Metastatic Death Based on Presenting Features and Treatment for Advanced Intraocular Retinoblastoma: A Multicenter Registry-Based Study.

PURPOSE: To evaluate presenting features, tumor size, and treatment methods for risk of metastatic death due to advanced intraocular retinoblastoma (RB). DESIGN: International, multicenter, registry-based retrospective case series. PARTICIPANTS: A total of 1841 patients with advanced RB. METHODS: Advanced RB was defined by 8th edition American Joint Committee on Cancer (AJCC) categories cT2 and cT3 and new AJCC-Ophthalmic Oncology Task Force (OOTF) Size Groups (1: < 50% of globe volume, 2: > 50% but < 2/3, 3: > 2/3, and 4: diffuse infiltrating RB). Treatments were primary enucleation, systemic chemotherapy with secondary enucleation, and systemic chemotherapy with eye salvage. MAIN OUTCOME MEASURES: Metastatic death. RESULTS: The 5-year Kaplan-Meier cumulative survival estimates by patient-level AJCC clinical subcategories were 98% for cT2a, 96% for cT2b, 88% for cT3a, 95% for cT3b, 92% for cT3c, 84% for cT3d, and 75% for cT3e RB. Survival estimates by treatment modality were 96% for primary enucleation, 89% for systemic chemotherapy and secondary enucleation, and 90% for systemic chemotherapy with eye salvage. Risk of metastatic mortality increased with increasing cT subcategory (P < 0.001). Cox proportional hazards regression analysis confirmed a higher risk of metastatic mortality in categories cT3c (glaucoma, hazard ratio [HR], 4.9; P = 0.011), cT3d (intraocular hemorrhage, HR, 14.0; P < 0.001), and cT3e (orbital cellulitis, HR, 19.6; P < 0.001) than in category cT2a and with systemic chemotherapy with secondary enucleation (HR, 3.3; P < 0.001) and eye salvage (HR, 4.9; P < 0.001) than with primary enucleation. The 5-year Kaplan-Meier cumulative survival estimates by AJCC-OOTF Size Groups 1 to 4 were 99%, 96%, 94%, and 83%, respectively. Mortality from metastatic RB increased with increasing Size Group (P < 0.001). Cox proportional hazards regression analysis revealed that patients with Size Group 3 (HR, 10.0; P = 0.002) and 4 (HR, 41.1; P < 0.001) had a greater risk of metastatic mortality than Size Group 1. CONCLUSIONS: The AJCC-RB cT2 and cT3 subcategories and size-based AJCC-OOTF Groups 3 (> 2/3 globe volume) and 4 (diffuse infiltrating RB) provided a robust stratification of clinical risk for metastatic death in advanced intraocular RB. Primary enucleation offered the highest survival rates for patients with advanced intraocular RB.

High-risk Pathologic Features Based on Presenting Findings in Advanced Intraocular Retinoblastoma: A Multicenter, International Data-Sharing American Joint Committee on Cancer Study.

PURPOSE: To determine the value of clinical features for advanced intraocular retinoblastoma as defined by the eighth edition of the American Joint Committee on Cancer (AJCC) cT3 category and AJCC Ophthalmic Oncology Task Force (OOTF) Size Groups to predict the high-risk pathologic features. DESIGN: International, multicenter, registry-based retrospective case series. PARTICIPANTS: Eighteen ophthalmic oncology centers from 13 countries over 6 continents shared evaluations of 942 eyes enucleated as primary treatment for AJCC cT3 and, for comparison, cT2 retinoblastoma. METHODS: International, multicenter, registry-based data were pooled from patients enrolled between 2001 and 2013. High-risk pathologic features were defined as AJCC categories pT3 and pT4. In addition, AJCC OOTF Size Groups were defined as follows: (1) less than half, (2) more than half but less than two thirds, (3) more than two thirds of globe volume involved, and (4) diffuse infiltrating retinoblastoma. MAIN OUTCOME MEASURES: Statistical risk of high-risk pathologic features corresponding to AJCC cT3 subcategories and AJCC OOTF Size Groups. RESULTS: Of 942 retinoblastoma eyes treated by primary enucleation, 282 (30%) showed high-risk pathologic features. Both cT subcategories and AJCC OOTF Size Groups (P < 0.001 for both) were associated with high-risk pathologic features. On logistic regression analysis, cT3c (iris neovascularization with glaucoma), cT3d (intraocular hemorrhage), and cT3e (aseptic orbital cellulitis) were predictive factors for high-risk pathologic features when compared with cT2a with an odds ratio of 2.3 (P = 0.002), 2.5 (P = 0.002), and 3.3 (P = 0.019), respectively. Size Group 3 (more than two-thirds globe volume) and 4 (diffuse infiltrative retinoblastoma) were the best predictive factors with an odds ratio of 3.3 and 4.1 (P < 0.001 for both), respectively, for high-risk pathologic features when compared with Size Groups 1 (i.e., < 50% of globe volume). CONCLUSIONS: The AJCC retinoblastoma staging clinical cT3c-e subcategories (glaucoma, intraocular hemorrhage, and aseptic orbital cellulitis, respectively) as well as the AJCC OOTF Size Groups 3 (tumor more than two thirds of globe volume) and 4 (diffuse infiltrative retinoblastoma) both allowed stratification of clinical risk factors that can be used to predict the presence of high-risk pathologic features and thus facilitate treatment decisions.

Global Retinoblastoma Treatment Outcomes: Association with National Income Level.

PURPOSE: To compare metastasis-related mortality, local treatment failure, and globe salvage after retinoblastoma in countries with different national income levels. DESIGN: International, multicenter, registry-based retrospective case series. PARTICIPANTS: Two thousand one hundred ninety patients, 18 ophthalmic oncology centers, and 13 countries on 6 continents. METHODS: 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. MAIN OUTCOME MEASURES: Metastasis-related mortality and local treatment failure (defined as use of secondary enucleation or external beam radiation therapy). RESULTS: 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). CONCLUSIONS: 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.

A Multicenter, International Collaborative Study for American Joint Committee on Cancer Staging of Retinoblastoma: Part I: Metastasis-Associated Mortality.

PURPOSE: 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). DESIGN: International, multicenter, registry-based retrospective case series. PARTICIPANTS: A total of 2190 patients from 18 ophthalmic oncology centers from 13 countries over 6 continents. METHODS: 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. MAIN OUTCOME MEASURES: 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. RESULTS: 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. CONCLUSIONS: 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.

A Multicenter, International Collaborative Study for American Joint Committee on Cancer Staging of Retinoblastoma: Part II: Treatment Success and Globe Salvage.

PURPOSE: 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). DESIGN: International, multicenter, registry-based retrospective case series. PARTICIPANTS: A total of 2854 eyes of 2097 patients from 18 ophthalmic oncology centers from 13 countries over 6 continents. METHODS: 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. MAIN OUTCOME MEASURES: 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). RESULTS: 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). CONCLUSIONS: 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.

Retinoblastoma seeds: impact on American Joint Committee on Cancer clinical staging.

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.

Contact lenses in pediatrics study in Singapore.

PURPOSE: Previous studies in the United States have evaluated the benefits of soft contact lenses (CLs) in 8- to 12-year-old children and 13- to 17-year-old teens. This study was undertaken in Singapore and evaluated the safety, efficacy, and physiologic performance of daily disposable soft lenses in a population of children. METHODS: In this open-label, bilateral, 3-month dispensing study, 59 children (8-11 years) were fit with etafilcon A spherical or toric daily disposable lenses (1-DAY ACUVUE or 1-DAY ACUVUE for ASTIGMATISM, Vistakon, Jacksonville, FL). All subjects were neophytes requiring visual correction in both eyes. The refractive inclusion criteria were plano to -9.00 diopter (D) with astigmatism of < or =2.00DC in both eyes, or hyperopia of +0.50 to +6.00D with astigmatism of 0.75D or less. The subjects underwent follow-up evaluations, which included a questionnaire for parents and subjects, at 1 week, 1 month, and 3 months. RESULTS: Of the 59 subjects enrolled, 53 (90%) completed the study successfully. Six subjects were discontinued because of lens handling difficulties (four), unacceptable lens fit (one), and an adverse event (one). Adverse events were reported in three subjects, including the discontinuation, and in each case were due to a chalazion. Overall vision quality, overall comfort, and end-of-day comfort were graded significantly better at each of the follow-up visits compared with baseline with spectacles (P< or =0.0001). Both handling and reported symptoms improved during the course of the study. The questionnaire results indicated that most of both parents and subjects preferred CLs to spectacles across a wide variety of aspects including vision, comfort, handling, and appearance. Significantly, more limbal and bulbar hyperemia was noted at follow-up visits than at baseline (P=0.0001); however, no instances of hyperemia greater than grade 2 were noted at any visit. Significantly, more corneal staining was also noted at the 1- and 3-month follow-up visits than at baseline (21% at 3 months). CONCLUSION: A high proportion of Singaporean children requiring vision correction are able to successfully wear daily disposable soft CLs over a 3-month period. Overall, slit lamp findings showed the prevalence of corneal staining in this study to be 21% at 3 months, which is lower than that previously reported in adults, but higher than that reported in the US Contact Lenses in Pediatrics study (6%).

An unusual cause of acute bilateral optic disk swelling with macular star in a 9-year-old girl.

We report a rare case of bilateral optic disk swelling with macular exudates and cottonwool spots secondary to a pheochromocytoma in a 9-year-old girl. Malignant hypertensive changes in the eyes are uncommon and may sometimes resemble neuroretinitis. Overaggressive treatment of malignant hypertension can cause optic nerve infarction, leading to blindness.

Surgical experiences with two-muscle surgery for the treatment of intermittent exotropia.

BACKGROUND: The surgical management of intermittent exotropia, or X(T), remains a challenge. Not only are some quoted success rates relatively low (40-83%), but the outcome is notoriously unpredictable with a tendency to exotropic drift over time. METHODS: In this retrospective study, 118 patients who underwent either bilateral lateral rectus muscle recession (BLR) or unilateral medial rectus muscle resection and lateral rectus muscle recession (R&R) surgery during a 4-year period were reviewed. Surgical outcome between the 2 groups in addition to factors that influence outcome within groups were analyzed. Success was defined as an X(T) < or = 10PD. RESULTS: Sixty-four subjects underwent BLR, and 54 subjects underwent R&R surgery. Mean preoperative distant X(T) size was 38.7 +/- 6.7 PD. Subjects who underwent R&R did significantly better at 1-year follow-up (success 74.2% vs. 42.2%) but showed significantly more exotropic drift over time (P = 0.01). Within both BLR and R&R groups, subjects with basic-type X(T) did worse than those with divergence-excess X(T) at 1-year follow-up. Consecutive esotropias, however, were more likely with R&R surgery and in those with divergence excess X(T). Preoperative strabismus control, distant X(T) size, and patient age at surgery did not significantly influence outcome. CONCLUSION: In many cases, selection of surgery type continues to depend on the surgeon's preference, which is in turn influenced by his/her past experiences. The debate about which surgical type is best for different X(T) types continues.

Dissociated hypotropia: clinical features and surgical management of two cases.

BACKGROUND: Dissociated vertical deviation (DVD), which almost always shows a hypertropia of the affected eye, occasionally can manifest as a hypotropia, either unilaterally or bilaterally. Two patients are presented who had this rare variant of DVD, which has been termed "dissociated hypotropia," both of whom underwent surgery and had good outcomes. METHODS: Two patients, ages 13 and 14, with unilateral dissociated hypotropia underwent large inferior rectus muscle recessions on their affected eyes. In one case, a video-based eye tracker was used to record the dissociated hypotropic drifts in the eye to plot the changes in the drift amplitudes in response to increasing density filters over the fixating eye (Bielschowsky phenomenon) and to confirm whether the deviation changed in the light versus the dark. RESULTS: In case 1, the hypotropia drift measured up to 18(Delta), and it was reduced to zero with a 6 mm inferior rectus recession in the affected eye. In case 2, the drift measured up to 20(Delta). Eye movement recordings showed a time course of the downward drift that mirrored that of upward drift of hypertropic DVD and confirmed the presence of a Bielschowsky phenomenon. The drift amplitude did not change in bright versus dark conditions. An 8 mm inferior rectus recession on the affected eye reduced the hypotropia to 5(Delta). CONCLUSIONS: Dissociated hypotropia is a rare form of the dissociated strabismus complex. The downward drift has a time course similar to the upward drift of hypertropic DVD and shows the Bielschowsky phenomenon. It responds to a large inferior rectus muscle recession.

A retrospective review of 287 consecutive children in singapore presenting with intermittent exotropia.

BACKGROUND: Intermittent exotropia, X(T), is a relatively common form of strabismus among children in Singapore. The purpose of this study is to see how children presenting with this condition fared during a period of 5 years. METHODS: The medical records of all children younger than 16 years who presented to the eye clinic at the Singapore National Eye Centre with X(T) between January 1992 and December 1995 were reviewed retrospectively. RESULTS: A total of 287 patients satisfied the entry requirements of this study. Estimated age of onset of exotropia was documented in 161 subjects. The mean age of estimated onset was 3.0 +/- 2.5 years. The mean age of presentation was 6.1 +/- 3.1 years. The mean amount of distant exotropia was 36.4 +/- 12.5 prism diopters (PD). Seventy-two percent of children had poor/no distant control. During a 3-year period, the size of exotropia appears to remain constant (within 5 PD of original) in 48% and improved >5 PD in 32%. Control of distant exotropia remained the same in 63%, improved in 17% and worsened in 20%. Near exotropia was initially present in only 35.5%. The mean amount of near exotropia, when present, was 25.9 +/- 13.7PD. Near control remained the same in 65% and worsened in 22%. More variation was observed in subjects presenting before 5 years of age. One hundred sixty-two (56.4%) subjects underwent surgery. The mean age of surgery was 8.0 +/- 2.6 years. Surgery resulted in a final strabismus size between 10 PD exotropia and 5PD esotropia in 65.2% at 1 year postoperation. CONCLUSION: Half the subjects presenting with an intermittent exotropia eventually had surgery. In the remaining nonsurgical subjects, intermittent exotropia, once present, appeared to be a relatively stable condition.