperative day was significantly lower in the fibrin glue groups compared with the suture group (P = 0.047). There were no significant group differences in the change in logarithm of the minimum angle of resolution VA before surgery and 3 months after surgery (P = 0.7). There were also no significant group differences in the SIRC (P = 0.108). The recurrence rate was 17.24% in the sutures group, 4.17% in the Evicel group, and 0% in the Tisseel group (P = 0.027 sutures vs. fibrin glue groups). Complications included 5 cases of conjunctival graft dislocation in the Evicel group, 1 case of pyogenic granuloma in the Tisseel group, and no complications in the sutures group (P = 0.019 sutures vs. fibrin glue groups). CONCLUSIONS: Tisseel fibrin glue for the repositioning of conjunctival autografts in pterygium surgery was associated with a similar functional outcome as that of Vicryl sutures in terms of VA and SIRC. Pterygium recurrence, patient discomfort level, and surgery time were reduced markedly, as were flap dislocation and pterygium recurrence with Tisseel fibrin glue compared with Evicel fibrin glue.

Alveolar Rhabdomyosarcoma of the foot metastasizing to the Iris: report of a rare case.

BACKGROUND: Intraocular iris rhabdomyosarcoma is extremely rare, and in the 3 cases reported to date occurred as the primary site of tumour growth. We report a case of rhabdomyosarcoma of the foot metastasizing to the iris. CASE PRESENTATION: An 18-year-old white female was referred to the London Ocular Oncology Service for management of a metastatic rhabdomyosarcomatous deposit in the iris, a metastasis from alveolar rhabdomyosarcoma of the foot. She was diagnosed nearly 2 years earlier with the primary sarcoma with extensive systemic spread and treated by resection of the foot lesion and chemotherapy, and achieved a partial remission. The left iris deposit was noted while she was receiving systemic chemotherapy, heralding a relapse. However, anterior uveitis and raised intraocular pressure developed and she was referred to our service for further management. A left iris secondary rhabdomyosarcoma deposit was noticed and in addition a lacrimal gland mass, as indicated by ultrasound B scan of the eye and orbit. The patient was treated with external beam radiotherapy to the globe and orbit, but died 2 months after treatment completion. CONCLUSION: Rhabdomyosarcoma of the iris is very rare and was previously documented only as a primary malignancy in this location. We report that secondary spread to the iris can also occur, in this case as the first sign of widely disseminated systemic relapse.

A biological tissue adhesive and dissolvent system for intraocular tumor plaque radiotherapy: an in vivo animal model experiment.

PURPOSE: To examine a novel biological adhesive and dissolvent system for plaque placement and removal using fibrin glue and urokinase, respectively, in an in vivo animal model. METHODS: The study was performed on 23 rabbit eyes. Of these, eight underwent a technical feasibility study and ultrasonographic plaque displacement measurements, nine were examined clinically and by magnetic resonance imaging and histopathology for tissue reaction to the biological substances used, and in six the impact of fibrin glue as an orbital space occupier on intraocular pressure was assessed. In an additional ex vivo experiment, the glue's radiation attenuating properties were tested using an oncology EDR2 film. RESULTS: Plaque horizontal movement throughout follow-up (7-10 days) was negligible (0.5 ± 0.2 mm), and there was no tilting whatsoever. In the tissue response experiment, no adverse effects were recorded after application of fibrin or urokinase throughout the 21-day follow-up period. Interestingly, a circumscribed local inflammatory response was noted in tissue surrounding the fibrin glue, and persisted at 21 days. In the orbital space-occupying experiment, application of 1 cc fibrin glue did not cause a significant elevation in intraocular pressure (IOP) (P = 0.06), and in the ex vivo experiment, there was no significant difference between radiation readings with and without glue separation of the radioactive sources and film (P = 0.065). CONCLUSIONS: The adhesive and dissolvent system was feasible and safe for plaque placement and removal. It may be superior to conventional surgical plaque placement methods in eliminating the relatively common risk of plaque tilting and complications due to scleral suturing.

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.

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.

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.

Diagnosis of posttraumatic stress disorder after surgery for primary rhegmatogenous retinal detachment.

PURPOSES: To investigate the prevalence of posttraumatic stress disorder (PTSD) in patients who underwent surgery for primary rhegmatogenous retinal detachment and to explore variables associated with the disorder. METHODS: Subjects eligible for the study were patients aged 18 years or older, who underwent surgery for primary rhegmatogenous retinal detachment at the Goldschleger Eye Institute, from January 1, 2004, to December 31, 2009, and were followed for at least 1 month. Study patients were screened for the existence of PTSD symptoms via a telephone survey, and positively identified patients were asked to undergo a structured psychiatric interview. Posttraumatic stress disorder was assessed by the Clinician Administered PTSD Scale, and the 25-item National Eye Institute visual function questionnaire (NEI-VFQ-25) was used as a measure of vision-related quality of life. Objective clinical measures were obtained from the patient's medical records. Clinical variables were compared between PTSD-diagnosed patients, patients who were screened for PTSD but were found to be PTSD negative in the interview (false-positive group), and patients who were found negative for PTSD in the screening survey. RESULTS: Of the 547 eligible patients, 366 were enrolled in the study. Nine patients (2.5%) met the criteria for PTSD diagnosis. Posttraumatic stress disorder patients reported significantly more traumatic events in their past (P = 0.015), and for these patients, NEI-VFQ-25 composite score was significantly lower (P < 0.001). Clinical measures were not found as independent risk factors for PTSD prediction. CONCLUSION: Posttraumatic stress disorder may develop in the aftermath of primary rhegmatogenous retinal detachment. Previous traumatic events and NEI-VFQ-25 scores were found as independent risk factors for PTSD prediction.

[Pseudopapilledema--optic disc drusen].

Optic disc drusen (ODD) are benign calcified deposits, which are located at the head of the optic disc. Most ODD patients are asymptomatic. Ocular complications, related to ODD, are considered rare. Optic disc drusen, especially if it is bilateral, may mimic the clinical presentation of papilledema. The clinical discrimination between ODD and papilledema may be a challenging task, and in many cases, especially in the pediatric population, an ocular ultrasound examination is needed. A fundus examination, in order to rule out papilledema, is a common daily task for the ophthalmologist and is considered perhaps the most common interface between pediatricians, neurologists, internal physicians and ophthalmologists. In this review, we focused on the pathogenesis, epidemiology, diagnosis and clinical implications of ODD.

[Congenital orbital teratoma].

Congenital orbital teratoma is a rare benign tumor, composed of all three germ cell layers. The Lesion presents clinically as uniLateral proptosis in the newborn. In order to diagnose the tumor correctly a multidisciplinary approach is needed, including ophthalmologists, neurosurgeons, pediatrics, radiologists, and pathologists to eventually diagnose the lesion. Early detection and treatment is needed in order to prevent mechanical destruction of adjacent tissues, and blindness from mechanical pressure on the optic nerve. Surgical excision is the treatment of choice. We present a case report of a newborn, diagnosed with congenital orbital teratoma, and discuss the clinical and histological characteristics of the tumor.