Changes in vessel density patterns assessed with OCTA in patients with diabetic macular edema treated with anti-VEGF therapy.

AIMS: To determine the presence of sectoral changes in vessel density (VD) patterns induced by vascular endothelial growth factor inhibitors (anti-VEGF) in patients with diabetic macular edema (DME) using optical coherence tomography angiography (OCTA). METHODS: Prospective, interventional study. A total of 43 patients (63 eyes) were initially enrolled in the study. We performed swept source (SS) OCT and sectorial OCTA measurement to determine parafoveal VD at baseline and after six months of anti-VEGF treatment. In the locations with statistically significant differences in VD between baseline and month 6, we performed univariate and multivariate analyses to determine which, if any, of the baseline variables were associated with the observed changes. RESULTS: A total of 34 patients (48 eyes) were included in the final analysis. Mean VD decreased from baseline to month 6 (from 45.2 (± 3.5) to 44.6 (± 3.2) % in the SCP and from 50 (± 3.3) to 49 (± 3.9) % in the DCP). The only significant changes in VD were observed in the nasal sector of the deep capillary plexus, with a decrease of 2.9% (p = 0.001). On univariate and multivariate analyses, the only variable significantly associated with changes in VD in the nasal sector after 6 months of treatment was baseline VD in the same sector. CONCLUSIONS: Anti-VEGF therapy has a small impact on VD values over time. These variations observed after treatment seems to be related to changes over areas of vascular anomalies and displaced vessels adjacent to cystic areas, with no significant changes over ischemic areas. No correlation was observed between this trend and other clinical baseline features.

Local Resection in Choroidal Melanoma: A Review.

Surgical resection is widely used to treat small tumours located in the iris and the ciliary body, due to the accessibility of these sites. By contrast, surgical removal of choroidal tumours is substantially more challenging, which is why this procedure is performed only at specialised centres. In the present article, we review the literature on surgical resection of choroidal tumours, which can be performed as endoresection (ab interno) or transscleral resection (ab externo). An important aim of this review is to describe and compare the two approaches in terms of visual outcomes, survival rates, and complications. Both approaches are indicated for the removal of large tumours (thickness > 8 mm) with small base diameters. Surgical resection of the tumour allows clinicians to obtain valuable histopathologic and cytogenetic data from the specimen and eliminates the risks associated with radiotherapy. However, both of these surgical approaches are technically challenging procedures involving the risk of severe early and late postoperative complications.

Patients presenting with metastases: stage IV uveal melanoma, an international study.

OBJECTIVE: To analyse ocular and systemic findings of patients presenting with systemic metastasis. METHODS AND ANALYSIS: It is an international, multicentre, internet-enabled, registry-based retrospective data analysis. Patients were diagnosed between 2001 and 2011. Data included: primary tumour dimensions, extrascleral extension, ciliary body involvement, American Joint Committee on Cancer (AJCC)-tumour, node, metastasis staging, characteristics of metastases. RESULTS: Of 3610 patients with uveal melanoma, 69 (1.9%; 95% CI 1.5 to 2.4) presented with clinical metastasis (stage IV). These melanomas originated in the iris, ciliary body and choroid in 4%, 16% and 80% of eyes, respectively. Using eighth edition AJCC, 8 (11%), 20 (29%), 24 (35%), and 17 (25%) belonged to AJCC T-categories T1-T4. Risk of synchronous metastases increased from 0.7% (T1) to 1.5% (T2), 2.6% (T3) and 7.9% (T4). Regional lymph node metastases (N1a) were detected in 9 (13%) patients of whom 6 (67%) had extrascleral extension. Stage of systemic metastases (known for 40 (59%) stage IV patients) revealed 14 (35%), 25 (63%) and 1 (2%) had small (M1a), medium-sized (M1b) and large-sized (M1c) metastases, respectively. Location of metastases in stage IV patients were liver (91%), lung (16%), bone (9%), brain (6%), subcutaneous tissue (4%) and others (5%). Multiple sites of metastases were noted in 24%. Compared with the 98.1% of patients who did not present with metastases, those with synchronous metastases had larger intraocular tumours, more frequent extrascleral extension, ciliary body involvement and thus a higher AJCC T-category. CONCLUSIONS: Though higher AJCC T-stage was associated with risk for metastases at diagnosis, even small T1 tumours were stage IV at initial presentation. The liver was the most common site of metastases; however, frequent multiorgan involvement supports initial whole-body staging.

Uveal Melanoma, Angiogenesis and Immunotherapy, Is There Any Hope?

Uveal melanoma is considered a rare disease but it is the most common intraocular malignancy in adults. Local treatments are effective, but the systemic recurrence rate is unacceptably high. Moreover, once metastasis have developed the prognosis is poor, with a 5-year survival rate of less than 5%, and systemic therapies, including immunotherapy, have rendered poor results. The tumour biology is complex, but angiogenesis is a highly important pathway in these tumours. Vasculogenic mimicry, the ability of melanomas to generate vascular channels independently of endothelial cells, could play an important role, but no effective therapy targeting this process has been developed so far. Angiogenesis modulates the tumour microenvironment of melanomas, and a close interplay is established between them. Therefore, combining immune strategies with drugs targeting angiogenesis offers a new therapeutic paradigm. In preclinical studies, these approaches effectively target these tumours, and a phase I clinical study has shown encouraging results in cutaneous melanomas. In this review, we will discuss the importance of angiogenesis in uveal melanoma, with a special focus on vasculogenic mimicry, and describe the interplay between angiogenesis and the tumour microenvironment. In addition, we will suggest future therapeutic approaches based on these observations and mention ways in which to potentially enhance current treatments.

Clinical predictors of survival in metastatic uveal melanoma.

PURPOSE: To determine the clinical factors that influence survival in patients with metastatic uveal melanoma. STUDY DESIGN: Single-center, retrospective review of patients' medical records. METHODS: The following data of ninety-nine consecutive patients (49 men, 50 women) with metastatic uveal melanoma were registered: patient demographics; primary tumor characteristics; features of first melanoma-related metastasis; symptoms and patient status at distant disease debut and metastasis treatment. Overall survival was analyzed by Kaplan-Meier estimates. A Cox proportional hazards regression model was applied to identify independent predictors associated with survival. RESULTS: Mean patient age at metastatic diagnosis was 60.7 years (standard deviation, 12.8). The liver was the first metastatic site in most (92.9%) cases. The median disease-free interval was 26 months (interquartile range, 34). Median overall survival after detection of the first metastasis was 8 months (interquartile range, 14). The baseline characteristics of the primary uveal melanoma were not associated with survival in patients with stage IV disease. In the multivariate analysis, the following factors at first metastatic diagnosis were associated with improved overall survival: disease-free interval > 36 months; better performance status; and normal serum lactate dehydrogenase and gamma glutamyl transpeptidase levels. Overall survival was not influenced by specific metastatic treatment. CONCLUSION: Although metastatic uveal melanoma has a poor prognosis, this study reveals the existence of several independent prognostic factors for prolonged overall survival. These findings may help improve survival estimates in patients with advanced disease.

Prognostic Factors and Decision Tree for Long-Term Survival in Metastatic Uveal Melanoma.

PURPOSE: The purpose of this study was to demonstrate the existence of a bimodal survival pattern in metastatic uveal melanoma. Secondary aims were to identify the characteristics and prognostic factors associated with long-term survival and to develop a clinical decision tree. MATERIALS AND METHODS: The medical records of 99 metastatic uveal melanoma patients were retrospectively reviewed. Patients were classified as either short (≤ 12 months) or long-term survivors (> 12 months) based on a graphical interpretation of the survival curve after diagnosis of the first metastatic lesion. Ophthalmic and oncological characteristicswere assessed in both groups. RESULTS: Of the 99 patients, 62 (62.6%) were classified as short-term survivors, and 37 (37.4%) as long-term survivors. The multivariate analysis identified the following predictors of long-term survival: age ≤ 65 years (p=0.012) and unaltered serum lactate dehydrogenase levels (p=0.018); additionally, the size (smaller vs. larger) of the largest liver metastasis showed a trend towards significance (p=0.063). Based on the variables significantly associated with long-term survival, we developed a decision tree to facilitate clinical decision-making. CONCLUSION: The findings of this study demonstrate the existence of a bimodal survival pattern in patients with metastatic uveal melanoma. The presence of certain clinical characteristics at diagnosis of distant disease is associated with long-term survival. A decision tree was developed to facilitate clinical decision-making and to counsel patients about the expected course of disease.

Relative survival of patients with uveal melanoma managed in a single center.

To assess the 5-year relative survival of patients diagnosed with uveal melanoma (UM) in a single center. UM patients were recruited from 1995 to 2004 (N = 155) and were followed until December 2008. Relative survival (RS) methods were used to assess excess mortality. An RS regression model was fitted by sex, age, tumor origin, treatment, and tumor size to estimate the excess hazard rate (EHR) of death from UM. The overall 5-year RS was 90%, lower in women (84.6%) than in men (100%), lower in patients older than 60 years (88.8%) compared with those younger than or of 60 years of age (94.8%). Large tumors (80.8%) showed lower RS than medium (95.1%) and small ones (98.3%). Enucleated patients (80.5%) had lower RS compared with those who received brachytherapy (93.6%) and other treatments (94.7%). A significant EHR was found for women (EHR: 3.65), patients older than 60 years (EHR: 2.25), large-sized melanoma (EHR: 2.45), and during the third (EHR: 5.37) and fourth year (EHR: 3.01) of follow-up. This is the first Spanish study in a single center reporting RS among UM patients, taking into account clinical characteristics. Prognostic factors that explained RS among UM patients were sex, age, tumor size, and the year of follow-up. We also found a peak of excess mortality from the third until the fourth year after diagnosis, which warrants strict follow-up of these patients during this time interval.

Metastatic uveal melanoma: is there a role for conventional chemotherapy? - A single center study based on 58 patients.

Uveal melanoma metastases develop in 6.5-35% of patients, most commonly to the liver. Metastatic uveal melanoma (MUM) survival is poor, with 5-7 months of median survival. We reviewed retrospectively all patients with MUM diagnosed between January 1990 and December 2008 at our institution. We analyzed a total of 58 patients with a median age of 61 years (31-84 years). Median time for metastases development was 25.63 months (0.17-102.43 months). Fifty-six patients had hepatic involvement, 63.8% bilobar and 51.7% had more than or equal to five hepatic metastatic lesions. Sixteen patients (27.6%) had two or more organs involved. Six patients (10.71%) were treated with surgery, 25 patients (44.67%) received systemic chemotherapy, and 23 (41.07%) had best supportive care (BSC). The median overall survival (OS) for all the patients was 10.83 months [95% confidence interval (CI): 6.92-14.74]. Patients who had undergone chemotherapy presented 10.83 months (95% CI: 5.35-16.308) of median OS whereas the patients who did not undergo this treatment had an OS of 8.033 months (95% CI: 2.46-13.61). There were more patients with poor survival characteristics such as worse Eastern Cooperative Oncology Group performance status in the BSC group. OS was poor in treated and BSC patients. Differences in survival are more likely to be related to patient characteristics rather than to a chemotherapy effect. Patients with MUM should be included in clinical trials evaluating other options with newer agents.

(125)I episcleral plaque brachytherapy in the treatment of choroidal melanoma: a single-institution experience in Spain.

PURPOSE: To analyze the results of episcleral plaque brachytherapy from the Catalan Institute of Oncology in Spain. MATERIALS AND METHODS: From September 1996 through December 2004, 120 patients with choroidal melanoma (median age, 59 years) were treated with iodine-125 seeds at our institution. Patients were classified according to the criteria developed by the Collaborative Ocular Melanoma Study (COMS) group, as follows-COMS-I: 3 patients; COMS-II: 87 patients; COMS-III: 24 patients; and indeterminate COMS: 9 patients. Followup ranged from 1 year to 8.4 years. RESULTS: Overall survival at 5 and 8 years was 83.9% and 73.3%, respectively. The 5- and 8-year specific survival rate was 85.7%. Local control was 88.2% and 72.7% at 5 and 8 years, respectively. The most common treatment-related toxicity was cataract formation (31.6% of cases), followed by radiation retinopathy (7.5%) and retinal detachment (4.1%). CONCLUSION: The results of this institutional retrospective study confirm that the use of iodine-125 episcleral plaques to treat choroidal melanoma offers the potential for conserving a functioning eyeball. The toxicity profile is favorable and disease control is similar to other techniques.

Intravitreal bevacizumab (Avastin) in the treatment of macular edema secondary to retinal vein occlusion.

OBJECTIVE: To evaluate efficacy and safety of intravitreal injections of bevacizumab in the treatment of macular edema secondary to retinal vein occlusion (RVO). METHODS: Prospective study, noncomparative, interventional case series. Twelve consecutive patients (12 eyes) with macular edema associated with nonischemic retinal vein occlusion were treated with intravitreal bevacizumab (1.25 mg). All subjects underwent standardized ophthalmic evaluation at baseline and at weeks 1, 4, 12, and 24, consisting of visual acuity (VA) measurement using ETDRS charts, and imaging with ocular coherence tomography evaluating changes in foveal thickness (FT) and macular volume (MV). RESULTS: The median age was 66 years (+/- 4.16), and the median duration of symptoms was 4 months (+/- 1.81). There were six cases of inferior branch vein occlusion and six cases of superior branch retinal vein occlusion. Mean VA improved from 1.32 +/- 0.24 (logMAR values) at baseline to 0.8 +/- 0.15 (p = 0.0003) at the 6-month follow-up. The macular edema responded promptly, and a trend to restoration of normal macular anatomy was observed at by the seventh day. Mean FT improved from 615.50 +/- 116.29 microns to 420 +/- 72.53 microns (p = 0.001), and the mean MV improved from 19.81 +/- 2.31mm3 to 9.23 +/- 1.38 (p = 0.0001) at the 6-month follow-up.