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Aim: To investigate whether the American Joint Committee on Cancer (AJCC) clinical category cT2b needs to be subclassified by the type and distribution of retinoblastoma (RB) seeding., Methods: Multicentre, international registry-based data were collected from RB centres enrolled between January 2001 and December 2013. 1054 RB eyes with vitreous or subretinal seeds from 18 ophthalmic oncology centres, in 13 countries within six continents were analysed. Local treatment failure was defined as the use of secondary enucleation or external beam radiation therapy (EBRT) and was estimated with the Kaplan-Meier method., Results: Clinical category cT2b included 1054 eyes. Median age at presentation was 16.0 months. Of these, 428 (40.6%) eyes were salvaged, and 430 (40.8%) were treated with primary and 196 (18.6%) with secondary enucleation. Of the 592 eyes that had complete data for globe salvage analysis, the distribution of seeds was focal in 143 (24.2%) and diffuse in 449 (75.8%). The 5-year Kaplan-Meier cumulative globe-salvage (without EBRT) was 78% and 49% for eyes with focal and diffuse RB seeding, respectively. Cox proportional hazards regression analysis confirmed a higher local treatment failure risk with diffuse seeds as compared with focal seeds (hazard rate: 2.8; p<0.001). There was insufficient evidence to prove or disprove an association between vitreous seed type and local treatment failure risk(p=0.06)., Conclusion: This international, multicentre, registry-based analysis of RB eyes affirmed that eyes with diffuse intraocular distribution of RB seeds at diagnosis had a higher risk of local treatment failure when compared with focal seeds. Subclassification of AJCC RB category cT2b into focal vs diffuse seeds will improve prognostication for eye salvage., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To describe the clinical and molecular spectrum of Stargardt disease (STGD) in a cohort of Argentinean patients., Methods: This retrospective study included 132 subjects comprising 95 probands clinically diagnosed with STGD and relatives from 16 of them. Targeted next-generation sequencing of the coding and splicing regions of ABCA4 and other phenocopying genes ( ELOVL4 , PROM1 , and CNGB3 ) was performed in 97 STGD patients., Results: We found two or more disease-causing variants in the ABCA4 gene in 69/95 (73%) probands, a single ABC A4 variant in 9/95 (9.5%) probands, and no ABCA4 variants in 17/95 (18%) probands. The final analysis identified 173 variants in ABCA4 . Seventy-nine ABCA4 variants were unique, of which nine were novel. No significant findings were seen in the other evaluated genes., Conclusion: This study describes the phenotypic and genetic features of STGD1 in an Argentinean cohort. The mutations p.(Gly1961Glu) and p.(Arg1129Leu) were the most frequent, representing almost 20% of the mutated alleles. We also expanded the ABCA4 mutational spectrum with nine novel disease-causing variants, of which eight might be associated with South American natives., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mena, Moresco, Vidal, Aguilar-Cortes, Obregon, Fandiño, Sendoya, Llera and Podhajcer.)

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.

Importance: Multi-institutional collaborative studies that include large patient populations for the management of retinoblastoma with histopathological risk factors could provide important information for patient management., Objective: To evaluate the implementation of a strategy for the management of nonmetastatic unilateral retinoblastoma in children based on standardized diagnostic and treatment criteria., Design, Setting, and Participants: This single-arm prospective study applied a strategy based on a single-center experience. The setting was a multicenter study in Latin America (Grupo de America Latina de Oncologia Pediatrica [GALOP]). Participants were children with nonmetastatic unilateral retinoblastoma (staged with the International Retinoblastoma Staging System). The study opened on July 1, 2008, and closed on December 31, 2014. Follow-up was updated until June 30, 2017., Interventions: Stage 0 patients (without enucleation) were given conservative therapy without a protocol. Stage I patients (with enucleation and no residual tumor) were divided into a high-risk group (retrolaminar invasion and/or scleral invasion) and a low-risk group (all remaining patients). High-risk children received adjuvant chemotherapy with 4 alternating cycles of regimen 1 (cyclophosphamide [65 mg/kg/d] [plus sodium-2-mercaptoethane sulfonate], idarubicin hydrochloride [10 mg/m2/d], and vincristine sulfate [0.05 mg/kg/d]) and 4 cycles of regimen 2 (carboplatin [500 mg/m2/d, days 1 and 2] and etoposide [100 mg/m2/d, days 1-3]). Low-risk children did not receive adjuvant therapy. Children with buphthalmia received neoadjuvant and adjuvant chemotherapy for a total of 8 cycles., Main Outcomes and Measures: Probability of event-free survival (extraocular relapse and death from any cause were considered events)., Results: Among 187 children registered in the study, 175 were evaluable (92 [52.5%] female; median age, 22 months; age range, 3-100 months). Forty-two were stage 0 children, 84 were stage I low-risk children, and 42 were stage I high-risk children; there were 7 children in the buphthalmia group. With a median follow-up of 46 months, the 3-year probability of event-free survival was 0.97 (95% CI, 0.94-0.99), and the probability of overall survival was 0.98 (95% CI, 0.94-1.00). Stage 0 patients had no events, stage I low-risk patients had 1 event (orbital relapse treated with second-line therapy), stage I high-risk patients had 2 events (1 central nervous system relapse and 1 death from sepsis), and the buphthalmia group had 1 event (orbital relapse, followed by central nervous relapse and death)., Conclusions and Relevance: Adjuvant therapy may be effective for high-risk unilateral retinoblastoma but is toxic, and neoadjuvant chemotherapy for buphthalmus appears feasible.

Competing Interests: Authors' disclosures of potential conflicts of interest and contributions are found at the end of this article.The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. Guillermo L. ChantadaNo relationship to discloseIra J. DunkelConsulting or Advisory Role: Bristol-Myers Squibb, Ipsen, Esai Research Funding: Bristol-Myers Squibb (Inst), Genentech (Inst), GlaxoSmithKline (Inst)Paula S. SchaiquevichNo relationship to discloseEdith L. GrynszpancholcNo relationship to discloseJasmine FrancisNo relationship to discloseAlejandro CecilianoNo relationship to disclosePedro A. ZubizarretaNo relationship to discloseAdriana C. FañdinoNo relationship to discloseDavid H. AbramsonNo relationship to disclose

Background: Few studies were reported from developing countries regarding patient outcome and ocular survival in children with bilateral retinoblastoma treated with chemoreduction compared to external beam radiotherapy (EBRT)., Procedure: We undertook a retrospective study of three treatment eras: (1) (1988-1995) n = 68 when EBRT was used as primary conservative therapy; (2) (1995-2003) n = 46 when carboplatin-based systemic chemoreduction was introduced and (3) (2003-2009) (n = 83) when additional periocular chemotherapy was added for advanced tumors and pre-enucleation chemotherapy was given for those with massive buphthalmia., Results: The probability of 5-year disease-free survival was 0.94 (95% confidence interval [CI] 0.91-0.98%) without significant differences among the three eras. Chemoreduction reduced the use of EBRT from 84.6% to 68.7% in eras 1 and 3, respectively (P = 0.008), which was more evident in cases with less advanced disease. Chemoreduction also significantly improved the 5-year probability of preservation of eyes with advanced disease from 0.13 (95% CI 0.04-0.27) during era 1 to 0.49 (95% CI 0.34-0.62) in era 3 (P < 0.0001). Chemoreduction was not associated with changes in the probability of extraocular relapse, which was reduced after the introduction of pre-enucleation chemotherapy. Second malignancies occurred in nine cases, acute myeloid leukemia being the most fatal one. Trilateral retinoblastoma occurred in three cases and all of them had been exposed to chemotherapy., Conclusions: Chemoreduction reduced the need for EBRT in eyes with less advanced disease and improved the preservation of eyes with advanced disease while its effects on secondary malignancies or trilateral disease remain unclear., (© 2013 Wiley Periodicals, Inc.)

Background: Few prospective studies about the management of unilateral retinoblastoma with pathology risk factors (PRFs) have been published., Methods: Patients (n = 114) were divided into four groups: Group 1 (initial chemoreduction) (n = 17). Groups 2 and 3, included patients initially enucleated with no, or lower risk PRFs: (n = 65) and with higher risk PRFs (n = 30), respectively. The later included postlaminar optic nerve involvement (PLONI) (n = 23), tumor at resection margin of optic nerve (n = 5) or isolated scleral invasion (n = 2). Group 3 received adjuvant chemotherapy including a total eight cycles of carboplatin and etoposide, alternating with cyclophosphamide, idarubicin, and vincristine. Orbital radiotherapy (45 Gy) was given to patients with invasion to the resection margin. Group 4 included patients with metastatic disease (n = 2). They were given neoadjuvant therapy followed by surgery and high-dose chemotherapy and autologous stem cell rescue., Results: Five-year event-free survival is 0.94 (1 for Group 1, 0.94 for Group 2, 0.96 for Group 3, and 0 for Group 4). Events included. Group 2: Systemic relapse (n = 2) and combined orbital and CNS relapse (n = 1). Relapsing patients had PLONI (n = 2) and isolated focal choroidal invasion (n = 1). Group 3: CNS relapse (n = 1) in a patient with tumor at the resection margin of optic nerve. Group 4: CNS relapse (n = 2). Only one relapsed patient survived. Eight of 17 eyes treated conservatively were preserved., Conclusions: The survival of patients with unilateral retinoblastoma was excellent and 60% were spared from adjuvant treatment. Our intensive regimen was likely to be effective for prevention of metastasis in patients with higher risk PRFs.

Purpose. Intravenous or periocular topotecan has been proposed as new treatment modality for patients with advanced intraocular retinoblastoma, but systemic topotecan lactone exposure induced by both approaches may cause toxicity. The purpose of this study was to develop a topotecan-loaded ocular delivery system to minimize systemic exposure and achieve selective transscleral penetration. Methods. Biocompatible polymer implants containing low (0.3 mg) or high (2.3 mg) topotecan load were manufactured and characterized in vitro. Adrenaline (500 mug) was coloaded to induce local vasoconstriction in vivo in 2 of 4 animal groups. Implants were inserted into the episclera of rabbits, and topotecan (lactone and total) concentrations in ocular tissues and plasma were determined over a period of 48 hours. Results. In vitro, implants released 30% to 50% of the loaded drug within 48 hours and 45% to 70% by day 10. In vivo, topotecan lactone was highly accumulated in locally exposed ocular tissues (ranging from 10(5) to 10(6) ng/g in sclera and choroid and 10(2) to10(3) ng/g in retina) over 48 hours with all the formulations studied. Low vitreous topotecan lactone levels (approximately 5 ng/mL) were found in animals receiving concomitant local vasoconstriction and high load implants. Topotecan lactone concentrations in plasma and in contralateral eyes were minimal or undetectable as a marker of tissue selectivity of the proposed strategy. Conclusions. These studies may contribute to improving the efficacy and safety of chemotherapy treatments for retinoblastoma and may support the role of the local vasculature and tissues promoting drug clearance and local accumulation during transscleral drug delivery.

Background: There is little information on the outcome of patients with retinoblastoma and tumor at the resection margin of the optic nerve., Procedure: Retrospective evaluation of three successive prospective protocols. Twenty-six consecutive patients were analyzed (International Staging System-IRSS-stage 2 = 21, stage 3 = 5) from three successive prospective protocols (1988-2006). Patients with stage 2 were enucleated upfront and those with stage 3 had neoadjuvant chemotherapy followed by enucleation and adjuvant therapy. Both groups received adjuvant chemotherapy and orbital radiotherapy after enucleation. Patients in protocol 1 received 1 year of the lower-dose chemotherapy regimen including cyclophosphamide, vincristine and doxorubicin along with intrathecal chemotherapy. Patients of protocols 2 and 3 received a more intense and shorter intravenous regimen including carboplatin and etoposide alternating with cyclophosphamide, idarubicin and vincristine with no intrathecal treatment. The components of protocol 2 and 3 were similar except for the dose of carboplatin which was 10% lower in protocol 3., Results: Thirteen were treated in protocol 1 and 13 in protocols 2 and 3. The probability of event-free survival was 0.70 at 5 years. Events included: CNS relapse = 3, second malignancies = 3, death in complete remission = 2. There were no significant differences in outcome between protocols or stages. Endocrinological disturbances related to the hypothalamus-hypophysis axis were evident in 6/8 patients evaluated. Severe orbital sequelae occurred in 12 cases., Conclusions: A substantial number of patients with tumor at the resection margin of the optic nerve can be cured with current therapy; however, therapy related sequelae are frequent., ((c) 2008 Wiley-Liss, Inc.)

Purpose: To evaluate the outcome of patients with retinoblastoma and postlaminar optic nerve invasion (PLONI)., Design: Retrospective interventional case series., Participants: Sixty-one consecutive patients included in 3 successive protocols were analyzed., Methods: Pathologic review was done in each case. Patients were stratified into 2 risk groups: the high-risk group included those with concomitant full choroidal and/or scleral invasion and were given adjuvant chemotherapy. Those without these features were considered low risk and chemotherapy was withheld after 1994., Main Outcome Measures: Extraocular relapse and survival according to stratification., Results: The probability of event-free survival (pEFS) was 0.91 and the probability of overall survival (pOS) was 0.94 at 5 years. Patients in the high-risk group (n = 22) had pEFS of 0.86. Three had extraocular relapse (involving the central nervous system; all died of disease). Microscopic scleral invasion was associated to extraocular relapse (P = 0.05). Lower risk patients (n = 39) had a pEFS of 0.94 and pOS of 1. Eighteen received postenucleation chemotherapy and none relapsed. Twenty-one received no adjuvant therapy and 2 had a systemic relapse but were successfully retrieved. Relapsing patients had a higher ratio of affected optic nerve (>25% of it overall length; P = 0.02)., Conclusions: Patients with PLONI have an excellent outcome with current therapy. Risk stratification according to the presence of concomitant choroidal and/or scleral invasion may help in the decision of giving adjuvant therapy.

Objective: To assess the outcome and determine risk factors for extraocular relapse in patients with retinoblastoma who had been enucleated after failure of chemoreduction., Methods: Retrospective study (1995-2002) at three institutions. Pathological risk factors (PRF) were defined as invasion of the anterior segment, choroid, post-laminar optic nerve, subarachnoid space, or sclera according to the local pathology report. Extraocular relapse was defined as an event., Results: One hundred twenty-two patients were included (17 had bilateral enucleation). Chemoreduction included vincristine, carboplatin, and etoposide (n=80, 65.6%), vincristine, and carboplatin (n=17, 13.9%), or carboplatin (n=25, 20.5%). Thirty-five also received external beam radiotherapy (28.7%). PRF included: 39 with choroidal involvement, 9 with anterior segment, 9 with scleral, and 2 with post-laminar optic nerve with subarachnoid invasion. Adjuvant chemotherapy was given to eight patients (6.5%) because of scleral invasion. Four patients had an extraocular relapse after enucleation, two of whom survive after intensive treatment including stem cell rescue. Five-year probability of event-free survival is 0.96. Only scleral invasion and bilateral enucleation were significantly associated with extraocular relapse., Conclusions: The risk of extraocular relapse is low after enucleation following failure of chemoreduction. Patients who underwent bilateral enucleation and those with scleral invasion are at higher risk of extraocular relapse., (Copyright (c) 2006 Wiley-Liss, Inc.)

Purpose: To determine the extent and the mechanism by which topotecan, a candidate agent for the treatment of retinoblastoma, gains access to the vitreous when administered by periocular injection or intravenous infusion., Methods: In vivo experiments were conducted in which albino rabbits received 1 mg topotecan by periocular injection (POI group; n = 30) or as a 30-minute intravenous infusion (IV group; n = 16). Plasma and vitreal topotecan concentrations were analyzed during the 10 hours after administration. A population pharmacokinetic model was fit to the data. Additionally, periocular injections were performed postmortem to study the effect of removing the blood vasculature barrier., Results: Potentially active lactone topotecan levels were detected in the vitreous in the POI and IV groups. Both administration schedules induced high total topotecan plasma exposures because of absorption from the periocular depot, though plasma lactone area under the curve (AUC) was significantly higher in the IV group. Similar vitreal concentrations were found in treated and control eyes in the POI group. The transfer from the periocular compartment to the vitreous was negligible. The absence of drug levels in the control eye of the postmortem-injected rabbits confirmed the systemic delivery of topotecan. Local toxicity was not observed., Conclusions: As a consequence of a favored passage across the blood-retinal barrier, considerable topotecan vitreous levels were detected in a rabbit model after systemic or periocular administration. Transscleral entry in vivo was constrained by rapid clearance from the administration site.

Background: Chemoreduction is used for the treatment of retinoblastoma in industrialized nations; however, there are fewer data from developing countries. Before the implementation of this program, radiotherapy was used in almost all preserved eyes., Methods: Retrospective evaluation from 1995 to 2001 at the Hospital Garrahan (Argentina). Carboplatin 18.7 mg/kg/day 1 and vincristine (0.05 mg/kg/day 1) were offered to patients with Reese-Ellsworth (RE) groups I-III and all unilateral cases. Etoposide (3.3 mg/kg/day 1 and 2) was added for groups IV and V. The number of cycles was tailored according to response., Results: Fifty-eight patients (78 eyes) were evaluated (39 bilateral, 19 unilateral). With a median follow-up of 47 months, 40 patients had unilateral enucleation, 14 were not enucleated, and 4 had bilateral enucleation. Nineteen patients had unilateral initial enucleation. Eye preservation at 5 years was: RE groups I-III (n = 24 eyes), 0.9 (SE: 0.095) IV-V (n = 54), 0.45 (SE 0.07). Patients received a median of four cycles of chemotherapy. Acute toxicity was mild. External beam radiotherapy was avoided in 41% of eyes with groups I-III. Etoposide was avoided in 24 patients. Two patients died of metastasis. No secondary malignancy occurred., Conclusions: Compared to our previous experience, eye preservation was better and even though less radiotherapy was used, it was prescribed more often than currently recommended in eyes with less advanced disease because of limited availability of sophisticated local therapy., (2004 Wiley-Liss, Inc.)

Purpose: To report our experience with topotecan in children with relapsed/refractory metastatic and intraocular retinoblastoma., Patients and Methods: Topotecan was administered intravenously as a 30-min infusion at a dose of 2 mg/m2/d for five consecutive days and repeated after three weeks. If obvious progression was detected by physical examination in patients with overt extraocular disease or if progressive disease was noted after fundoscopic examination in patients with intraocular disease, a second cycle was not administered. Response was evaluated at Week 6., Results: Nine patients (6 extraocular, 3 intraocular) were treated from November 1998 to March 2002. A total of 16 cycles were administered. In patients with extraocular disease, there were three partial responses, two cases of stable disease, and one case of progressive disease. Two patients with relapsed/resistant intraocular disease had partial response. allowing local therapy to be performed, and the third patient had progressive disease. The drug was well-tolerated. No patient developed fever or documented infections. No other serious toxicity was found., Conclusion: Topotecan is active in extraocular and relapsed/resistant intraocular retinoblastoma. The role of this drug in the treatment of retinoblastoma should be explored in further studies.

Background: Intravenous etoposide is widely used in multiagent chemotherapy regimens for intraocular retinoblastoma despite the lack of phase II data documenting its efficacy. Because oral etoposide has been found to be highly effective in patients with relapsed medulloblastoma and neuroblastoma who had previously received intravenous etoposide, we investigated its use for intraocular retinoblastoma., Procedure: A pilot trial of oral etoposide (50 mg/m2/ day for 21 days) in five children (6 eyes) with relapsed refractory intraocular retinoblastoma was performed. All had previously received chemotherapy, including intravenous etoposide in four patients, and all had received radiation therapy. Three patients (3 eyes) had vitreous seeds. Response was evaluated after one cycle., Results: No serious acute toxicity was encountered, and no responses were noted. Four patients (5 eyes) had progressive disease. Stable disease was noted in one eye without vitreous disease. One patient developed secondary acute myeloid leukemia 30 months after exposure to oral etoposide., Conclusions: Oral etoposide was not an effective agent in this population. The role of etoposide in the treatment of higher risk intraocular retinoblastoma deserves further study.