Zélia M. Corrêa

Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma.

PURPOSE This study evaluates the prognostic performance of a 15 gene expression profiling (GEP) assay that assigns primary posterior uveal melanomas to prognostic subgroups: class 1 (low metastatic risk) and class 2 (high metastatic risk). DESIGN Prospective, multicenter study. PARTICIPANTS A total of 459 patients with posterior uveal melanoma were enrolled from 12 independent centers. TESTING Tumors were classified by GEP as class 1 or class 2. The first 260 samples were also analyzed for chromosome 3 status using a single nucleotide polymorphism assay. Net reclassification improvement analysis was performed to compare the prognostic accuracy of GEP with the 7th edition clinical Tumor-Node-Metastasis (TNM) classification and chromosome 3 status. MAIN OUTCOME MEASURES Patients were managed for their primary tumor and monitored for metastasis. RESULTS The GEP assay successfully classified 446 of 459 cases (97.2%). The GEP was class 1 in 276 cases (61.9%) and class 2 in 170 cases (38.1%). Median follow-up was 17.4 months (mean, 18.0 months). Metastasis was detected in 3 class 1 cases (1.1%) and 44 class 2 cases (25.9%) (log-rank test, P<10(-14)). Although there was an association between GEP class 2 and monosomy 3 (Fisher exact test, P<0.0001), 54 of 260 tumors (20.8%) were discordant for GEP and chromosome 3 status, among which GEP demonstrated superior prognostic accuracy (log-rank test, P = 0.0001). By using multivariate Cox modeling, GEP class had a stronger independent association with metastasis than any other prognostic factor (P<0.0001). Chromosome 3 status did not contribute additional prognostic information that was independent of GEP (P = 0.2). At 3 years follow-up, the net reclassification improvement of GEP over TNM classification was 0.43 (P = 0.001) and 0.38 (P = 0.004) over chromosome 3 status. CONCLUSIONS The GEP assay had a high technical success rate and was the most accurate prognostic marker among all of the factors analyzed. The GEP provided a highly significant improvement in prognostic accuracy over clinical TNM classification and chromosome 3 status. Chromosome 3 status did not provide prognostic information that was independent of GEP.

Effectiveness of Treatments for Metastatic Uveal Melanoma

PURPOSE To evaluate and comment on published peer-reviewed literature for evidence of effectiveness of treatments for metastatic uveal melanoma. DESIGN Analytical nonexperimental study of published peer-reviewed data. METHODS Literature search and analysis of pertinent articles published between January 1, 1980 and June 30, 2008. RESULTS Of 80 identified publications, 12 (15.0%) were review articles without original information, 2 (2.5%) were review articles combined with case reports, 22 (27.5%) were case reports, 16 (20.0%) were retrospective descriptive case series reports, 3 (3.75%) were pilot studies of a novel intervention, 2 (2.5%) were prospective phase I clinical trials, 8 (10.0%) were prospective phase I/II clinical trials, and 15 (18.75%) were prospective phase II clinical trials. None of the articles reported a prospective, randomized phase III clinical trial. The largest reported unselected patient groups had a median survival of 3 to 4 months after detection of metastasis, whereas the largest selected patient groups showed substantially longer median survival times. CONCLUSIONS Although median survival time after diagnosis of metastatic uveal melanoma tends to be substantially longer in selected patient subgroups subjected to aggressive invasive interventions than it is in unselected groups, much if not most of this apparent difference in survival is likely to be attributable to selection bias, surveillance bias, and publication bias rather than treatment-induced alteration of expected outcome. Published peer-reviewed articles do not provide compelling scientific evidence of any survival benefit of any method of treatment for any subgroup of patients with metastatic uveal melanoma.

Long-term survival in choroidal and ciliary body melanoma after enucleation versus plaque radiation therapy ☆

OBJECTIVE This study aimed to determine whether the long-term melanoma-specific mortality rate of patients with a primary choroidal or ciliary body melanoma treated by enucleation is appreciably lower than that of similar patients treated by plaque radiation therapy. DESIGN Retrospective, nonrandomized, comparative clinical trial. PARTICIPANTS A previously reported group of 237 patients, 140 treated by enucleation and 97 treated by cobalt-60 (Co-60) plaque between May 1976 and June 1980, and a residual group of 122 patients, 51 treated by enucleation and 71 treated by Co-60 plaque, were identified by variable-by-variable range matching. INTERVENTION Primary treatment by enucleation or Co-60 plaque radiation therapy was performed. MAIN OUTCOME MEASURES Melanoma-specific mortality and duration of post-treatment survival were measured. RESULTS The melanoma-specific mortality rate was substantially worse in the original enucleation subgroup over the entire 15-year follow-up interval; however, differences in baseline prognostic factors between the subgroups are likely to explain the difference in survival curves. After elimination of patients with nonoverlapping values of individual clinical variables to adjust for recognized intergroup differences at baseline, there was no significant or clinically important difference in the 15-year mortality curves of the residual subgroups. The relative rate ratio for the treatment effect in the residual patients was 0.97 (95% confidence interval, 0.51-1.86). There was no late downturn in the survival curve of the plaque-treated patients or late crossing of the curves. CONCLUSION A large difference in survival between equivalent groups of patients with primary choroidal or ciliary body melanoma treated by enucleation versus plaque radiation therapy appears to be unlikely.

Ultrasound biomicroscopy as a tool for detecting and localizing occult foreign bodies after ocular trauma

OBJECTIVE To show the utility of ultrasound biomicroscopy (UBM) in imaging small ocular foreign bodies of the anterior segment. DESIGN Retrospective case series. PARTICIPANTS Twelve eyes of 12 consecutive patients evaluated in the emergency department or referred to specialty services at 1 institution between August 1994 and November 1997 were examined. INTERVENTION Ocular ultrasound biomicroscopy was performed. MAIN OUTCOME MEASURES Detection and localization of an ocular foreign body were measured. RESULTS An intraocular or superficial foreign body was detected by UBM in 9 (75%) of 12 eyes. The foreign body was classified as corneal in two eyes, subconjunctival in two, intrascleral in three, and intraocular in two eyes. The foreign body was not visible by ophthalmic physical examination in seven of the nine eyes with a confirmed ocular foreign body. In the remaining two eyes, UBM was used to determine the depth of a visible foreign body. In three of the eyes with a confirmed foreign body, computed tomography and/or contact B-scan ultrasonography was obtained and failed to show a foreign body. Six of the foreign bodies were nonmetallic. CONCLUSIONS Clinical detection of ocular foreign bodies after trauma can be hindered by small size, haziness of the optical media, poor patient cooperation, or hidden location. Ultrasound biomicroscopy is a valuable adjunct in the evaluation of suspected ocular foreign bodies, especially in cases involving small, nonmetallic objects.

Histopathological review of sebaceous carcinoma of the eyelid

Background:  Sebaceous carcinoma of the eyelid can clinically mimic benign conditions, such as recurrent chalazion and inflammation and histopathologically squamous cell and basal cell carcinoma (BCC). This retrospective study was undertaken as an attempt to improve the characterization and consequently the diagnosis of these tumors.

Gene therapy for Leber congenital amaurosis: advances and future directions

BackgroundLeber congenital amaurosis (LCA) is a congenital retinal dystrophy that results in significant and often severe vision loss at an early age. Comprehensive analysis of the genetic mutations and phenotypic correlations in LCA patients has allowed for significant improvements in understanding molecular pathways of photoreceptor degeneration and dysfunction. The purpose of this article is to review the literature on the subject of retinal gene therapy for LCA, including historical descriptions, preclinical animal studies, and human clinical trials.MethodsA literature search of peer-reviewed and indexed publications from 1996–2011 using the PubMed search engine was performed. Key terms included “Leber congenital amaurosis”, LCA, RPE65, ”cone-rod dystrophy”, “gene therapy”, and “human trials” in various combinations. Seminal articles prior to 1996 were selected from primary sources and reviews from the initial search. Articles were chosen based on pertinence to clinical, genetic, and therapeutic topics reviewed in this manuscript. Fundus photographs from LCA patients were obtained retrospectively from the clinical practice of one of the authors (R.A.S).ResultsHerein, we reviewed the literature on LCA as a genetic disease, the results of human gene therapy trials to date, and possible future directions towards treating inherited retinal diseases at the genetic level. Original descriptions of LCA by Theodor Leber and subsequent research demonstrate the severity of this disease with early-onset blindness. Discoveries of the causative heritable mutations revealed genes and protein products involved in photoreceptor development and visual transduction. Animal models have provided a means to test novel therapeutic strategies, namely gene therapy. Stemming from these experiments, three independent clinical trials tested the safety of subretinal delivery of viral gene therapy to patients with mutations in the RPE65 gene. More recently, efficacy studies have been conducted with encouraging results.ConclusionsInitial safety studies indicated promising results of subretinal delivery of viral vector with subclinical immunologic or surgical sequelae. Overall, these initial studies demonstrate that viral vector gene therapy results are very promising, safe, and effective. Future studies measuring potential improvement in photoreceptor function may rely on recent advances in retinal imaging and electrophysiologic testing.

The role of c-kit and imatinib mesylate in uveal melanoma

Background Uveal melanoma (UM) is the most common primary intraocular tumor in adults, leading to metastasis in 40% of the cases and ultimately to death in 10 years, despite local and/or systemic treatment. The c-kit protein (CD117) is a membrane-bound tyrosine kinase receptor and its overexpression has been observed in several neoplasms. Imatinib mesylate is a FDA approved compound that inhibits tyrosine quinase receptors, as well as c-kit. Imatinib mesylate controls tumor growth in up to 85% of advanced gastrointestinal stromal tumors, a neoplasia resistant to conventional therapy. Methods Fifty-five specimens of primary UM selected from the archives of the Ocular Pathology Laboratory, McGill University, Montreal, Canada, were immunostained for c-kit. All cells displaying distinct immunoreactivity were considered positive. Four human UM cell lines and 1 human uveal transformed melanocyte cell line were tested for in vitro proliferation Assays (TOX-6) and invasion assay with imatinib mesylate (concentration of 10 μM). Results The c-kit expression was positive in 78.2% of the UM. There was a statistical significant decrease in the proliferation and invasion rates of all 5 cell lines. Conclusion The majority of UM expressed c-kit, and imatinib mesylate does decrease the proliferation and invasion rates of human UM cell lines. These results justify the need for a clinical trial to investigate in vivo the response of UM to imatinib mesylate.

Independent Prognostic Significance of Gene Expression Profile Class and Largest Basal Diameter of Posterior Uveal Melanomas.

PURPOSE To determine whether any conventional clinical prognostic factors for metastasis from uveal melanoma retain prognostic significance in multivariate models incorporating gene expression profile (GEP) class of the tumor cells. DESIGN Prospective, interventional case series with a prognostic model. METHODS Single-institution study of GEP testing and other conventional prognostic factors for metastasis and metastatic death in 299 patients with posterior uveal melanoma evaluated by fine-needle aspiration biopsy (FNAB) at the time of or shortly prior to initial treatment. Univariate prognostic significance of all evaluated potential prognostic variables (patient age, largest linear basal diameter of tumor [LBD], tumor thickness, intraocular location of tumor, melanoma cytomorphologic subtype, and GEP class) was performed by comparison of Kaplan-Meier event rate curves and univariate Cox proportional hazards modeling. Multivariate prognostic significance of combinations of significant prognostic factors identified by univariate analysis was performed using step-up and step-down Cox proportional hazards modeling. RESULTS GEP class was the strongest prognostic factor for metastatic death in this series. However, tumor LBD, tumor thickness, and intraocular tumor location also proved to be significant individual prognostic factors in this study. On multivariate analysis, a 2-term model that incorporated GEP class and largest basal diameter was associated with strong independent significance of each of the factors. CONCLUSION Although GEP test is the most robust prognostic indicator in uveal melanoma and early studies of mostly larger tumors found that no clinicopathologic factors had significant prognostic value independent of GEP, our single-center study, which included a substantial proportion of smaller tumors, showed that both GEP and LBD of the tumor are independent prognostic factors for metastasis and metastatic death in multivariate analysis.

Size Overlap between Benign Melanocytic Choroidal Nevi and Choroidal Malignant Melanomas

PURPOSE To estimate size overlap between large choroidal nevi and small choroidal melanomas by using plotted frequency distributions of tumor size. METHODS Frequency distributions of largest linear basal diameter (LBD) and thickness (TH) of choroidal nevi and melanomas were plotted from published data and cases in the senior authors practice. Relative frequencies of choroidal nevi and melanomas were estimated from published data. Relative frequency distributions of the tumors were plotted to illustrate the extent of overlap between them. RESULTS Comparison of plotted frequency distribution curves for thickness indicated that there were approximately 125 nevi for every melanoma in the TH range 1.5 to 2 mm, approximately 25 nevi for every melanoma in the TH range 2 to 2.5 mm, and approximately 5 nevi for every melanoma in the TH range 2.5 to 3 mm. Similarly, comparison of the plotted frequency distribution curves for LBD of these tumor types indicated that there were approximately 70 nevi for every choroidal melanoma in the LBD range 5 to 6 mm, approximately 10 nevi for every melanoma in the LBD range 6 to 7 mm, and approximately 3 nevi for every melanoma in the LBD range 7 to 8 mm. CONCLUSIONS Because of the markedly greater cumulative lifetime incidence of choroidal nevi, the results of this analysis suggest considerable size overlap between larger nevi and smaller melanomas. Attempts to classify small melanocytic choroidal tumors clinically as benign nevi versus malignant melanomas on the basis of tumor size appear likely to result in multiple misclassifications.

Risk factors related to the severity of diabetic retinopathy

OBJETIVO: Determinar a relacao entre a gravidade ou estagio da retinopatia diabetica e os fatores de risco associados em uma populacao do sul do Brasil. METODOS: Estudo transversal de pacientes diabeticos, sem tratamento oftalmologico previo, atendidos em servico de oftalmologia terciario. Estes pacientes foram submetidos a retinografia colorida, exames laboratoriais, medida da pressao arterial sistemica e interrogados quanto a fatores de risco previamente estipulados pelos autores. A presenca, ou ausencia, de fatores de risco foi correlacionada a gravidade da retinopatia diabetica. RESULTADOS: Foram selecionados 81 pacientes, 28 homens, 53 mulheres, 55 brancos, 26 negros, 28 com diabete melito insulino-dependente, 53 com diabete melito nao insulino-dependente. Fatores correlacionados estatisticamente com estagios mais avancados da retinopatia diabetica incluem: dependencia a insulina (a<0,01), nefropatia (a<0,05), proteinuria (a<0,05), maior tempo de doenca (p<0,001), valores elevados de glicemia de jejum (p=0,11), hemoglobina glicosilada (p=0,001), colesterol total (p=0,019) e valores mais baixos de hematocrito (p=0,004) e hemoglobina (p=0,001). CONCLUSOES: Concluiu-se que, neste grupo estudado, a gravidade de retinopatia diabetica sofreu influencia de fatores de risco como tempo de duracao da doenca, tipo de diabete, controle metabolico da doenca, niveis de hematocrito e hemoglobina, colesterol total e proteinuria. Fatores que nao pareceram influenciar a gravidade da retinopatia incluem idade, sexo, hipertensao arterial e magnesio plasmatico. Tais dados sao semelhantes a maioria dos estudos publicados na literatura.