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To study the long-term efficacy of intravitreal topotecan (IVT) for vitreous seeds in eyes with retinoblastoma and risk factors for their recurrence. Retrospective, non-comparative, interventional study. Ninety-one eyes of 90 patients with retinoblastoma treated between January 2013 and April 2019. Patients with recurrent or refractory vitreous seeds after completion of intravenous or intra-arterial chemotherapy were treated with IVT (30 μg/0.15 ml) by the safety-enhanced technique. The injection was repeated every 4 weeks until the regression of seeds. Patients with a minimum follow-up of 12 months were included in the analysis. Primary outcome measures were vitreous seed regression and eye salvage. Secondary outcomes were risk factors for vitreous seed recurrence after treatment with IVT, vision salvage, and complications of IVT. The median age of the patients was 18 months, with most having group D (n = 58 [64%]) and group E (n = 26 [29%]) retinoblastoma. Vitreous seeds were refractory in 46 eyes (51%) and recurrent in 45 eyes (49%). A total of 317 IVT injections were administered, with the median being 3 injections. The median number of IVT injections required was 2.5 injections for dust, 3 injections for sphere, and 5 injections for cloud morphologic features. Recurrence of vitreous seeds after IVT was seen in 17 eyes (19%) at a mean follow-up of 7.9 months. At a mean follow-up 34 months, vitreous seed regression was achieved in 88 eyes (97%) and eye salvage was achieved in 77 eyes (85%). Older age (P = 0.018) and recurrence of retinal tumor (15/17 eyes; P < 0.01) significantly increased the risk of vitreous seed recurrence. Cataract was the most common complication seen in 17 eyes (9%). Intravitreal topotecan at an every 3- to 4-week regimen is effective against both refractory and recurrent vitreous seeds. The vitreous seed morphologic features correspond to the number of injections required for regression. Increasing age and recurrence of retinal tumor increase the risk of vitreous seed recurrence after treatment with IVT. The author(s) have no proprietary or commercial interest in any materials discussed in this article. [ABSTRACT FROM AUTHOR]

To describe the clinical presentation and treatment outcomes of children who received a diagnosis of retinoblastoma in 2017 throughout Asia. Multinational, prospective study including treatment-naïve patients in Asia who received a diagnosis of retinoblastoma in 2017 and were followed up thereafter. A total of 2112 patients (2797 eyes) from 96 retinoblastoma treatment centers in 33 Asian countries. Chemotherapy, radiotherapy, enucleation, and orbital exenteration. Enucleation and death. 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. 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. The author(s) have no proprietary or commercial interest in any materials discussed in this article. [ABSTRACT FROM AUTHOR]

PurposeTo determine the usefulness of a comprehensive, targeted-capture next-generation sequencing (NGS) assay for the clinical management of children undergoing enucleation for retinoblastoma.DesignCohort study.ParticipantsThirty-two children with retinoblastoma.MethodsWe performed targeted NGS using the UCSF500 Cancer Panel (University of California, San Francisco, San Francisco, CA) on formalin-fixed, paraffin-embedded tumor tissue along with constitutional DNA isolated from peripheral blood, buccal swab, or uninvolved optic nerve. Peripheral blood samples were also sent to a commercial laboratory for germline RB1 mutation testing.Main outcome measuresPresence or absence of germline RB1 mutation or deletion, tumor genetic profile, and association of genetic alterations with clinicopathologic features.ResultsGermline mutation or deletion of the RB1 gene was identified in all children with bilateral retinoblastoma (n = 12), and these NGS results were 100% concordant with commercial germline RB1 mutation analysis. In tumor tissue tested with NGS, biallelic inactivation of RB1 was identified in 28 tumors and focal MYCN amplification was identified in 4 tumors (2 with wild-type RB1 and 2 with biallelic RB1 inactivation). Additional likely pathogenic alterations beyond RB1 were identified in 13 tumors (41%), several of which have not been reported previously in retinoblastoma. These included focal amplifications of MDM4 and RAF1, as well as damaging mutations involving BCOR, ARID1A, MGA, FAT1, and ATRX. The presence of additional likely pathogenetic mutations beyond RB1 inactivation was associated with aggressive histopathologic features, including higher histologic grade and anaplasia, and also with both unilateral and sporadic disease.ConclusionsComprehensive NGS analysis reliably detects relevant mutations, amplifications, and chromosomal copy number changes in retinoblastoma. The presence of genetic alterations beyond RB1 inactivation correlates with aggressive histopathologic features.

To report the clinical and imaging findings of 4 patients with benign intraretinal tumors, 2 of which were associated with retinal pigment epithelium (RPE) hypertrophy. To our knowledge, this condition has not been described previously and should be distinguished from retinoblastoma and other malignant retinal neoplasms. Retrospective case series. Four patients from 3 institutions. Four patients with intraretinal tumors of the inner nuclear layer (INL) underwent a combination of ophthalmic examination, fundus photography, fluorescein angiography, OCT, OCT angiography, and whole exome sequencing. Description of multimodal imaging findings and systemic findings from 4 patients with benign intraretinal tumors and whole exome studies from 3 patients. Six eyes of 4 patients 5, 13, 32, and 27 years of age were found to have white intraretinal tumors that remained stable over the follow-up period (range, 9 months–4 years). The tumors were unilateral in 2 patients and bilateral in 2 patients. The tumors were white, centered on the posterior pole, and multifocal, with some consisting of multiple lobules with arching extensions that extended beyond the central tumor mass. OCT demonstrated these lesions to be centered within the INL at the border of the inner plexiform layer. In addition, 2 patients demonstrated congenital hypertrophy of the RPE (CHRPE) lesions. Three of 4 patients underwent whole exome sequencing of the blood that revealed no candidate variants that plausibly could account for the phenotype. We characterize a novel benign tumor of the INL that, in 2 patients, was associated with separate CHRPE lesions. We propose the term benign lobular inner nuclear layer proliferation to describe these lesions. Proprietary or commercial disclosure may be found after the references. [ABSTRACT FROM AUTHOR]

To investigate the prevalence and magnetic resonance imaging (MRI) phenotype of retinoblastoma-associated orbital cellulitis. Additionally, this study aimed to identify postlaminar optic nerve enhancement (PLONE) patterns differentiating between inflammation and tumor invasion. A monocenter cohort study assessed the prevalence of orbital cellulitis features on MRI in retinoblastoma patients. A multicenter case–control study compared MRI features of the retinoblastoma-associated orbital cellulitis cases with retinoblastoma controls. A consecutive retinoblastoma patient cohort of 236 patients (311 eyes) was retrospectively investigated. Subsequently, 30 retinoblastoma cases with orbital cellulitis were compared with 30 matched retinoblastoma controls without cellulitis. In the cohort study, retinoblastoma MRI scans were scored on presence of inflammatory features. In the case–control study, MRI scans were scored on intraocular features and PLONE patterns. Postlaminar enhancement patterns were compared with histopathologic assessment of postlaminar tumor invasion. Interreader agreement was assessed, and exact tests with Bonferroni correction were adopted for statistical comparisons. Prevalence of retinoblastoma-associated orbital cellulitis on MRI was calculated. Frequency of intraocular MRI features was compared between cases and controls. Sensitivity and specificity of postlaminar optic nerve patterns for detection of postlaminar tumor invasion were assessed. The MRI prevalence of retinoblastoma-associated orbital cellulitis was 6.8% (16/236). Retinoblastoma with orbital cellulitis showed significantly more tumor necrosis, uveal abnormalities (inflammation, hemorrhage, and necrosis), lens luxation (all P < 0.001), and a larger eye size (P = 0.012). The inflammatory pattern of optic nerve enhancement (strong enhancement similar to adjacent choroid) was solely found in orbital cellulitis cases, of which none (0/16) showed tumor invasion on histopathology. Invasive pattern enhancement was found in both cases and controls, of which 50% (5/10) showed tumor invasion on histopathology. Considering these different enhancement patterns suggestive for either inflammation or tumor invasion increased specificity for detection of postlaminar tumor invasion in orbital cellulitis cases from 32% (95% confidence interval [CI], 16–52) to 89% (95% CI, 72–98). Retinoblastoma cases presenting with orbital cellulitis show MRI findings of a larger eye size, extensive tumor necrosis, uveal abnormalities, and lens luxation. Magnetic resonance imaging contrast-enhancement patterns within the postlaminar optic nerve can differentiate between tumor invasion and inflammatory changes. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the outcomes of retinoblastoma (RB) based on the 8 th edition of the American Joint Committee on Cancer (AJCC) pathological classification in a global cohort of patients., Design: Retrospective, multicentre, intercontinental collaborative study PARTICIPANTS: 1411 patients INTERVENTION(S): Primary enucleation with/without adjuvant chemotherapy/radiotherapy MAIN OUTCOMES(S): Orbital tumor recurrence, tumor-related metastasis, tumor-related death RESULTS: Based on the 8 th edition AJCC pathological classification, 645 (46%) eyes belonged to pT1, 164 (11%) to pT2, 493 (35%) to pT3, and 109 (8%) to pT4 categories. At a mean follow-up of 38 months (median, 35 months; <1-149 months), orbital tumor recurrence was seen in 8 (1%), 5 (3%), 22 (4%) and 25 (23%) of pT1, pT2, pT3, and pT4 (p<0.001) categories, respectively; tumor-related metastasis was seen in 7 (1%), 5 (3%), 40 (8%), and 46 (43%) of pT1, pT2, pT3, and pT4 (p<0.001) categories, respectively; tumor-related death was seen in 12 (2%), 7 (4%), 64 (13%), and 64 (59%) of pT1, pT2, pT3, and pT4 (p<0.001) categories, respectively. Multivariate Cox proportional hazards analysis of outcomes revealed pT category and adjuvant therapy as independent predictors of outcomes. Categories pT3b (p=0.005), pT3c (p<0.001), pT3d (p<0.001), and pT4 (p<0.001) had a greater hazard for orbital recurrence; categories pT2a (p=0.015), pT3a (p<0.001), pT3b (p<0.001), pT3c (p<0.001), pT3d (p<0.001) and pT4 (p<0.001) had a greater hazard for tumor-related metastasis; and categories pT2a (p=0.068), pT2b (p=0.004), pT3a (p<0.001), pT3b (p<0.001), pT3c (p<0.001), pT3d (p<0.001) and pT4 (p<0.001) had a greater hazard for tumor-related death when compared to the pT1 category. Patients who did not receive adjuvant therapy had greater hazards of orbital tumor recurrence in categories pT3b (p=0.005), pT3c (p=0.003), and pT4 (p=0.002); greater hazards of tumor-related metastasis in categories pT3a (p=0.001), pT3b (p=0.01), pT3c (p=0.001), and pT4 (p=0.007); and tumor-related death in categories pT3a (p<0.001), pT3b (p=0.009), pT3c (p=0.018), and pT4 (p<0.001) when compared to those who received adjuvant therapy., Conclusion: The 8 th edition AJCC pathological classification predicts outcomes in patients undergoing primary enucleation for RB, and adjuvant therapy is associated with a lower risk of orbital recurrence, tumor-related metastasis, and tumor-related death in the pT3 and pT4 categories., (Copyright © 2024. Published by Elsevier Inc.)

This study attempted to estimate the impact of eye-preserving therapies for the long-term prognosis of patients with advanced retinoblastoma with regard to overall survival and ocular salvage. Retrospective cohort study covering all 31 provinces (38 retinoblastoma treating centers) of mainland China. One thousand six hundred seventy-eight patients diagnosed with group D or E retinoblastoma from January 2006 through May 2016. Chart review was performed. The patients were divided into primary enucleation and eye-preserving groups, and they were followed up for survival status. The impact of initial treatment on survival was evaluated by Cox analyses. Overall survival and final eye preservation. After a median follow-up of 43.9 months, 196 patients (12%) died, and the 5-year overall survival was 86%. In total, the eyeball preservation rate was 48%. In this cohort, 1172 patients (70%) had unilateral retinoblastoma, whereas 506 patients (30%) had bilateral disease. For patients with unilateral disease, 570 eyes (49%) underwent primary enucleation, and 602 patients (51%) received eye-preserving therapies initially. During the follow-up (median, 45.6 months), 59 patients (10%) from the primary enucleation group and 56 patients (9.3%) from the eye-preserving group died. Multivariate Cox analyses indicated no significant difference in overall survival between the 2 groups (hazard ratio [HR], 1.25; 95% confidence interval [CI], 0.85–1.84; P = 0.250). For patients with bilateral disease, 95 eyes (19%) underwent primary enucleation, and 411 patients (81%) received eye-preserving therapies initially. During the follow-up (median, 40.1 months), 12 patients (13%) from the primary enucleation group and 69 patients (17%) from the eye-preserving group died. For bilateral retinoblastoma with the worse eye classified as group E, patients undergoing primary enucleation exhibited better overall survival (HR, 2.35; 95% CI, 1.10–5.01; P = 0.027); however, this survival advantage was not evident until passing 22.6 months after initial diagnosis. Eye-preserving therapies have been used widely for advanced retinoblastoma in China. Patients with bilateral disease whose worse eye was classified as group E and who initially underwent eye-preserving therapies exhibited a worse overall survival. The choice of primary treatment for advanced retinoblastoma should be weighed carefully. [ABSTRACT FROM AUTHOR]

To compare metastasis-related mortality, local treatment failure, and globe salvage after retinoblastoma in countries with different national income levels. International, multicenter, registry-based retrospective case series. Two thousand one hundred ninety patients, 18 ophthalmic oncology centers, and 13 countries on 6 continents. Multicenter registry-based data were pooled from retinoblastoma patients enrolled between January 2001 and December 2013. Adequate data to allow American Joint Committee on Cancer staging, eighth edition, and analysis for the main outcome measures were available for 2085 patients. Each country was classified by national income level, as defined by the 2017 United Nations World Population Prospects, and included high-income countries (HICs), upper middle-income countries (UMICs), and lower middle-income countries (LMICs). Patient survival was estimated with the Kaplan-Meier method. Logistic and Cox proportional hazards regression models were used to determine associations between national income and treatment outcomes. Metastasis-related mortality and local treatment failure (defined as use of secondary enucleation or external beam radiation therapy). Most (60%) study patients resided in UMICs and LMICs. The global median age at diagnosis was 17.0 months and higher in UMICs (20.0 months) and LMICs (20.0 months) than HICs (14.0 months; P < 0.001). Patients in UMICs and LMICs reported higher rates of disease-specific metastasis-related mortality and local treatment failure. As compared with HICs, metastasis-related mortality was 10.3-fold higher for UMICs and 9.3-fold higher for LMICs, and the risk for local treatment failure was 2.2-fold and 1.6-fold higher, respectively (all P < 0.001). This international, multicenter, registry-based analysis of retinoblastoma management revealed that lower national income levels were associated with significantly higher rates of metastasis-related mortality, local treatment failure, and lower globe salvage. [ABSTRACT FROM AUTHOR]

To identify risk factors for acute choroidal ischemia (ACI) after intra-arterial chemotherapy (IAC) for retinoblastoma. Retrospective cohort study. Two hundred twenty patients (248 eyes) treated with IAC in Lausanne between November 2008 and September 2019 (665 procedures). All patients were evaluated on a monthly basis with fundus photography and fluorescein angiography before and after each IAC injection. Acute choroidal ischemia, defined as any new choroidal ischemia clinically diagnosed within 35 days after an IAC injection, were noted. Eyes with choroidal complications diagnosed later than 35 days after the last IAC injection (n = 7) or those for which the status of the choroid was not assessable (n = 35) were excluded. Specific procedure parameters and treatment regimens were compared between the group of eyes with and without ACI. Procedure-related risk factors for ACI after IAC injection and visual acuity assessment in the group of eyes with ACI. Acute choroidal ischemia developed in 35 of 206 included eyes after a mean of 2 injections. No differences were found between the two study groups regarding age at first IAC injection, disease grouping at diagnosis, previously administered treatments, number of IAC injections, drug dose, mean injection time, injection method (pulsatile vs. continuous), or concomitant intravitreal melphalan use. Treatment regimen (melphalan vs. combined melphalan plus topotecan; P < 0.05), catheterization route (internal carotid artery vs. external carotid or posterior communicating artery; P < 0.001), and catheterization type (occlusive into the ophthalmic artery [OA] vs. nonocclusive; P < 0.001) were included in multivariate analysis, and occlusive catheterization was identified as an independent risk factor for ACI (P < 0.001). In the subgroup undergoing an occlusive procedure, placement of the catheter tip into the OA distal third versus medial and proximal thirds (P = 0.04) and a mean catheter diameter-to-OA lumen ratio of 0.6 or more (P < 0.001) were correlated significantly with ACI. Complete vision loss was noted in 27% of the eyes with ACI that were old enough for visual assessment (n = 9/33), whereas 33% maintained a useful vision ranging between 0.1 and 0.8 (n = 11/33). Catheterization of the OA should be attempted from an ostial position or an external carotid approach to minimize the risk of potentially vision-threatening choroidal complications. [ABSTRACT FROM AUTHOR]

To evaluate the efficacy of integrating a telemedicine-based twinning partnership and centralized care for retinoblastoma on survival and eye salvage. Four hundred seventy-eight retinoblastoma patients treated at a tertiary referral cancer center (King Hussein Cancer Centre [KHCC]) from 2003 through 2019. Four hundred seventy-eight retinoblastoma patients treated at KHCC after implementing a telemedicine-based program with St. Jude Children's Research Hospital. We reviewed the outcomes of retinoblastoma patients who were treated at KHCC after implementing a telemedicine-based eye salvage program with St. Jude Children's Research Hospital, and we compared that with outcomes for retinoblastoma patients who were treated before implementing a telemedicine-based retinoblastoma service at KHCC. We analyzed patient demographics, clinical characteristics, treatments received, consultation type and duration, and long-term patient outcomes before and after implementing the twinning program. Over 17 years, 813 eyes from 478 children with retinoblastoma were treated at KHCC. Three hundred thirty-five patients (70%) had bilateral disease. Six patients (4%) with unilateral disease and 66 patients (20%) with bilateral disease had a family history of retinoblastoma. After the twinning program was established in 2003, the mortality rate decreased from 38% to 5% (P < 0.0001), and the overall eye salvage rate increased from 4% to 61% (98% for group A, 93% for group B, 81% for group C, and 48% for group D; P < 0.0001). Initially, all cases were discussed via telemedicine, but as knowledge transfer increased, the proportion of cases that required discussion decreased to less than 3% 10 years later. Similarly, treatment changes based on consultations decreased from 70% to 7% after 10 years. Both survival and eye-salvage rates were comparable at the early and later stages of implementing the twinning program. At a median follow-up of 120 months, 5% of patients had died of metastases or secondary neoplasms, 81% were alive, and 14% were lost to follow-up. Centralization of care at a single center in developing countries can achieve patient outcomes comparable with those of developed countries via twinning and telemedicine. This benefit can extend to a large region because two thirds of patients treated at KHCC were non-Jordanians. [ABSTRACT FROM AUTHOR]

To evaluate the ability of the American Joint Committee on Cancer (AJCC) 8th edition to predict local tumor control and globe salvage for children with retinoblastoma (RB). International, multicenter, registry-based retrospective case series. A total of 2854 eyes of 2097 patients from 18 ophthalmic oncology centers from 13 countries over 6 continents. International, multicenter, registry-based data were pooled from patients enrolled between January 2001 and December 2013. All RB eyes with adequate records to allow tumor staging by the AJCC 8th edition criteria and follow-up to ascertain treatment outcomes were included. Globe-salvage rates were estimated by AJCC clinical (cTNMH) categories and tumor laterality. Local treatment failure was defined as use of enucleation or external beam radiation therapy (EBRT), with or without plaque brachytherapy or intra-arterial chemotherapy (IAC). Unilateral RB occurred in 1340 eyes (47%). Among the 2854 eyes, tumor categories were cT1 to cT4 in 696 eyes (24%), 1334 eyes (47%), 802 eyes (28%), and 22 eyes (1%), respectively. Of these, 1275 eyes (45%) were salvaged, and 1179 eyes (41%) and 400 eyes (14%) underwent primary and secondary enucleation, respectively. The 2- and 5-year Kaplan–Meier cumulative globe-salvage rates without the use of EBRT by cTNMH categories were 97% and 96% for category cT1a tumors, 94% and 88% for cT1b tumors, 68% and 60% for cT2a tumors, 66% and 57% for cT2b tumors, and 32% and 25% for cT3 tumors, respectively. Risk of local treatment failure increased with increasing cT category (P < 0.001). Cox proportional hazards regression analysis confirmed a higher risk of local treatment failure in categories cT1b (hazard ratio [HR], 3.5; P = 0.004), cT2a (HR, 15.1; P < 0.001), cT2b (HR, 16.4; P < 0.001), and cT3 (HR, 45.0; P < 0.001) compared with category cT1a. Use of plaque brachytherapy and IAC improved local tumor control in categories cT1a (P = 0.031) and cT1b (P < 0.001). Multicenter, international, internet-based data sharing validated the 8th edition AJCC RB staging to predict globe-salvage in a large, heterogeneous, real-world patient population with RB. [ABSTRACT FROM AUTHOR]

To evaluate the ability of the 8th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual to estimate metastatic and mortality rates for children with retinoblastoma (RB). International, multicenter, registry-based retrospective case series. A total of 2190 patients from 18 ophthalmic oncology centers from 13 countries over 6 continents. Patient-specific data fields for RB were designed and selected by subcommittee. All patients with RB with adequate records to allow tumor staging by the AJCC criteria and follow-up for metastatic disease were studied. Metastasis-related 5- and 10-year survival data after initial tumor staging were estimated with the Kaplan–Meier method depending on AJCC clinical (cTNM) and pathological (pTNM) tumor, node, metastasis category and age, tumor laterality, and presence of heritable trait. Of 2190 patients, the records of 2085 patients (95.2%) with 2905 eyes were complete. The median age at diagnosis was 17.0 months. A total of 1260 patients (65.4%) had unilateral RB. Among the 2085 patients, tumor categories were cT1a in 55 (2.6%), cT1b in 168 (8.1%), cT2a in 197 (9.4%), cT2b in 812 (38.9%), cT3 in 835 (40.0%), and cT4 in 18 (0.9%). Of these, 1397 eyes in 1353 patients (48.1%) were treated with enucleation. A total of 109 patients (5.2%) developed metastases and died. The median time (n = 92) from diagnosis to metastasis was 9.50 months. The 5-year Kaplan–Meier cumulative survival estimates by clinical tumor categories were 100% for category cT1a, 98% (95% confidence interval [CI], 97–99) for cT1b and cT2a, 96% (95% CI, 95–97) for cT2b, 89% (95% CI, 88–90) for cT3 tumors, and 45% (95% CI, 31–59) for cT4 tumors. Risk of metastasis increased with increasing cT (and pT) category (P < 0.001). Cox proportional hazards regression analysis confirmed a higher risk of metastasis in category cT3 (hazard rate [HR], 8.09; 95% CI, 2.55–25.70; P < 0.001) and cT4 (HR, 48.55; 95% CI, 12.86–183.27; P < 0.001) compared with category cT1. Age, tumor laterality, and presence of heritable traits did not influence the incidence of metastatic disease. Multicenter, international, internet-based data sharing facilitated analysis of the 8th edition AJCC RB Staging System for metastasis-related mortality and offered a proof of concept yielding quantitative, predictive estimates per category in a large, real-life, heterogeneous patient population with RB. [ABSTRACT FROM AUTHOR]

To generate recommendations for long-term follow-up of adult survivors of heritable retinoblastoma. We convened a meeting of providers from retinoblastoma centers around the world to review the state of the science and to evaluate the published evidence. Retinoblastoma is a rare childhood cancer of the retina. Approximately 40% of retinoblastoma cases are heritable, resulting from a germline mutation in RB1. Dramatic improvements in treatment and supportive care have resulted in a growing adult survivor population. However, survivors of heritable retinoblastoma have a significantly increased risk of subsequent malignant neoplasms, particularly bone and soft tissue sarcomas, uterine leiomyosarcoma, melanomas, and radiotherapy-related central nervous system tumors, which are associated with excess morbidity and mortality. Despite these risks, no surveillance recommendations for this population currently are in place, and surveillance practices vary widely by center. Following the Institute of Medicine procedure for clinical practice guideline development, a PubMed, EMBASE, and Web of Science search was performed, resulting in 139 articles; after abstract and full-text review, 37 articles underwent detailed data abstraction to quantify risk and evidence regarding surveillance, if available. During an in-person meeting, evidence was presented and discussed, resulting in consensus recommendations. Diagnosis and mortality from subsequent neoplasm. Although evidence for risk of subsequent neoplasm, especially sarcoma and melanoma, was significant, evidence supporting routine testing of asymptomatic survivors was not identified. Skin examination for melanoma and prompt evaluation of signs and symptoms of head and neck disease were determined to be prudent. This review of the literature confirmed some of the common second cancers in retinoblastoma survivors but found little evidence for a benefit from currently available surveillance for these malignancies. Future research should incorporate international partners, patients, and family members. [ABSTRACT FROM AUTHOR]

To determine the age up to which children are at risk of trilateral retinoblastoma (TRb) developing, whether its onset is linked to the age at which intraocular retinoblastomas develop, and the lead time from a detectable pineal TRb to symptoms. Approximately 45% of patients with retinoblastoma—those with a germline RB1 pathogenic variant—are at risk of pineal TRb developing. Early detection and treatment are essential for survival. Current evidence is unclear regarding the usefulness of screening for pineal TRb and, if useful, the age up to which screening should be continued. We conducted a study according to the Meta-analysis of Observational Studies in Epidemiology guidelines for reporting meta-analyses of observational studies. We searched PubMed and Embase between January 1, 1966, and February 27, 2019, for published literature. We considered articles reporting patients with TRb with survival and follow-up data. Inclusion of articles was performed separately and independently by 2 authors, and 2 authors also independently extracted the relevant data. They resolved discrepancies by consensus. One hundred thirty-eight patients with pineal TRb were included. Of 22 asymptomatic patients, 21 (95%) were diagnosed before the age of 40 months (median, 16 months; interquartile range, 9–29 months). Age at diagnosis of pineal TRb in patients diagnosed with retinoblastoma at 6 months or younger versus older than 6 months were comparable (P = 0.44), suggesting independence between the ages at diagnosis of intraocular retinoblastoma and pineal TRb. The laterality of intraocular retinoblastoma and its treatment were not associated with the age at which pineal TRb was diagnosed. The lead time from asymptomatic to symptomatic pineal TRb was approximately 1 year. By performing a screening magnetic resonance imaging scan every 6 months after the diagnosis of heritable retinoblastoma (median age, 6 months) until 36 months of age, at least 311 and 776 scans would be required to detect 1 case of asymptomatic pineal TRb and to save a single life, respectively. Patients with retinoblastoma are at risk of pineal TRb developing for a shorter period than previously assumed, and the age at diagnosis of pineal TRb is independent of the age at diagnosis of retinoblastoma. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) level of evidence for these conclusions remains low. [ABSTRACT FROM AUTHOR]

Invisible retinoblastoma tumors are now detected with screening for retinal tumors in at-risk neonates (those inheriting RB1 pathogenic alleles from affected parents) using handheld OCT. Laser photocoagulation is challenging, requiring exact localization of a tumor invisible to indirect ophthalmoscopy and standard imaging. We describe OCT-guided localization and photocoagulation of these invisible tumors with 1-year follow-up. Retrospective, noncomparative, single-institutional, observational case series. Children with any clinically invisible retinoblastoma tumor that was detected on OCT posterior pole screening. OCT revealed round homogeneous invisible tumors within the inner nuclear layer. Software calipers placed beside anatomic retinal landmarks (branched/curved vessels, fovea, or optic disc) mapped the tumor location and extent. A single laser (532 nm) burn flagged the location, and OCT evaluated the tumor–laser burn relationship; laser treatment was then continued in the correct location. Post-laser OCT ensured complete treatment. Accuracy (frequency of geographic miss and skip areas), effectiveness (recurrence rate), and burden (scar size and characteristics at final follow-up) of laser treatment. Eleven new invisible posterior pole tumors in 7 eyes of 5 children were treated by this technique. Localization and tumor–laser burn relationships were accurate in 11 of 11 tumors (100%, 95% confidence interval [CI], 49.9–100), and all showed swelling and hyper-reflectiveness of the tumor in post-laser OCT. Two photocoagulation sessions (2 weeks apart) were sufficient to successfully manage 9 of 11 tumors (82%, 95% CI, 37.4–100) with resulting permanent flat scars. One tumor (9%, 95% CI, 0.2–50.6) developed OCT-detected subclinical recurrences within 3 months, treated by 1 laser session. No treatment scar showed gliosis, foveal involvement, or retinal traction at 1-year follow-up. Scar expansion occurred in 1 tumor (9%, 95% CI, 0.2–50.6), and all scars (100%, 95% CI, 49.9–100) showed pigmentary changes. The OCT-guided localization and photocoagulation technique is valuable in achieving precision results in managing invisible new retinoblastoma tumors. This technique shows a potential to improve outcomes of secondary prevention screening for retinoblastoma. [ABSTRACT FROM AUTHOR]

Attempted eye salvage for unilateral (cT2b/group D) retinoblastoma may risk tumor spread compared with primary enucleation. Identification of clinical features predictive of low histopathologic risk support safe trial salvage. Retrospective, noncomparative single-institutional observational case series. Children with unilateral cT2b/group D retinoblastoma managed with primary enucleation at the Hospital for Sick Children, Toronto, Canada, January 2008 through February 2018. Data included clinical features (intraocular pressure, optic nerve obscuration, macular involvement, tumor seeding, and serous retinal detachment [RD] >1 quadrant), timing to enucleation, histopathologic features, and follow-up. Primary outcome was low-risk (LR; pT1/pT2) versus high-risk (HR; pT3/pT4) histopathologic features with clinicopathologic correlations. Secondary outcomes were positive predictive (probability that certain clinical features would predict LR histopathologic features) and negative predictive values (probability that absence of these clinical features would predict HR histopathologic features). Thirty-eight eyes were eligible and showed vitreous seeding and normal intraocular pressure. The median diagnosis to enucleation interval was 4 days (range, 0–14 days). Histopathologic analysis diagnosed 4 (10.5%) HR and 34 (89.5%) LR eyes. High-risk eyes demonstrated massive choroidal invasion (4/38) or trans-scleral, extraocular, and postlaminar optic nerve invasion (1/38). Clinical findings included macular involvement (31/38), complete optic nerve obscuration (27/38), and RD (28/38). The proportion of eyes with HR histopathologic features was 13% (4/31; 95% confidence interval [CI], 1%–25%) with macular involvement, 15% (4/27; 95% CI, 1%–28%) with complete optic nerve obscuration, and 14% (4/28; 95% CI, 1%–27%) with RD. The predictability of LR histopathologic features was 100% with macular sparing (7/7; 95% CI, 47%-100%), optic nerve visibility (10/10; 95% CI, 63%-100%), and less than 1 quadrant of RD (10/10; 95% CI, 63%-100%). In 1 child lacking all 3 clinical LR predictive features with HR histopathologic features (pT3a), metastases developed and the patient died; other children are alive and well (mean follow-up, 65 months). Presence of macular sparing, optic nerve visibility, less than 1 quadrant of RD, or a combination thereof predicted LR histopathologic features at primary enucleation, suggesting safe trial eye salvage. No clinical sign predicted HR histopathologic features. [ABSTRACT FROM AUTHOR]

Purpose To assess risk factors for ophthalmic vascular events after intra-arterial chemotherapy (IAC) for retinoblastoma. Design Retrospective cohort study. Participants Patients who received unilateral IAC as primary treatment for retinoblastoma from January 1, 2009, to November 30, 2017, at a single center. Methods Records were reviewed for patient demographics, tumor features, IAC parameters, and treatment-related vascular events in the early IAC era (2009–2011) compared with the recent era (2012–2017) using the t test and Fisher exact test. Change in event rates over time was assessed using Poisson regression analysis, with Spearman's rho used to test correlation. Main Outcome Measures Rate of IAC-induced ophthalmic vascular events. Results There were 243 chemotherapy infusions in 76 eyes of 76 patients, divided into early (22 eyes, 57 infusions) and recent (54 eyes, 186 infusions) eras. Intra-arterial chemotherapy consisted of melphalan (243 infusions), topotecan (124 infusions), and carboplatin (9 infusions). A comparison (early vs. recent era) revealed fewer mean number of infusions (2.6 vs. 3.4, P = 0.02) with similar mean patient age and presenting tumor features. Event rates decreased over time (P < 0.01), with fewer ophthalmic vascular events (early era vs. recent era) in the recent era (59% vs. 9% per eye, 23% vs. 3% per infusion, P < 0.01), including peripheral retinal nonperfusion (5% vs. 2% per eye, P = 0.50), vitreous hemorrhage (9% vs. 2%, P = 0.20), subretinal hemorrhage (0% vs. 2%, P = 0.99), branch retinal vein occlusion (5% vs. 0%, P = 0.29), choroidal ischemia (14% vs. 4%, P = 0.14), and ophthalmic artery spasm/occlusion (27% vs. 0%, P < 0.01). Events did not correlate to patient age (P = 0.75), tumor diameter (P = 0.32), tumor thickness (P = 0.59), or cumulative dosage of melphalan (P = 0.13) or topotecan (P = 0.59). There were no IAC-induced vascular events in 72 infusions of 21 consecutively treated eyes in 2016 to 2017. Conclusions Ophthalmic vascular events after IAC have decreased from the early era (2009–2011) through the current era (2012–2017) at this center. Experience performing this highly specialized procedure could be an important factor predicting IAC-related vascular events. [ABSTRACT FROM AUTHOR]

Purpose To provide a set of surveillance guidelines for children at risk for development of retinoblastoma. Design Consensus panel. Participants Expert panel of ophthalmic oncologists, pathologists, and geneticists. Methods A group of members of the American Association of Ophthalmic Oncologists and Pathologists (AAOOP) with support of the American Association for Pediatric Ophthalmology and Strabismus and the American Academy of Pediatrics (AAP) was convened. The panel included representative ophthalmic oncologists, pathologists, and geneticists from retinoblastoma referral centers located in various geographic regions who met and discussed screening approaches for retinoblastoma. A patient “at risk” was defined as a person with a family history of retinoblastoma in a parent, sibling, or first- or second-degree relative. Main Outcome Measures Screening recommendations for children at risk for retinoblastoma. Results Consensus statement from the panel: (1) Dedicated ophthalmic screening is recommended for all children at risk for retinoblastoma above the population risk. (2) Frequency of examinations is adjusted on the basis of expected risk for RB1 mutation. (3) Genetic counseling and testing clarify the risk for retinoblastoma in children with a family history of the disease. (4) Examination schedules are stratified on the basis of high-, intermediate-, and low-risk children. (5) Children at high risk for retinoblastoma require more frequent screening, which may preferentially be examinations under anesthesia. Conclusions Risk stratification including genetic testing and counseling serves as the basis for screening of children at elevated risk for development of retinoblastoma. [ABSTRACT FROM AUTHOR]

Objective Intravitreal chemotherapy has emerged as an important modality for treating vitreous seeding in retinoblastoma. A classification system has been described as predictive of response to intravitreal melphalan (IVM) in patients treated predominantly with primary intra-arterial chemotherapy. The objective of this study is to evaluate the outcomes of retinoblastoma treated with intravenous chemotherapy and IVM as salvage for vitreous seeding, and further to determine whether vitreous seed classification (dust, spheres, cloud) is predictive of the total number and dose of IVM injections required for treatment in this cohort. Design A nonrandomized retrospective review. Participants Retinoblastoma patients treated at a single center with intravenous chemotherapy and IVM. Methods Retrospective review of patients with vitreous seeding from retinoblastoma treated with intravenous chemotherapy and IVM from 2012 to 2016. Main Outcome Measures Primary outcome measure was eradication of seeds and globe salvage. Secondary measures included IVM-associated toxicity and complications. Results Overall, 28 eyes of 25 patients were included, with a total of 110 IVM injections. By seed classification, eyes with dust (n = 15) required a median of 3 injections, spheres (n = 8) required 4 injections, and clouds (n = 5) required 6 injections. Spherical seeds were only seen in recurrent vitreous seeding. Of the 28 treated eyes, 9 were enucleated, 6 for recurrent retinal disease, resulting in an overall globe salvage rate of 68%. The salvage rate secondary to active retinoblastoma was 79%. Dust classification was the most prevalent seeding type of the 9 enucleated eyes. There was 100% regression of vitreous seeds after intravitreal injection and no eye was treated with radiation or enucleated for seeding. Twelve eyes demonstrated grade 3 or greater IVM-associated retinal or anterior segment toxicity post injection. Mean follow-up was 33 months (range, 9–51 months). Conclusions IVM is an effective treatment for vitreous seeding after intravenous chemotherapy for retinoblastoma. As with eyes treated with intra-arterial chemotherapy, seed classification is predictive of the total number and dose of IVM injections in eyes treated with intravenous chemotherapy. Eyes with clouds required significantly more injections than eyes with dust or spheres. [ABSTRACT FROM AUTHOR]

Purpose To compare the efficacy and toxicity of treating class 3 retinoblastoma vitreous seeds with ophthalmic artery chemosurgery (OAC) alone versus OAC with intravitreous chemotherapy. Design Retrospective cohort study. Participants Forty eyes containing clouds (class 3 vitreous seeds) of 40 retinoblastoma patients (19 treated with OAC alone and 21 treated with OAC plus intravitreous and periocular chemotherapy). Methods Ocular survival, disease-free survival and time to regression of seeds were estimated with Kaplan-Meier estimates. Ocular toxicity was evaluated by clinical findings and electroretinography: 30-Hz flicker responses were compared at baseline and last follow-up visit. Continuous variables were compared with Student t test, and categorical variables were compared with the Fisher exact test. Main Outcome Measures Ocular survival, disease-free survival, and time to regression of seeds. Results There were no disease- or treatment-related deaths and no patient demonstrated externalization of tumor or metastatic disease. There was no significant difference in the age, laterality, disease, or disease status (treatment naïve vs. previously treated) between the 2 groups. The time to regression of seeds was significantly shorter for eyes treated with OAC plus intravitreous chemotherapy (5.7 months) compared with eyes treated with OAC alone (14.6 months; P < 0.001). The 18-month Kaplan-Meier estimates of disease-free survival were significantly worse for the OAC alone group: 67.1% (95% confidence interval, 40.9%–83.6%) versus 94.1% (95% confidence interval, 65%–99.1%) for the OAC plus intravitreous chemotherapy group ( P = 0.05). The 36-month Kaplan-Meier estimates of ocular survival were 83.3% (95% confidence interval, 56.7%–94.3%) for the OAC alone group and 100% for the OAC plus intravitreous chemotherapy group ( P = 0.16). The mean change in electroretinography responses was not significantly different between groups, decreasing by 11 μV for the OAC alone group and 22 μV for the OAC plus intravitreous chemotherapy group ( P = 0.4). Conclusions Treating vitreous seed clouds with OAC and intravitreous and periocular chemotherapy, compared with OAC alone, resulted in a shorter time to regression and was associated with fewer recurrences requiring additional treatment and fewer enucleations. The toxicity to the retina does not seem to be significantly worse in the OAC plus intravitreous chemotherapy group. [ABSTRACT FROM AUTHOR]

Purpose A recent classification scheme for retinoblastoma vitreous seeds has shown promise in predicting treatment response. For the first time, we correlate this clinical classification scheme with its histopathologic features. Design Retrospective review. Participants Enucleated eyes received at the pathology department of the Retinoblastoma Center of Houston from 2010 to 2015. Methods Macroscopic photographs of the enucleated eyes of patients with retinoblastoma were analyzed to select those with vitreous seeds. Cases with adequate material for clinicopathologic correlation were selected for further analysis, and clinical photographs were reviewed. Routine histopathologic slides were reviewed and compared with the clinical and macroscopic photographs. Seeds were classified as type 1 (“dust”), type 2 (“sphere”), or type 3 (“cloud”). To confirm the presence of macrophages, CD68 immunohistochemical staining was used. Synaptophysin was used to stain retinoblastoma cells. Main Outcome Measures To correlate clinical vitreous seed type with histopathologic features. Results A total of 14 eyes with adequate amounts of tumor seeds along with clinical and macroscopic photographic correlation were selected from a total of 138 eyes reviewed. Type 1 seeds consisted of individual viable tumor cells and scattered macrophages. Type 2 seeds consisted of 2 submorphologies: spheres with viable cells throughout and spheres with an outer rim of viable cells but necrotic cells centrally. Type 3 seeds were composed of more than 90% necrotic material admixed with few macrophages and viable cells at their outer rim. Untreated (8/14) and previously treated (6/14) eyes showed similar histopathologic features for each type of seeds. Treated eyes had more type 1 and 3 seeds. Conclusions We provide the first histopathologic correlation of the clinical classification scheme for vitreous seeds in retinoblastoma. “Dust” is formed by scattered single cells alternating with macrophages. “Spheres” with translucent centers contain multiple layers of viable tumor cells that shed single cells and may be more clinically aggressive. “Cloud” seeds are mostly composed of necrotic material, explaining their lack of therapeutic response. Pretreated eyes showed tumor seeds morphologically similar to untreated eyes. Knowledge of the underlying histopathology of vitreous seed types is a fundamental component of classification and may aid in understanding clinical response to treatment. [ABSTRACT FROM AUTHOR]

Purpose To evaluate the rate and identify the risk factors for high-risk histopathologic features in group D retinoblastoma eyes enucleated as primary or secondary treatment. Design Retrospective analysis. Participants A total of 64 enucleated group D eyes (62 patients), of which 40 (40 patients) were primary and 24 (22 patients) were secondary to other treatments. Methods Clinicopathologic correlation of consecutive group D eyes enucleated from 2002 to 2014. High-risk histopathologic features were defined as the presence of anterior chamber seeds, iris infiltration, ciliary body/muscle infiltration, massive (≥3 mm) choroidal invasion, retrolaminar optic nerve invasion, or combined non-massive choroidal and prelaminar/laminar optic nerve invasion. Main Outcome Measures High-risk histopathologic features, metastasis, and death. Results Of the 64 group D eyes, 37 (58%) were classified as cT2bN0M0H0, 24 (38%) were classified as cT2bN0M0H1, and 3 (5%) were classified as cT2aN0M0H1, according to the 8th edition cTNMH Retinoblastoma Staging. High-risk histopathologic features were detected in 10 eyes (16%) in the entire cohort, 5 eyes (13%) of the primary enucleated group (pT3aNxM0, n = 2 and pT3bNxM0, n = 3, 8th edition pTNM), and 5 eyes (21%) of the secondary enucleated group (pT2bNxM0, n = 2, pT3aNxM0, n = 2 and pT3cNxM0, n = 1). Absence of vitreous seeds at presentation was the only predictive factor found for high-risk histopathologic features in the primary enucleation group ( P = 0.042), whereas none were found in the secondary group ( P ≥ 0.179). Invasion of the anterior structures (anterior chamber, iris, ciliary body/muscle) was detected significantly more after secondary enucleation ( P = 0.048). All patients with high-risk histopathologic features were treated with adjuvant chemotherapy, and no metastases were recorded in a median follow-up time of 73.2 months (mean, 71.5; range, 13.7–153.0). Conclusions The choice of primary treatment for group D retinoblastoma should be carefully weighed, because according to this study, 13% of eyes harbor high-risk histopathologic features at presentation, with the absence of vitreous seeds being a potential risk factor. It is of special importance in group D eyes being considered for nonsystemic treatment, such as primary intraophthalmic artery chemotherapy. Secondary enucleated group D eyes with high-risk histopathologic features more commonly involved anterior structures, warranting meticulous clinical and histologic examinations for this subset of patients. [ABSTRACT FROM AUTHOR]

Purpose Assess the role of handheld optical coherence tomography (OCT) in guiding management decisions during diagnosis, treatment, and follow-up of eyes affected by retinoblastoma. Design Retrospective, noncomparative, single-institution case series. Participants All children newly diagnosed with retinoblastoma from January 2011 to December 2015 who had an OCT session during their active treatment at The Hospital for Sick Children (SickKids) in Toronto, Canada. The OCT sessions for fellow eyes of unilateral retinoblastoma without any suspicious lesion and those performed more than 6 months after the last treatment were excluded. Methods Data collected included age at presentation, sex, family history, RB1 mutation status, 8th edition TNMH cancer staging and International Intraocular Retinoblastoma Classification (IIRC), and number of OCT sessions per eye. Details of each session were scored for indication-related details (informative or not) and assessed for guidance (directive or not), diagnosis (staging changed, new tumors found or excluded), treatment (modified, stopped, or modality shifted), or follow-up modified. Main Outcome Measures Frequency of OCT-guided management decisions, stratified by indication and type of guidance (confirmatory vs. influential). Results Sixty-three eyes of 44 children had 339 OCT sessions over the course of clinical management (median number of OCT scans per eye, 5; range, 1–15). The age at presentation and presence of a heritable RB1 mutation significantly correlated with an increased number of OCT sessions. Indications included evaluation of post-treatment scar (55%) or fovea (16%), and posterior pole scanning for new tumors (11%). Of all sessions, 92% (312/339) were informative; 19 of 27 noninformative sessions had large, elevated lesions; of these, 14 of 19 were T2a or T2b (IIRC group C or D) eyes. In 94% (293/312) of the informative sessions, OCT directed treatment decisions (58%), diagnosis (16%), and follow-up (26%). Optical coherence tomography influenced and changed management from pre-OCT clinical plans in 15% of all OCT sessions and 17% of directive sessions. Conclusions Optical coherence tomography improves the accuracy of clinical evaluation in retinoblastoma management. [ABSTRACT FROM AUTHOR]

Purpose To investigate the efficacy and toxicity of intravitreous melphalan for treatment of retinoblastoma, as a single agent or with concomitant topotecan. Participants A total of 130 eyes of 120 patients with retinoblastoma receiving 630 intravitreous (melphalan, topotecan) or topotecan periocular injections. A total of 83 (64%) of these eyes were treated with concomitant ophthalmic artery chemosurgery (OAC). Design Retrospective cohort study. Methods Indirect ophthalmoscopy and clinical imaging were used to evaluate clinical response. Ocular survival and disease-free survival were estimated using Kaplan–Meier methods in 130 eyes. Ocular toxicity was evaluated by clinical findings and electroretinography (ERG) on 244 evaluable injections in 63 patients using 30-Hz flicker responses. Analysis was performed using linear mixed effects models with a random intercept and slope for each patient and a fixed effect for number of injections, in addition to any other fixed effect of interest. Main Outcome Measures Ocular survival, disease-free survival, ERG: peak-to-peak ERG amplitudes in response to 30-Hz photopic flicker stimulation. Results There were no disease- or treatment-related deaths, and no patient developed externalization of tumor or metastatic disease. Two-year Kaplan–Meier estimates of ocular survival and disease-free survival were 94.2% (95% confidence interval, 89.2–99.4) and 86.2% (95% confidence interval, 78.7–94.5), respectively. There was a significant association between the number of injections and diminished ERG responses, such that on average each intravitreous melphalan injection was associated with a 5.3-μV decrease in ERG amplitude ( P < 0.001). Concomitant intra-arterial chemotherapy ( P = 0.01) and greater inherent ocular pigment also were significantly associated with a reduction in ERG ( P = 0.045). Patient age and weight, new injection site location, addition of topotecan, concomitant focal treatment, and time interval between injections were not significantly associated with toxicity. Conclusions Intravitreous melphalan is an effective treatment for vitreous seeding in retinoblastoma, resulting in high rates of ocular survival and disease-free survival. However, in this study, each injection of melphalan was associated, on average, with a decrement in ERG response. The findings suggest increased toxicity (1) when OAC is given within 1 week of the intravitreous injection and (2) in more deeply pigmented eyes. [ABSTRACT FROM AUTHOR]

Purpose To compare overall outcomes of conventional postnatal screening of familial retinoblastoma and prenatal RB1 mutation identification followed by planned early-term delivery. Design Retrospective, observational study. Participants Twenty children with familial retinoblastoma born between 1996 and 2014 and examined within 1 week of birth. Methods Cohort 1 included spontaneously delivered neonates examined within 1 week of birth and confirmed postnatal to carry their family's RB1 mutant allele. Cohort 2 included infants identified by amniocentesis to carry their family's RB1 mutant allele, and therefore scheduled for early-term delivery (36–38 weeks' gestation). Treatment for retinoblastoma was performed at the Hospital for Sick Children, Toronto, Canada. Main Outcome Measures Age at first tumor in each eye, eye stage, treatments given, ocular salvage, treatment success (defined as avoidance of enucleation, external-beam irradiation, or both), visual outcome, number of anesthetics, pregnancy or delivery complications, and estimated treatment burden. Results Vision-threatening tumors were present at birth in 4 of 8 infants in cohort 1 and in 3 of 12 infants in cohort 2. Eventually, all infants demonstrated tumors in both eyes. At the first treatment, 1 of 8 infants in cohort 1 had eyes in stage cT1a/cT1a or cT1a/cT0 (smallest and least vision-threatening tumors), compared with 8 of 12 infants in cohort 2 ( P = 0.02). Null RB1 germline alleles induced earlier tumors than low-penetrance alleles ( P = 0.03). Treatment success was achieved in 3 of 8 children in cohort 1 compared with 11 of 12 children in cohort 2 ( P = 0.002). Acceptable vision (better than 0.2 decimal) was achieved for 8 of 16 eyes in cohort 1 compared with 21 of 24 eyes in cohort 2 ( P = 0.014). Useful vision (better than 0.1, legal blindness) was achieved for 8 of 9 children in cohort 1 compared with 12 of 12 children in cohort 2. There were no complications related to early-term delivery. Median follow-up was 5.6 years, cohort 1 and 5.8 years, cohort 2. Conclusions When a parent had retinoblastoma, prenatal molecular diagnosis with early-term delivery increased the likelihood of infants born with no detectable tumors, better vision outcomes, and less invasive therapy. Prenatal molecular diagnosis facilitates anticipatory planning for both the child and family. [ABSTRACT FROM AUTHOR]

Purpose To compare the efficacy of 2 chemotherapeutic drug combinations as part of multimodal therapy for orbital retinoblastoma. Design Prospective, comparative, study. Participants Patients with stage III retinoblastoma (International Retinoblastoma Staging System). Methods Demographic and clinical features were recorded at presentation. Treatment consisted of a multimodal protocol with neoadjuvant chemotherapy, enucleation, orbital external-beam radiotherapy, and adjuvant chemotherapy. For chemotherapy, patients were randomized into 2 groups: group A patients were treated with vincristine, etoposide, and carboplatin (VEC) and group B patients were treated with carboplatin and etoposide, alternating with cyclophosphamide, idarubicin, and vincristine. Treatment outcomes and adverse effects were recorded. Efficacy parameters were compared between the groups. Main Outcome Measures Survival probability, cause of death, and chemotherapy-related toxicity. Results A total of 54 children were recruited (27 in each group). The mean ± SD follow-up was 21.3±11.34 months. The overall Kaplan-Meier survival probability was 80% (95% confidence interval [CI], 0.67–0.89) and 42% (95% CI, 0.24–0.59) at 1 year and 4 years, respectively. There were 9 deaths in group A and 15 deaths in group B. The Kaplan-Meier survival probability at 1 year was similar between the groups: 81% (95% CI, 0.60–0.91) and 79% (95% CI, 0.58–0.9) for groups A and B, respectively. At 4 years, the survival probability for group A was higher (63% [95% CI, 0.41–0.79] vs. 25% [95% CI, 0.08–0.46] for groups A and B, respectively), with a strong trend of better survival in group A over time ( P = 0.05). The major cause of death was central nervous system relapse (8 patients in group A and 7 patients in group B). Two patients in group B died of sepsis after febrile neutropenia. Grade 3 and grade 4 hematologic toxicities were more common in group B, with a significant difference in grade 4 neutropenia ( P = 0.002). Conclusions This study compared the outcomes of VEC chemotherapy with a 5-drug combination of vincristine and carboplatin, alternating with cyclophosphamide, idarubicin, and vincristine, for stage III retinoblastoma. The VEC combination was found to be more effective and may be recommended as neoadjuvant and adjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Purpose To determine whether insurance status, race, and ethnicity correlate with increased retinoblastoma invasiveness as a marker of both risk and time to diagnosis. Design Retrospective case-control study. Participants All 203 patients from the United States enrolled in the Children's Oncology Group (COG) trial ARET0332, a study of patients with unilateral retinoblastoma requiring enucleation. Main Outcome Measures All surgical specimens underwent pathologic review to determine the presence of well-defined histopathologic features correlating with a higher risk of disease progression. Insurance status, race, and ethnicity were compiled from the study record for each patient. Results On institutional pathologic review, nonprivate insurance, nonwhite race, and Hispanic ethnicity all correlated significantly with a greater rate of high-risk pathologic findings. Hispanic ethnicity remained a significant predictor on multivariate analysis. On central pathologic review, these correlations remained but did not reach statistical significance. The differences in results from institutional versus central pathologic reviews appeared to be due to a higher likelihood of patients in minority groups of being misclassified as high risk by institutional pathologists. Conclusions In this controlled study population of patients with retinoblastoma who had central pathologic review, our findings suggest a higher rate of more advanced disease associated with nonprivate insurance, nonwhite race, and Hispanic ethnicity; these findings may be due to delays in diagnosis for these groups. Future work should use direct methods to study the impact of other variables, including English-language proficiency and socioeconomic status. Further effort also should focus on where in the diagnostic process potential delays exist, so that interventions can be designed to overcome barriers to care for these groups. In addition, potential systematic differences in pathologic reads based on demographic variables deserve further study. [ABSTRACT FROM AUTHOR]

Purpose To evaluate the patient, disease, and tumor characteristics of the 3 morphologically distinct groups of vitreous seeds in retinoblastoma presenting for treatment with ophthalmic artery chemosurgery (OAC): dust (class 1), spheres (class 2), and clouds (class 3) in primary and recurrent vitreous seeds. Design Retrospective cohort study of patients treated for vitreous seeds at Memorial Sloan Kettering Cancer Center between May 2006 and March 2015. Participants A total of 135 eyes with active vitreous seeds, presenting for primary treatment with OAC or with recurrent vitreous disease. Methods Vitreous seeds were classified into 3 groups: dust, spheres, and clouds. Indirect ophthalmoscopy, fundus photography, ultrasonography, and ultrasonic biomicroscopy were used to locate and evaluate the extent of retinal and vitreous disease. Patient and disease characteristics (age, laterality of disease, treatment status) were compared among classification groups. A 2-tailed Fisher exact test and paired Student t test were used for statistical analysis. Main Outcome Measures Age of patient, laterality of disease, location of retinal disease, extent of vitreous disease, and treatment status. Results Primary treated disease: Patients with eyes containing class 3 (cloud) vitreous seeds were significantly older than patients with class 1 or 2 seeds ( P < 0.05). The median age of patients with class 1, 2, and 3 seeds was 11, 15.5, and 32 months, respectively. Eyes containing class 3 seeds were significantly more likely to occur in the equator-ora region of the fundus ( P < 0.0001), in a diffuse pattern ( P < 0.0001), and in patients with unilateral disease ( P < 0.05), compared with class 1 and 2 seeds. Recurrent disease: Recurrent vitreous seeds were significantly more common to class 2 ( P < 0.05), occurring in a diffuse pattern ( P = 0.01) and in patients with bilateral disease ( P < 0.001). Conclusions The 3 classes of vitreous seeds have distinct clinical characteristics associated with the age of patient, laterality of disease, and extent and location of tumor-producing seeds. Furthermore, recurrent vitreous seeds appear to have a unique clinical profile compared with seeds receiving primary treatment. [ABSTRACT FROM AUTHOR]

Purpose Orbital tumor recurrence is a rare but serious complication in children with retinoblastoma, leading to a high risk of metastasis and death. Therefore, we assume that these recurrences have to be detected and treated as early as possible. Preliminary studies used magnetic resonance imaging (MRI) to evaluate postsurgical findings in the orbit. In this study, we assessed the diagnostic accuracy of high-resolution MRI to detect orbital tumor recurrence in children with retinoblastoma in a large study cohort. Design Consecutive retrospective study (2007–2013) assessing MRI findings after enucleation. Participants A total of 103 MRI examinations of 55 orbits (50 children, 27 male/23 female, mean age 16.3±12.4 months) with a median time of 8 months (range, 0–93) after enucleation for retinoblastoma. Methods High-resolution MRI using orbital surface coils was performed on 1.5 Tesla MRI systems to assess abnormal orbital findings. Main Outcome Measures Five European experts in retinoblastoma imaging evaluated the MRI examinations regarding the presence of abnormal orbital gadolinium enhancement and judged them as “definitive tumor,” “suspicious of tumor,” “postsurgical condition/scar formation,” or “without pathologic findings.” The findings were correlated to histopathology (if available), MRI, and clinical follow-up. Results Abnormal orbital enhancement was a common finding after enucleation (100% in the first 3 months after enucleation, 64.3% >3 years after enucleation). All histopathologically confirmed tumor recurrences (3 of 55 orbits, 5.5%) were correctly judged as “definitive tumor” in MRI. Two orbits from 2 children rated as “suspicious of tumor” received intravenous chemotherapy without histopathologic confirmation; further follow-up (67 and 47 months) revealed no sign of tumor recurrence. In 90.2%, no tumor was suspected on MRI, which was clinically confirmed during follow-up (median follow-up after enucleation, 45 months; range, 8–126). Conclusions High-resolution MRI with orbital surface coils may reliably distinguish between common postsurgical contrast enhancement and orbital tumor recurrence, and therefore may be a useful tool to evaluate orbital tumor recurrence after enucleation in children with retinoblastoma. We recommend high-resolution MRI as a potential screening tool for the orbit in children with retinoblastoma to exclude tumor recurrence, especially in high-risk patients within the critical first 2 years after enucleation. [ABSTRACT FROM AUTHOR]

Purpose Diffuse anterior retinoblastoma is an exquisitely rare variant of retinoblastoma in which the tumor resides in the anterior segment of the eye, without apparent retinal involvement. Previously published cases have been managed with enucleation. We describe globe salvage and visual preservation in 3 consecutive cases using chemotherapy and radiotherapy. Design Retrospective case series. Participants Three children with diffuse anterior retinoblastoma. Methods Plaque radiotherapy plus intravenous chemotherapy. Main Outcome Measures Globe and vision preservation. Results The mean patient age at presentation elsewhere was 5.7 years (median, 7; range, 3–7 years). There were 2 white female patients and 1 African American male patient. The initial observation by parents/caregiver was reduced vision (n = 1), red eye (n = 1), or cloudy eye (n = 1), and the initial finding by physician was iris tumor (n = 2) or hyphema (n = 1). Referring diagnosis was iris melanoma (n = 1), infectious endotheliitis (n = 1), and possible tumor (nonspecified) (n = 1). At our evaluation, visual acuity was 20/50 to 20/60 (n = 2) and fix no follow (n = 1). In all cases, the opposite eye was normal. Mean intraocular pressure was 20 mm Hg (median, 16; range, 15–30 mmHg). Our examination revealed solid iris tumor (n = 3), ciliary body involvement (n = 2), and anterior chamber seeding (n = 3). In no case was there choroidal or retinal tumor, vitreous seed or subretinal seed, or extrascleral extension. Clear corneal fine-needle aspiration biopsy confirmed the diagnosis as retinoblastoma in each case. Treatment included plaque radiotherapy (n = 3) plus additional systemic chemotherapy (n = 2). At mean follow-up of 35 months (median, 34; range, 20–51 months), there has been no recurrence, extrascleral extension, enucleation, metastasis, or death. In all 3 cases, cataract surgery was necessary at a mean interval of 16 months after complete and stable regression of retinoblastoma. Conclusions The rare diffuse anterior form of retinoblastoma can be managed with globe-salvaging alternatives and with visual preservation in selected cases. [ABSTRACT FROM AUTHOR]

Purpose To evaluate the clinical characteristics of the 3 classifications of vitreous seeds in retinoblastoma—dust (class 1), spheres (class 2), and clouds (class 3)—and their responses to intravitreal melphalan. Design Retrospective, bi-institutional cohort study. Participants A total of 87 patient eyes received 475 intravitreal injections of melphalan (median dose, 30 μg) given weekly, a median of 5 times (range, 1–12 times). Methods At presentation, the vitreous seeds were classified into 3 groups: dust, spheres, and clouds. Indirect ophthalmoscopy, fundus photography, ultrasonography, and ultrasonic biomicroscopy were used to evaluate clinical response to weekly intravitreal melphalan injections and time to regression of vitreous seeds. Kaplan–Meier estimates of time to regression and ocular survival, patient survival, and event-free survival (EFS) were calculated and then compared using the Mantel–Cox test of curve. Main Outcome Measures Time to regression of vitreous seeds, patient survival, ocular survival, and EFS. Results The difference in time to regression was significantly different for the 3 seed classes ( P < 0.0001): the median time to regression was 0.6, 1.7, and 7.7 months for dust, spheres, and clouds, respectively. Eyes with dust received significantly fewer injections and a lower median and cumulative dose of melphalan, whereas eyes with clouds received significantly more injections and a higher median and cumulative dose of melphalan. Overall, the 2-year Kaplan–Meier estimates for ocular survival, patient survival, and EFS (related to target seeds) were 90.4% (95% confidence interval [CI], 79.7–95.6), 100%, and 98.5% (95% CI, 90–99.7), respectively. Conclusions The regression and response of vitreous seeds to intravitreal melphalan are different for each seed classification. The vitreous seed classification can be predictive of time to regression, number, median dose, and cumulative dose of intravitreal melphalan injections required. [ABSTRACT FROM AUTHOR]

Purpose To identify the clinical features predictive of high-risk retinoblastoma on histopathology. Design Case-control study. Participants A total of 145 cases with histopathologic high-risk features of retinoblastoma and 258 controls without high-risk features. Methods Enucleation and adjuvant chemotherapy. Main Outcome Measures High-risk features on histopathology were defined as the presence of anterior chamber seeds, iris infiltration, ciliary body infiltration, massive (≥3 mm) choroidal invasion, postlaminar optic nerve invasion, invasion of optic nerve transection, combined nonmassive choroidal and prelaminar/laminar optic nerve invasion, or scleral/extrascleral infiltration. Results Of 403 patients who underwent primary enucleation for the treatment of retinoblastoma, 145 (36%) had high-risk features on histopathology (cases) and 258 (64%) had no high-risk features (controls). High-risk retinoblastoma occurred in 16% of (8/50) group D eyes and 39% of (137/353) group E eyes. The histopathologic high-risk features in these 145 patients included anterior chamber seeds (n = 25, 17%), iris infiltration (n = 12, 8%), ciliary body infiltration (n = 17, 12%), massive (≥3 mm) choroidal invasion (n = 69, 48%), postlaminar optic nerve invasion (n = 71, 49%), invasion of optic nerve transection (n = 3, 2%), combined choroidal and optic nerve invasion (n = 17, 12%), scleral infiltration (n = 20, 14%), and extrascleral involvement (n = 8, 6%). The mean number of high-risk features was 2 (median, 2; range, 1–7). The significant clinical features in cases versus controls included prolonged duration of symptoms of >6 months (21% vs. 7%; P < 0.001), poor visual acuity at presentation (74% vs. 64%; P = 0.05), buphthalmos (16% vs. 7%; P = 0.005), secondary glaucoma (47% vs. 15%; P < 0.001), iris neovascularization (46% vs. 22%; P < 0.001), ectropion uveae (39% vs. 14%; P < 0.001), and orbital cellulitis (3% vs. <1%; P = 0.05). On the basis of International Classification of Intraocular Retinoblastoma, group E tumor had a statistically significant higher incidence of high-risk retinoblastoma compared with controls (39% vs. 16%; P = 0.01). Multivariate analysis of clinical features at presentation that predicted high-risk features on histopathology included prolonged duration of symptoms of >6 months ( P = 0.008) and secondary glaucoma ( P = 0.021). Conclusions In this study, the clinical features at presentation predictive of high-risk features on histopathology included prolonged duration of symptoms of >6 months and secondary glaucoma. Globe-preserving methods of treatment should be used with caution in patients with these features. [ABSTRACT FROM AUTHOR]

Objective Assess the usefulness of second-course ophthalmic artery chemosurgery (OAC) for patients with intraocular retinoblastoma that recurred after prior OAC. This study evaluated the efficacy and toxicity of second-course OAC. Design Single-arm retrospective study of 29 eyes of 30 patients treated with second-course OAC at Memorial Sloan Kettering Cancer Center between May 2006 and July 2013, with a median follow-up of 25.9 months. Participants Retinoblastoma patients who underwent a course of OAC, with a minimum of 2 months of progression-free follow-up at monthly examinations, but who subsequently received additional OAC for recurrent tumor. Methods To determine efficacy, Kaplan-Meier survival estimates were generated and the Mantel-Cox test was used to compare curves. To determine toxicity, electroretinography (ERG) amplitudes were measured in response to 30-Hz photopic flicker stimulation before and after OAC treatment; systemic adverse events were graded according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0). Main Outcome Measures For efficacy, ocular progression-free survival, ocular event-free survival (e.g., enucleation, external-beam radiation, or intravitreal melphalan), and ocular survival. For toxicity, peak-to-peak comparisons between ERG studies before and after OAC treatment and CTCAE 4.0-graded systemic adverse events. Results Fifty percent of all recurrences were within 4.4 months and 90% were within 16 months of completion of the first course of OAC. The 2-year Kaplan-Meier ocular survival, event-free survival, and progression-free survival estimates after second-course OAC were 82.8% (95% confidence interval [CI], 60.1%–93.2%), 57.3% (95% CI, 36.1%–73.7%), and 26.5% (95% CI, 11.0%–45.0%), respectively. All eyes without vitreous seeding were progression free, whereas eyes with vitreous seeding were associated significantly with worse ocular survival after second-course OAC ( P = 0.03). After second-course OAC, 90% of eyes had stable or improved ERG responses. Of all evaluable cases, there was no increased risk of systemic toxicity during the second course compared with the initial course of OAC. Conclusions Retinoblastoma eyes requiring second-course OAC after initial OAC treatment have good salvage rates, and the treatment has an acceptable ocular and systemic toxicity profile. However, these eyes often require additional (third- or fourth-course) OAC or other treatment methods because of progression of disease after second-line OAC, particularly if vitreous seeds are present at the time of initial OAC failure. [ABSTRACT FROM AUTHOR]