Pseudoexfoliation and Cataract Syndrome Associated with Genetic and Epidemiological Factors in a Mayan Cohort of Guatemala.

The Mayan population of Guatemala is understudied within eye and vision research. Studying an observational homogenous, geographically isolated population of individuals seeking eye care may identify unique clinical, demographic, environmental and genetic risk factors for blinding eye disease that can inform targeted and effective screening strategies to achieve better and improved health care distribution. This study served to: (a) identify the ocular health needs within this population; and (b) identify any possible modifiable risk factors contributing to disease pathophysiology within this population. We conducted a cross-sectional study with 126 participants. Each participant completed a comprehensive eye examination, provided a blood sample for genetic analysis, and received a structured core baseline interview for a standardized epidemiological questionnaire at the Salama Lions Club Eye Hospital in Salama, Guatemala. Interpreters were available for translation to the patients' native dialect, to assist participants during their visit. We performed a genome-wide association study for ocular disease association on the blood samples using Illumina's HumanOmni2.5-8 chip to examine single nucleotide polymorphism SNPs in this population. After implementing quality control measures, we performed adjusted logistic regression analysis to determine which genetic and epidemiological factors were associated with eye disease. We found that the most prevalent eye conditions were cataracts (54.8%) followed by pseudoexfoliation syndrome (PXF) (24.6%). The population with both conditions was 22.2%. In our epidemiological analysis, we found that eye disease was significantly associated with advanced age. Cataracts were significantly more common among those living in the 10 districts with the least resources. Furthermore, having cataracts was associated with a greater likelihood of PXF after adjusting for both age and sex. In our genetic analysis, the SNP most nominally significantly associated with PXF lay within the gene KSR2 (p < 1 × 10-5). Several SNPs were associated with cataracts at genome-wide significance after adjusting for covariates (p < 5 × 10-8). About seventy five percent of the 33 cataract-associated SNPs lie within 13 genes, with the majority of genes having only one significant SNP (5 × 10-8). Using bioinformatic tools including PhenGenI, the Ensembl genome browser and literature review, these SNPs and genes have not previously been associated with PXF or cataracts, separately or in combination. This study can aid in understanding the prevalence of eye conditions in this population to better help inform public health planning and the delivery of quality, accessible, and relevant health and preventative care within Salama, Guatemala.

Delayed Enucleation With Neoadjuvant Chemotherapy in Advanced Intraocular Unilateral Retinoblastoma: AHOPCA II, a Prospective, Multi-Institutional Protocol in Central America.

PURPOSE: Treatment abandonment because of enucleation refusal is a limitation of improving outcomes for children with retinoblastoma in countries with limited resources. Furthermore, many children present with buphthalmos and a high risk of globe rupture during enucleation. To address these unique circumstances, the AHOPCA II protocol introduced neoadjuvant chemotherapy with delayed enucleation. PATIENTS AND METHODS: Patients with advanced unilateral intraocular disease (International Retinoblastoma Staging System [IRSS] stage I) were considered for upfront enucleation. Those with diffuse invasion of the choroid, postlaminar optic nerve, and/or anterior chamber invasion received six cycles of adjuvant chemotherapy (vincristine, carboplatin, and etoposide). Patients with buphthalmos and those with a perceived risk for enucleation refusal and/or abandonment were given two to three cycles of chemotherapy before scheduled enucleation followed by adjuvant chemotherapy to complete six cycles, regardless of pathology. RESULTS: A total of 161 patients had unilateral IRSS stage I disease; 102 underwent upfront enucleation, and 59 had delayed enucleation. The estimated 5-year abandonment-sensitive event-free and overall survival rates for the group were 0.81 ± 0.03 and 0.86 ± 0.03, respectively. The 5-year estimated abandonment-sensitive event-free survival rates for patients undergoing upfront and delayed enucleation were 0.89 ± 0.03 and 0.68 ± 0.06, respectively (P = .001). Compared with AHOPCA I, abandonment for patients with IRSS stage I retinoblastoma decreased from 16% to 4%. CONCLUSION: AHOPCA describes the results of advanced intraocular retinoblastoma treated with neoadjuvant chemotherapy. In eyes with buphthalmos and patients with risk of abandonment, neoadjuvant chemotherapy can be effective when followed by enucleation and adjuvant chemotherapy. Our study suggests that this approach can save patients with buphthalmos from ocular rupture and might reduce refusal of enucleation and abandonment.

Increased incidence and disparity of diagnosis of retinoblastoma patients in Guatemala.

Analysis of 327 consecutive cases at a pediatric referral hospital of Guatemala reveals that retinoblastoma accounts for 9.4% of all cancers and the estimated incidence is 7.0 cases/million children, higher than the United States or Europe. The number of familial cases is low, and there is a striking disparity in indigenous children due to late diagnosis, advanced disease, rapid progression and elevated mortality. Nine germline mutations in 18 patients were found; two known and five new mutations. Hypermethylation of RB1 was identified in 13% of the tumors. An early diagnosis program could identify cases at an earlier age and improve outcome of retinoblastoma in this diverse population.

Retinoblastoma in Central America: report from the Central American Association of Pediatric Hematology Oncology (AHOPCA).

BACKGROUND: Retinoblastoma is highly curable in high income countries. Low income countries have poor results due to advanced disease and lack of resources. Central American Association of Pediatric Hematology Oncology (AHOPCA) aimed to standardize the approach and to improve outcomes of patients with retinoblastoma. PROCEDURE: One hundred seventy-one patients, age <18 years newly diagnosed with retinoblastoma were treated according to laterality and stage. Therapeutic modalities were: surgery (enucleation), local control (laser therapy, cryotherapy), chemotherapy, and radiation therapy. Chemotherapy consisted of vincristine, etoposide, and carboplatin (6 cycles). Outcomes were measured by overall survival. Events were abandonment of therapy and death. RESULTS: One hundred seventy-one patients (129 unilateral, 42 bilateral) were treated. Median age was 2 years 4 months; 112 (66%) were diagnosed before 3 years of age. 119 (92%) eyes in patients with unilateral disease were Reese-Ellsworth IV or V versus 52 (62%) eyes in patients with bilateral disease. Extraocular disease was more prevalent in unilateral disease (65% vs. 50%). Older age at diagnosis correlated with higher stage. Estimated overall survival at 60 months was 0.48 ± 0.04. Outcome of patients with bilateral disease was significantly better than unilateral (62% ± 0.09 vs. 42% ± 0.05, P = 0.0006). Thirty-eight patients (22%) refused or abandoned therapy. CONCLUSIONS: Protocol-directed therapy for retinoblastoma in Central America is possible. Patients present with advanced disease and outcome is significantly worse than in middle and high-income countries. Refusal and abandonment of therapy are societal events that affect outcome. Initiatives aimed at improving early diagnosis, while dedicated treatment centers are developed, are critical.

Retinoblastoma en Guatemala: diagnóstico temprano salva vidas / Retinoblastoma in Guatemala: early diagnosis saves lives

El retinoblastoma es el más común cáncer ocular de la niñez. El sitio primario es la retina y que se desarrolla en los primeros 6 años de vida. Su incidencia mundial es 1 en 18,000 niños menores de 5 años en EEUU (1) (2-4). Además, la literatura sugiere que hispanos tienen una incidencia más alta que otras razas (5-6). En EEUU se diagnostican alrededor de 300 casos al año. En Guatemala, la Unidad Nacional de Oncología Pediátrica diagnostica 27-30 casos anuales; y pone al retinoblastoma como tercer cáncer de la niñez, después de leucemias y linfomas (Datos UNOP, 2010)...

Development of retinoblastoma programs in Central America.

BACKGROUND: Retinoblastoma, a curable eye tumor, is associated with poor survival in Central America (CA). To develop a retinoblastoma program in El Salvador, Guatemala, and Honduras, twinning initiatives were undertaken between local pediatric oncology centers, nonprofit foundations, St. Jude Children's Research Hospital, and the University of Tennessee Hamilton Eye Institute. PROCEDURE: The retinoblastoma program focused on developing early diagnosis programs in Honduras with national vaccination campaigns, developing treatment protocols suited to local conditions, building local networks of oncologists and ophthalmologists, training local healthcare providers, using modern donated equipment for diagnosis and treatment, and the ORBIS Cybersight consultation program and Internet meetings to further education and share expertise. Pediatric ophthalmologists and oncologists worked with foundations to treat patients locally with donated equipment and Internet consultations, or at the center in Guatemala. RESULTS: Number of patients successfully treated increased after the program was introduced. For 2000-2003 and 2004-2007, patients abandoning/refusing treatment decreased in Guatemala from 20 of 95 (21%) to 14 of 123 (11%) and in Honduras from 13 of 37 (35%) to 7 of 37 (19%). Survival in El Salvador was good and abandonment/refusal low for both periods. Of 18 patients receiving focal therapy for advanced disease, 14 have single remaining eyes. CONCLUSION: Development of the program in CA has decreased abandonment/refusal and enabled ophthalmologists at local centers to use modern equipment to provide better treatment. This approach might serve as a guide for developing other multispecialty programs.

Retinoblastoma: one world, one vision.

Retinoblastoma is curable when diagnosed early and treated appropriately; however, the prognosis is dismal when the basic elements of diagnosis and treatment are lacking. In developing countries, poor education, lower socioeconomic conditions, and inefficient health care systems result in delayed diagnosis and suboptimal care. Furthermore, the complexity of multidisciplinary care required is seldom possible. Whereas ocular salvage is a priority in the Western world, death from retinoblastoma is still a major problem in developing countries. To bring the 2 ends of this spectrum together and provide a forum for discussion, the "One World, One Vision" symposium was organized, at which clinicians and researchers from various cultural, geographic, and socioeconomic backgrounds converged to discuss their experiences. Strategies for early diagnosis in developing countries were discussed. Elements of the development of retinoblastoma centers in developing countries were discussed, and examples of successful programs were highlighted. An important component in this process is twinning between centers in developing countries and mentor institutions in high-income countries. Global initiatives by nongovernmental organizations such as the International Network for Cancer Treatment and Research, Orbis International, and the International Agency for Prevention of Blindness were presented. Treatment of retinoblastoma in developing countries remains a challenge; however, it is possible to coordinate efforts at multiple levels, including public administrations and nonprofit organizations, to improve the diagnosis and treatment of retinoblastoma and to improve the outcome for these children.