Validation of the East London Retinopathy of Prematurity algorithm to detect treatment-warranted retinopathy of prematurity: a cohort study.

AIM: To validate the East London Retinopathy of Prematurity algorithm (EL-ROP) in a cohort of infants at risk of developing retinopathy of prematurity (ROP). METHODS: The EL-ROP algorithm was applied retrospectively to routinely collected data from two tertiary neonatal units in England on infants eligible for ROP screening. The EL-ROP recommendation, to screen or not, was compared with the development of treatment-warranted ROP (TW-ROP) for each infant. The main outcome measures were (1) EL-ROP's sensitivity for predicting the future development of TW-ROP and (2) potential to reduce ROP screening examinations. RESULTS: Data from 568 infants were included in the trial. The median (IQR) birth weight (g) was 875 (704 - 1103) and gestational age (weeks) was 27.0 (25.4 - 29.0). Maternal ethnicity was black (33%) and non-black (67%). 58(10%) developed TW-ROP and in every case this was predicted by the EL-ROP algorithm. It's sensitivity was 100% (95% CI 94-100%) specificity: 44% (95% CI 39-48%) positive predictive value: 17% (95%CI 16-18%), negative predictive value: 100%. CONCLUSIONS: EL-ROP has been validated in a cohort of infants from two tertiary neonatal units in England. Further validation is required before its clinical usefulness can be assessed.

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.

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.

Microbial keratitis after penetrating keratoplasty: impact of sutures.

PURPOSE: To determine the impact of presence or absence of sutures in cases with post-penetrating keratoplasty (PKP) microbial keratitis. DESIGN: A 10-year retrospective chart review of post-PKP patients admitted with microbial keratitis at the Royal Victorian Eye and Ear Hospital, Melbourne, between January 1998 and December 2008 was undertaken. METHODS: Patients were categorized in 2 groups, "sutures present" and "sutures absent." Main parameters evaluated were clinical and microbiological profile and treatment outcome. RESULTS: One hundred and twenty-two episodes of microbial keratitis were noted in 101 patients: 71 (58.2%) with sutures present and 51 (41.8%) with sutures absent. Overall, pseudophakic bullous keratopathy was the most common indication for keratoplasty (P=.92). Ocular surface disorder was the commonest risk factor associated with the occurrence of infection in both groups (P=.17). Infections caused by Moraxella sp. (P=.001) were significantly more common in the "sutures absent" group. Surgical interventions were required for 47 episodes (39%), with corneal gluing performed in significantly higher number of cases in the "sutures absent" group (40% vs 15%; P=.05). Multivariate analyses did not reveal any significant associations. Final mean visual acuity outcome was poorer in the "sutures absent" group (logMAR 2.10 ± 0.92 vs 1.76 ± 0.96; P=.04). CONCLUSIONS: Corneal graft infections, in the presence and absence of sutures, share similar indications and risk factors. However, infections caused by indolent microorganisms were more prevalent in grafts without sutures. This group of patients required a higher number of surgical interventions in the form of corneal gluing and the overall visual outcome was poor.

Are lung disease and function related to age-related macular degeneration?

PURPOSE: To describe the relationship of lung disease and function with early age-related macular degeneration (AMD) in a population-based study. DESIGN: A population-based, cross-sectional study of 12,596 middle-aged participants from the Atherosclerosis Risk in Communities Study. METHODS: Lung function was assessed by spirometry. Physician diagnosis of asthma and lung disease was ascertained from a standardized questionnaire. AMD signs were graded from fundus photographs according to the Wisconsin grading protocol. RESULTS: Among the study population, 587 (4.7%) had early AMD, 638 (5.1%) had asthma, and 581 (4.6%) had lung disease. After adjusting for age, gender, smoking, and hypertension, each 1-L increase in predicted forced expiratory volume in 1 second (odds ratio [OR], 1.27; 95% confidence interval [CI], 0.89 to 1.80), forced vital capacity (OR, 1.18; 95% CI, 0.93 to 1.51), and peak expiratory flow rate (OR, 1.12; 95% CI, 0.95 to 1.33) were not significantly associated with early AMD. Forced expiratory volume in 1 second-to-forced vital capacity ratio (second quartile OR, 1.61; 95% CI, 0.88 to 2.93, third quartile OR, 1.65; 95% CI 0.90 to 3.03; fourth quartile OR, 1.28; 95% CI 0.68 to 2.40) was not associated significantly with early AMD. Similarly, asthma (OR, 1.06; 95% CI, 0.86 to 1.27) and other lung diseases (OR, 1.08; 95% CI, 0.90 to 1.29) were not associated with early AMD. CONCLUSIONS: Our data do not support a cross-sectional association between lung disease and risk of early AMD.

"Tuck in" lamellar keratoplasty for tectonic management of postkeratoplasty corneal ectasia with peripheral corneal involvement.

PURPOSE: Evaluation of "tuck in" lamellar keratoplasty (TILK) for the surgical management of postkeratoplasty corneal ectasia with peripheral corneal involvement. METHODS: Four eyes of 3 patients with post-penetrating keratoplasty corneal ectasia and contact lens intolerance underwent TILK that included a central lamellar keratoplasty with intrastromal tucking of the peripheral flange, at the Royal Victorian Eye and Ear Hospital, Melbourne, Australia. The main outcome measures analyzed were uncorrected visual acuity, best-corrected visual acuity, keratometry, and endothelial cell density. RESULTS: The original indication for surgery was keratoconus in all the cases. TILK was successfully performed in these patients. Mean follow-up period was 13 months (SD: 7.74) (range: 6-24 months). The preoperative best-corrected visual acuity improved from a mean value of 0.05 (SD: 0.05) to 0.34 (SD: 0.03) (P < 0.001). Mean keratometry decreased from 59.67 diopter (SD: 7.18) preoperatively to 43.50 diopter (SD: 2.23) postoperatively (P < 0.005). Mean endothelial cell loss after TILK was 5.93% (SD: 3.06) (P < 0.206). All grafts were clear at the last follow-up, and no cases of stromal or endothelial graft rejection were encountered. CONCLUSIONS: TILK can be successfully performed for post-penetrating keratoplasty corneal ectasia with peripheral corneal thinning.

Clinical experience with N-butyl cyanoacrylate tissue adhesive in corneal perforations secondary to herpetic keratitis.

PURPOSE: To evaluate the success of cyanoacrylate tissue adhesive in the management of corneal perforations associated with herpetic keratitis. METHODS: Case records of 46 patients with microbiologically proven herpetic keratitis associated with corneal perforations that were treated with corneal gluing were analyzed retrospectively in a tertiary care hospital. N-Butyl cyanoacrylate tissue adhesive and bandage contact lens were applied in addition to antiviral therapy. The main outcome measure was preservation of the structural integrity of the globe. RESULTS: Glue application could heal corneal perforations in only 17 eyes (37%). Therapeutic keratoplasty had to be performed in 26 eyes (57%) because of failure of the glue. Fourteen eyes (31%) required multiple applications of tissue adhesive, and 2 eyes had to be eviscerated. Location of perforation, additional anterior chamber intervention, and use of prophylactic acyclovir therapy had no statistically significant effect on the overall final outcome. CONCLUSION: Corneal perforations associated with herpetic keratitis may not heal with glue application alone, and corneal transplantation surgery may be required to maintain the ocular structural integrity.

Penetrating keratoplasty for unilateral corneal disease: outcomes from a tertiary care hospital in Australia.

PURPOSE: To assess the visual outcome after unilateral penetrating keratoplasty (PKP) in a heterogenous group of patients with unilateral corneal disease. METHODS: A retrospective analysis of hospital records of patients who had undergone PKP at the Royal Victorian Eye and Ear Hospital, Melbourne, Australia, over a 10-year period, was performed. All cases with a history of corneal transplantation surgery in one eye and a best-corrected visual acuity (BCVA) more than or equal to 0.5 in the fellow eye with no corneal pathologic condition were included. Outcome measures included BCVA at 2 years, and overall graft survival. RESULTS: Of the 498 grafts performed during the study period, 30 eyes (6%) met the inclusion criteria. The most common indications for PKP in the study group were bullous keratopathy (40%) and keratoconus (34%). The mean postoperative BCVA at 2 years (0.31 +/- 0.25; range, 0.033-1) was less than the mean BCVA of the fellow eye (0.77 +/- 0.20; range, 0.5-1) (P<0.00). Although there was a significant difference between the preoperative and postoperative BCVA (P<0.00), only 22% of patients could attain BCVA of more than or equal to 0.5. The major complications encountered were graft rejection (40%) and secondary graft failure (20%). CONCLUSIONS: Unilateral PKP is most commonly performed to treat bullous keratopathy and keratoconus in Australia and may be associated with suboptimal visual outcome as compared to the normal fellow eye.

Microbial keratitis in patients with down syndrome: a retrospective study.

PURPOSE: To study the microbiological and clinical profile of cases of microbial keratitis in patients with Down syndrome. METHODS: A retrospective chart review of all patients with Down syndrome and microbial keratitis admitted to the Royal Victorian Eye and Ear Hospital, Melbourne, Australia, between January 1997 and January 2007 was undertaken. Main parameters evaluated were clinical and microbiological profile and final outcome. RESULTS: Of 18 patients included in this study, 11 were men and 7 were women, with mean age of 50 +/- 29 years (range 20-61 years). The most common associated ocular abnormality was eyelid diseases (94%) followed by atopic keratoconjunctivitis (44%). Positive microbiological cultures were obtained in 5 (28%) cases with Streptococcus pneumoniae being the most prevalent isolate. Ocular herpes was detected in 2 patients with polymerase chain reaction. Surgical intervention was required in 13 (72%) patients in the form of keratoplasty (n = 3) corneal gluing (n = 2), tarsorrhaphy (n = 5), botox injection (n = 1), and enucleation (n = 2). CONCLUSIONS: Microbial keratitis in Down syndrome is associated with eyelid problems and ocular atopy, and due to failure of medical therapy alone, surgical intervention is required in majority of cases.