Association of TYRP1 with hypoxia and its correlation with patient outcome in uveal melanoma.

PURPOSE: Molecular mechanisms of uveal melanoma development in association with high pigmentation are unclear. Tyrosinase Related Protein (TYRP1) is not only one of the important melanogenesis marker that contributes to melanin synthesis, but can also prevents the melanocyte death. The induction of melanogenesis leads to induction of HIF-1α which can affect the behavior of melanoma cells and its surrounding environment. The aim of our study was to determine the expression of TYRP1 and HIF-1α at the protein and RNA level and determine its prognostic significance. METHODS: In the present study, the expression of TYRP1 and HIF-1α was investigated on 61 formalin-fixed paraffin-embedded choroidal melanoma samples by immunohistochemistry. Fresh 50 samples were validated by real-time PCR. Results were correlated with clinicopathological parameters and Kaplan-Meier was performed to determine the prognostic significance. RESULTS: High immunoexpression of TYRP1 and HIF-1α was present in 61 and 54% of patients, respectively. Both TYRP1 and HIF-1α correlated well with high pigmentation and BAP1 (BRCA1 Associated Protein-1) loss (p < 0.05) at IHC level as well as transcriptional level. There was reduced metastatic free survival in patients with necrosis and this was statistically significant (p = 0.010). CONCLUSION: Our findings indicate that TYRP1 can be used as a potential biomarker in the development of targeted therapy in UM. Further studies on melanogenesis markers associated with TYRP1 could provide us a better understanding in this field.

DNA damage response proteins and its role in tumor progression of uveal melanoma with patient outcome.

BACKGROUND: The role of DNA damage response (DDR) proteins is poorly understood in uveal melanoma. ATR belongs to one of those proteins that induce DDR by arresting the cell cycle which leads to DNA repair. ATR is localized at position 23 on the same chromosome 3 where BAP1 is located at position 21.1 which is a known poor prognostic marker of UM. The aim of our study is to detect the expression of ATR at the protein and RNA levels and determine its prognostic significance. METHODS: Expression of nuclear ATR was investigated on sixty-nine UM patients. Formalin-fixed paraffin-embedded choroidal melanoma samples were taken to evaluate the expression of ATR. Fifty samples were also validated by real-time PCR. Results of both protein and mRNA were then correlated with clinicopathological parameters. To determine the prognostic significance, Kaplan-Meier and multivariate analyses were performed. RESULTS: Loss of ATR protein was seen in 72% cases which was statistically significant with epithelioid cell type (p = 0.005), tumor thickness (p = 0.016), mitotic figures (p = 0.001) and BAP1 loss (p < 0.001). At the transcriptional level loss of ATR was seen in 76% cases which were statistically significant with metastasis (p = 0.046), staging (0.044) and loss of BAP1 (p = 0.022). On multivariate analysis loss of ATR and tumor staging came out to be independent prognostic parameters. CONCLUSION: Our data suggest that ATR might serve as a potential prognostic marker in UM patients and could serve as a potential therapeutic target.

Uveal Metastasis Based on Patient Sex in 2214 Tumors of 1111 Patients. A Comparison of Female Versus Male Clinical Features and Outcomes.

BACKGROUND: Lacking in previous studies on uveal metastasis is a robust statistical comparison of patient demographics, tumor features, and overall survival based on patient sex. OBJECTIVE: The aim of this study was to evaluate demographics, clinical features, and overall survival of patients with uveal metastasis based on sex. METHOD: This is a retrospective analysis. All patients were evaluated on the Ocular Oncology Service, Wills Eye Hospital, PA between January 1, 1974 and June 1, 2017. RESULTS: A total of 2214 uveal metastases were diagnosed in 1310 eyes of 1111 consecutive patients. A comparison (female versus male) revealed differences across several demographic and clinical features including, among others, mean age at metastasis diagnosis (58 vs 63 years, P < 0.001), bilateral disease (21% vs 11%, P < 0.001), and mean number of metastases per eye (1.8 vs 1.6 tumors per eye, P = 0.04). There were differences in overall mean survival (20 vs 13 months, P = 0.03) and 5-year survival (Kaplan-Meier estimate) (31% vs 21%, P < 0.001). CONCLUSIONS: There are demographic, clinical, and survival differences when patients with uveal metastases are compared by sex. Understanding these differences can aid the clinician in better anticipating patient outcomes.

Does NEMO/IKKγ protein have a role in determining prognostic significance in uveal melanoma?

PURPOSE: Uveal melanoma, although a rare form of cancer, is the most common primary malignancy of the eye in adults. Nuclear factor-κB (NF-κB) is a transcription factor that transactivates genes involved in the regulation of cell growth, apoptosis, angiogenesis, and metastasis, but the molecular mechanisms that negatively regulate NF-κB activation are not fully understood. NF-κB can also be activated by DNA damage pathway through NEMO protein. Therefore, the objective of this study is to elucidate the role of NEMO/IKKγ protein in uveal melanoma patients. METHODS: Seventy-five formalin-fixed paraffin-embedded prospective tissues of uveal melanoma were included in the present study. These cases were reviewed and investigated for the expression of NEMO/IKKγ protein by immunohistochemistry and validated by western blotting along with the qRT-PCR for mRNA expression. Expression levels were correlated with the clinicopathological parameters and patients' outcome. RESULTS: Immunohistochemistry showed cytoplasmic expression of NEMO/IKKγ expression in only 22 out of 75 (29.33%) cases. This result was confirmed by western blotting, and correlated well with the immunohistochemical expression of NEMO/IKKγ protein (48 kDa). In addition, downregulation of this gene was found in 87.93% of the cases when compared with the normal tissues. On statistical analysis, loss of NEMO/IKKγ protein was correlated with neovascularization, high mitotic count, and presence of vascular loop (p < 0.05). There was less overall survival rate with low expression of NEMO/IKKγ protein in patients with uveal melanoma. CONCLUSION: This was the first study suggesting the relevant role of NEMO/IKKγ protein, and highlights the prognostic significance with outcome in uveal melanoma patients. This protein might be used as a screening biomarker in these patients after large-scale validation and translational studies.

Prognostic implications of cytopathologic classification of melanocytic uveal tumors evaluated by fine-needle aspiration biopsy.

PURPOSE: Determine whether cytopathologic classification of melanocytic uveal tumors evaluated by fine-needle aspiration biopsy (FNAB) is a significant prognostic factor for death from metastasis. METHODS: Retrospective analysis of cases of clinically diagnosed uveal melanoma evaluated by fine-needle aspiration biopsy from 1980 to 2006. Main outcome evaluated was death from metastasis. Associations between baseline clinical variables and cytopathologic classification were evaluated using cross-tabulation. Prognostic significance of cytopathologic classification was evaluated by Kaplan-Meier and Cox proportional hazards analysis. RESULTS: Of 302 studied biopsies, 260 (86.1%) yielded sufficient cells for cytopathologic classification. Eighty of the 260 patients who had a sufficient specimen have already died (P=0.021), 69 from metastatic uveal melanoma. Cell type assigned by cytopathology was strongly associated with metastasis/metastatic death in this series (P=0.0048). Multivariate analysis showed cytopathologic classification to be an independently significant prognostic factor for metastatic death (P=0.0006). None of the 42 patients whose tumor yielded insufficient aspirates (sampled in at least two sites) have developed metastasis or died of metastasis thus far. CONCLUSION: In this series, cytopathology of fine-needle aspiration biopsy samples obtained from uveal melanomas was strongly prognostic of death from metastasis. Insufficiently aspirates (2 or more sites sampled) proved to be prognostic of a favorable outcome (i.e., not developing metastasis).

Prognostic implications of cytopathologic classification of melanocytic uveal tumors evaluated by fine-needle aspiration biopsy / Implicação prognóstica da classificação citopatológica dos tumores melanocíticos da úvea avaliados pela biópsia aspirativa com agulha fina

PURPOSE: Determine whether cytopathologic classification of melanocytic uveal tumors evaluated by fine-needle aspiration biopsy (FNAB) is a significant prognostic factor for death from metastasis. METHODS: Retrospective analysis of cases of clinically diagnosed uveal melanoma evaluated by fine-needle aspiration biopsy from 1980 to 2006. Main outcome evaluated was death from metastasis. Associations between baseline clinical variables and cytopathologic classification were evaluated using cross-tabulation. Prognostic significance of cytopathologic classification was evaluated by Kaplan-Meier and Cox proportional hazards analysis. RESULTS: Of 302 studied biopsies, 260 (86.1%) yielded sufficient cells for cytopathologic classification. Eighty of the 260 patients who had a sufficient specimen have already died (P=0.021), 69 from metastatic uveal melanoma. Cell type assigned by cytopathology was strongly associated with metastasis/metastatic death in this series (P=0.0048). Multivariate analysis showed cytopathologic classification to be an independently significant prognostic factor for metastatic death (P=0.0006). None of the 42 patients whose tumor yielded insufficient aspirates (sampled in at least two sites) have developed metastasis or died of metastasis thus far. CONCLUSION: In this series, cytopathology of fine-needle aspiration biopsy samples obtained from uveal melanomas was strongly prognostic of death from metastasis. Insufficiently aspirates (2 or more sites sampled) proved to be prognostic of a favorable outcome (i.e., not developing metastasis).

OBJETIVO: Determinar se a classificação citopatológica de tumores melanocíticos da úvea avaliados pela biópsia aspirativa com agulha fina (BAAF) é um fator prognóstico significativo para óbito por metástases. Métodos: Análise retrospectiva de casos diagnosticados clinicamente como melanoma uveal e avaliados pela biópsia aspirativa com agulha fina entre 1980 e 2006. O evento principal analisado foi óbito por metástase. Associações entre variáveis clínicas à apresentação e classificação citopatológica foram avaliadas usando tabulação cruzada. Significância prognóstica da classificação citopatológica foi avaliada por análise de riscos proporcionais de Cox e Kaplan-Meier. RESULTADOS: Das 302 biópsias estudadas, 260 (86,1%) renderam um número suficiente de células para classificação citopatológica. Oitenta dos 260 pacientes que obtiveram um espécime suficiente (adequado) foram a óbito (P=0,021), 69 destes por melanoma uveal metastático. O tipo celular designado pela citopatologia apresentou forte associação com metástase/óbito por metástase nessa série (P=0,0048). Análise multivariada mostrou que a classificação citopatológica foi um fator prognóstico independente significativo para o óbito por metástase (P=0,0006). Nenhum dos 42 pacientes cujos tumores renderam um aspirado insuficiente (quando foram amostrados pelo menos 2 sítios) desenvolveu metástase e foi a óbito por metástase até o presente momento. CONCLUSÃO: Nessa série, a citopatologia dos espécimes obtidos pela biópsia aspirativa com agulha fina de melanomas uveais foi fortemente prognóstica para óbito por metástase. Os aspirados insuficientes (se duas ou mais áreas foram amostradas) provou ser um resultado prognóstico favorável (i.e., de não desenvolvimento de metástases).

Episcleral brachytherapy for uveal melanoma: analysis of 136 cases.

PURPOSE: To assess the results of I-125 episcleral brachytherapy (EB) in uveal melanoma: tumour control, visual acuity (VA), eye preservation and survival. PATIENTS: Prospective and consecutive study of patients with a diagnosis of uveal melanoma at the Ocular Oncology Unit in the Valladolid University Teaching Hospital treated with EB between September 1997 and June 2008. Ocular examination and extraocular and systemic extension data were registered in a database at the time of the diagnosis and during the follow-up. RESULTS: Among a total of 310 patients diagnosed between September 1997 and June 2008, 136 were treated with EB (mean age, 58.3). Mean follow-up was 55.3 months. As for tumour type, 66.9% were nodular and 39% mushroom shaped. With respect to size, 80.9% were medium, 7.4% small and 11.8% large. After 4.6 years of follow-up, tumours were controlled in 97.1%, with a 55.1% reduction in mean height; only 2.9% of patients showed recurrence. VA was maintained in 16.2% of patients and 17.6% showed an increase; 33% had retinopathy and 14.6% optic neuropathy. Only 5.1% of patients underwent enucleation due to complications and there has been 1 melanoma-related death to date. CONCLUSIONS: I-125 EB is effective in tumour control, allowing preservation of the eye and useful visual function for the majority of patients.

Impact of delayed treatment in growing posterior uveal melanomas.

OBJECTIVE: To investigate the impact of pretreatment tumor growth on survival in patients with primary posterior uveal melanoma. DESIGN: Retrospective case-by-case matched comparative survival study. PATIENTS: Thirty patients with documented tumor growth of at least 3 mm in basal diameter, 1.5 mm in thickness, or both during a pretreatment interval of 6 months or more and a matched control group of 30 promptly treated patients. Matching criteria included patient age (+/- 10 years), largest basal tumor diameter (+/- 2 mm), tumor thickness (+/- 1.5 mm), location of anterior tumor margin (same defined zone), and visual symptoms (present or absent). SETTING: The Oncology Unit of the Retina Service at Wills Eye Hospital, Philadelphia, Pa. INTERVENTIONS: All patients were treated in a nonrandomized fashion by conventional therapeutic methods appropriate to the tumor's size, location, and other factors. MAIN OUTCOME MEASURES: Actuarial melanoma-specific mortality and all-cause mortality. RESULTS: The mean +/- SE cumulative 5-year probability of melanoma-specific mortality relative to the date of initial examination was 17.1% +/- 7% in the delayed treatment group and 18.4% +/- 8% in the prompt treatment group. This difference is not statistically significant (P > .5, log rank test). CONCLUSIONS: These results lend support to the belief that delayed treatment of selected small and dormant-appearing choroidal and ciliary body melanomas does not substantially increase the probability of melanoma-specific mortality; however, they do not prove that observation is the correct management option for all patients with a posterior uveal melanoma.

Estudio de factores de riesgo en mortalidad de pacientes enucleados por melanoma uveal en Chile: análisis de sobrevida / Study of risk factors in mortality of enucleated patients by uveal melanoma in Chile: analysis of survival

Este estudio es un análisis de los factores de riesgo en la sobrevida de pacientes por melanoma uveal en Chile durante el período de 1979 a 1989. Se analizaron 74 pacientes enucleados por melanoma uveal identificados en el laboratorio ocular del Hospital Clínico de la Universidad de Chile. Para determinar su estado vital al momento del estudio de obtuvo información de las fichas del hospital, informes de los médicos tratantes e informe oficial del Registro Civil e Identificación según el RUT del paciente. Los factores de riesgo considerados fueron la edad del paciente, localización del borde anterior del tumor, tipo histológico, radioterapia previa, invasión escleral y altura del tumor. Para el análisis de los datos se trabajó con el programa Epi Info. Se determinaron dos grupos de riesgo: riesgo alto de mortalidad (60 años de edad o más, al borde anterior del tumor preecuatorial y tipo celular epiteloídeo) y bajo riesgo de mortalidad (menos de 60 años de edad, borde anterior del tumor postecuatorial y tipo celular no epiteloídeo)