Differences in Childhood Growth Parameters Between Patients With Somatic and Heritable Retinoblastoma.

Purpose: Little is known regarding differences in childhood growth between somatic and heritable retinoblastoma (Rb) populations. We aimed to compare childhood growth parameters between somatic and heritable Rb cohorts at birth and at time of diagnosis with Rb. Methods: A multinational, longitudinal cohort study was conducted with patients from 11 centers in 10 countries who presented with treatment naïve Rb from January to December 2019. Variables of interest included age, sex, and size characteristics at birth and at time of presentation, as well as germline mutation status. After Bonferroni correction, results were statistically significant if the P value was less than 0.005. Results: We enrolled 696 patients, with 253 analyzed after exclusion criteria applied. Between somatic (n = 39) and heritable (n = 214) Rb cohorts, with males and females analyzed separately, there was no significant difference in birth weight percentile, weight percentile at time of diagnosis, length percentile at time of diagnosis, weight-for-length percentile at time of diagnosis, or change of weight percentile from birth to time of diagnosis. Patients with heritable Rb had a smaller mean weight percentile at birth and smaller mean weight and length percentiles at time of diagnosis with Rb, although this difference was not statistically significant. All cohorts experienced a slight negative change of weight percentile from birth to time of diagnosis. No cohort mean percentiles met criteria for failure to thrive, defined as less than the 5th percentile. Conclusions: Children with Rb seem to have normal birth and childhood growth patterns. There is no definitive evidence that somatic or heritable Rb has a biological or environmental impact on childhood growth parameters.

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.

The role of maternal age & birth order on the development of unilateral and bilateral retinoblastoma: a multicentre study.

BACKGROUND/OBJECTIVES: Retinoblastoma is a common childhood intraocular malignancy, the bilateral form of which most commonly results from a de novo germline pathogenic variant in the RB1 gene. Both advanced maternal age and decreasing birth order are known to increase the risk of de novo germline pathogenic variants, while the influence of national wealth is understudied. This cohort study aimed to retrospectively observe whether these factors influence the ratio of bilateral retinoblastoma cases compared to unilateral retinoblastoma, thereby inferring an influence on the development of de novo germline pathogenic variants in RB1. SUBJECTS/METHODS: Data from 688 patients from 11 centres in 10 countries were analysed using a series of statistical methods. RESULTS: No associations were found between advanced maternal age, birth order or GDP per capita and the ratio of bilateral to unilateral retinoblastoma cases (p values = 0.534, 0.201, 0.067, respectively), indicating that these factors do not contribute to the development of a de novo pathogenic variant. CONCLUSIONS: Despite a lack of a definitive control group and genetic testing, this study demonstrates that advanced maternal age, birth order or GDP per capita do not influence the risk of developing a bilateral retinoblastoma.

Risk factors associated with abandonment of care in retinoblastoma: analysis of 692 patients from 10 countries.

BACKGROUND: Rates of care abandonment for retinoblastoma (RB) demonstrate significant geographical variation; however, other variables that place a patient at risk of abandoning care remain unclear. This study aims to identify the risk factors for care abandonment across a multinational set of patients. METHODS: A prospective, observational study of 692 patients from 11 RB centres in 10 countries was conducted from 1 January 2019 to 31 December 2019. Multivariate logistic regression was used to identify risk factors associated with higher rates of care abandonment. RESULTS: Logistic regression showed a higher risk of abandoning care based on country (high-risk countries include Bangladesh (OR=18.1), Pakistan (OR=45.5) and Peru (OR=9.23), p<0.001), female sex (OR=2.39, p=0.013) and advanced clinical stage (OR=4.22, p<0.001). Enucleation as primary treatment was not associated with a higher risk of care abandonment (OR=0.59, p=0.206). CONCLUSION: Country, advanced disease and female sex were all associated with higher rates of abandonment. In this analysis, enucleation as the primary treatment was not associated with abandonment. Further research investigating cultural barriers can enable the building of targeted retention strategies unique to each country.

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.

Defining High-risk Retinoblastoma: A Multicenter Global Survey.

IMPORTANCE: High-risk histopathologic features of retinoblastoma are useful to assess the risk of systemic metastasis. In this era of globe salvage treatments for retinoblastoma, the definition of high-risk retinoblastoma is evolving. OBJECTIVE: To evaluate variations in the definition of high-risk histopathologic features for metastasis of retinoblastoma in different ocular oncology practices around the world. DESIGN, SETTING, AND PARTICIPANTS: An electronic web-based, nonvalidated 10-question survey was sent in December 2020 to 52 oncologists and pathologists treating retinoblastoma at referral retinoblastoma centers. INTERVENTION: Anonymized survey about the definition of high-risk histopathologic features for metastasis of retinoblastoma. MAIN OUTCOMES AND MEASURES: High-risk histopathologic features that determine further treatment with adjuvant systemic chemotherapy to prevent metastasis. RESULTS: Among the 52 survey recipients, the results are based on the responses from 27 individuals (52%) from 24 different retinoblastoma practices across 16 countries in 6 continents. The following were considered to be high-risk features: postlaminar optic nerve infiltration (27 [100%]), involvement of optic nerve transection (27 [100%]), extrascleral tissue infiltration (27 [100%]), massive (≥3 mm) choroidal invasion (25 [93%]), microscopic scleral infiltration (23 [85%]), ciliary body infiltration (20 [74%]), trabecular meshwork invasion (18 [67%]), iris infiltration (17 [63%]), anterior chamber seeds (14 [52%]), laminar optic nerve infiltration (13 [48%]), combination of prelaminar and laminar optic nerve infiltration and minor choroidal invasion (11 [41%]), minor (<3 mm) choroidal invasion (5 [19%]), and prelaminar optic nerve infiltration (2 [7%]). The other histopathologic features considered high risk included Schlemm canal invasion (4 [15%]) and severe anaplasia (1 [4%]). Four respondents (15%) said that the presence of more than 1 high-risk feature, especially a combination of massive peripapillary choroidal invasion and postlaminar optic nerve infiltration, should be considered very high risk for metastasis. CONCLUSIONS AND RELEVANCE: Responses to this nonvalidated survey conducted in 2020-2021 showed little uniformity in the definition of high-risk retinoblastoma. Postlaminar optic nerve infiltration, involvement of optic nerve transection, and extrascleral tumor extension were the only features uniformly considered as high risk for metastasis across all oncology practices. These findings suggest that the relevance about their value in the current scenario with advanced disease being treated conservatively needs further evaluation; there is also a need to arrive at consensus definitions and conduct prospective multicenter studies to understand their relevance.

The Effects of Breastfeeding on Retinoblastoma Development: Results from an International Multicenter Retinoblastoma Survey.

The protective effects of breastfeeding on various childhood malignancies have been established but an association has not yet been determined for retinoblastoma (RB). We aimed to further investigate the role of breastfeeding in the severity of nonhereditary RB development, assessing relationship to (1) age at diagnosis, (2) ocular prognosis, measured by International Intraocular RB Classification (IIRC) or Intraocular Classification of RB (ICRB) group and success of eye salvage, and (3) extraocular involvement. Analyses were performed on a global dataset subgroup of 344 RB patients whose legal guardian(s) consented to answer a neonatal questionnaire. Patients with undetermined or mixed feeding history, family history of RB, or sporadic bilateral RB were excluded. There was no statistically significant difference between breastfed and formula-fed groups in (1) age at diagnosis (p = 0.20), (2) ocular prognosis measures of IIRC/ICRB group (p = 0.62) and success of eye salvage (p = 0.16), or (3) extraocular involvement shown by International Retinoblastoma Staging System (IRSS) at presentation (p = 0.74), lymph node involvement (p = 0.20), and distant metastases (p = 0.37). This study suggests that breastfeeding neither impacts the sporadic development nor is associated with a decrease in the severity of nonhereditary RB as measured by age at diagnosis, stage of disease, ocular prognosis, and extraocular spread. A further exploration into the impact of diet on children who develop RB is warranted.

Parental Origin of the RB1 Gene Mutations in Families with Low Penetrance Hereditary Retinoblastoma.

Our aim was to identify RB1 alterations causing hereditary low penetrance retinoblastoma and to evaluate how the parental origin of an RB1 mutation affects its phenotypic expression. By NGS and MLPA, RB1 mutations were found in 191 from 332 unrelated retinoblastoma patients. Among patients with identified RB1 mutations but without clinical family history of retinoblastoma, 7% (12/175) were found to have hereditary disease with one of the parents being an asymptomatic carrier of an RB1 mutation. Additionally, in two families with retinoblastoma history, mutations were inherited by probands from unaffected parents. Overall, nine probands inherited RB1 mutations from clinically unaffected fathers and five, from mothers. Yet, we gained explanations of maternal "unaffectedness" in most cases, either as somatic mosaicism or as clinical presentation of retinomas in involution, rendering the proportion of paternal to maternal truly asymptomatic mutation carriers as 9:1 (p = 0.005). This observation supports an assumption that parental origin of an RB1 mutation influences the likelihood of developing retinoblastoma. Additionally, our study revealed a relatively high frequency of asymptomatic carriage of the RB1 mutations among the parents of retinoblastoma patients, highlighting the utmost necessity of molecular analysis among the probands' relatives irrespective of their clinical status and family history of retinoblastoma.

Lag Time between Onset of First Symptom and Treatment of Retinoblastoma: An International Collaborative Study of 692 Patients from 10 Countries.

BACKGROUND: The relationship between lag time and outcomes in retinoblastoma (RB) is unclear. In this study, we aimed to study the effect of lag time between onset of symptoms and diagnosis of retinoblastoma (RB) in countries based on their national-income and analyse its effect on the outcomes. METHODS: We performed a prospective study of 692 patients from 11 RB centres in 10 countries from 1 January 2019 to 31 December 2019. RESULTS: The following factors were significantly different among different countries based on national-income level: age at diagnosis of RB (p = 0.001), distance from home to nearest primary healthcare centre (p = 0.03) and mean lag time between detection of first symptom to visit to RB treatment centre (p = 0.0007). After adjusting for country income, increased lag time between onset of symptoms and diagnosis of RB was associated with higher chances of an advanced tumour at presentation (p < 0.001), higher chances of high-risk histopathology features (p = 0.003), regional lymph node metastasis (p < 0.001), systemic metastasis (p < 0.001) and death (p < 0.001). CONCLUSIONS: There is a significant difference in the lag time between onset of signs and symptoms and referral to an RB treatment centre among countries based on national income resulting in significant differences in the presenting features and clinical outcomes.

Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis.

Aims: Peritonitis is one of the most common causes of sepsis, a serious syndrome characterized by a dysregulated systemic inflammatory response. Recent evidence suggests that Granzyme A (GzmA), a serine protease mainly expressed by NK and T cells, could act as a proinflammatory mediator and could play an important role in the pathogenesis of sepsis. This work aims to analyze the role and the therapeutic potential of GzmA in the pathogenesis of peritoneal sepsis. Methods: The level of extracellular GzmA as well as GzmA activity were analyzed in serum from healthy volunteers and patients with confirmed peritonitis and were correlated with the Sequential Organ Failure Assessment (SOFA) score. Peritonitis was induced in C57Bl/6 (WT) and GzmA-/- mice by cecal ligation and puncture (CLP). Mice were treated intraperitoneally with antibiotics alone or in combination serpinb6b, a specific GzmA inhibitor, for 5 days. Mouse survival was monitored during 14 days, levels of some proinflammatory cytokines were measured in serum and bacterial load and diversity was analyzed in blood and spleen at different times. Results: Clinically, elevated GzmA was observed in serum from patients with abdominal sepsis suggesting that GzmA plays an important role in this pathology. In the CLP model GzmA deficient mice, or WT mice treated with an extracellular GzmA inhibitor, showed increased survival, which correlated with a reduction in proinflammatory markers in both serum and peritoneal lavage fluid. GzmA deficiency did not influence bacterial load in blood and spleen and GzmA did not affect bacterial replication in macrophages in vitro, indicating that GzmA has no role in bacterial control. Analysis of GzmA in lymphoid cells following CLP showed that it was mainly expressed by NK cells. Mechanistically, we found that extracellular active GzmA acts as a proinflammatory mediator in macrophages by inducing the TLR4-dependent expression of IL-6 and TNFα. Conclusions: Our findings implicate GzmA as a key regulator of the inflammatory response during abdominal sepsis and provide solid evidences about its therapeutic potential for the treatment of this severe pathology.

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.

An international survey of classification and treatment choices for group D retinoblastoma.

AIM: To determine which IIRC scheme was used by retinoblastoma centers worldwide and the percentage of D eyes treated primarily with enucleation versus globe salvaging therapies as well as to correlate trends in treatment choice to IIRC version used and geographic region. METHODS: An anonymized electronic survey was offered to 115 physicians at 39 retinoblastoma centers worldwide asking about IIRC classification schemes and treatment patterns used between 2008 and 2012. Participants were asked to record which version of the IIRC was used for classification, how many group D eyes were diagnosed, and how many eyes were treated with enucleation versus globe salvaging therapies. Averages of eyes per treatment modality were calculated and stratified by both IIRC version and geographic region. Statistical significance was determined by Chi-square, ANOVA and Kruskal-Wallis tests using Prism. RESULTS: The survey was completed by 29% of physicians invited to participate. Totally 1807 D eyes were diagnosed. Regarding IIRC system, 27% of centers used the Children's Hospital of Los Angeles (CHLA) version, 33% used the Children's Oncology Group (COG) version, 23% used the Philadelphia version, and 17% were unsure. The rate for primary enucleation varied between 0 and 100% and the mean was 29%. By IIRC version, primary enucleation rates were: Philadelphia, 8%; COG, 34%; and CHLA, 37%. By geographic region, primary enucleation rates were: Latin America, 57%; Asia, 40%; Europe, 36%; Africa, 10%, US, 8%; and Middle East, 8%. However, systemic chemoreduction was used more often than enucleation in all regions except Latin America with a mean of 57% per center (P<0.0001). CONCLUSION: Worldwide there is no consensus on which IIRC version is used, systemic chemoreduction was the most frequently used initial treatment during the study period followed by enucleation and primary treatment modality, especially enucleation, varied greatly with regards to IIRC version used and geographic region.