MuSIC report III: tumour microcirculation patterns and development of metastasis in long-term follow-up of melanocytic uveal tumours.

PURPOSE: To statistically determine differences in microcirculation patterns between nevi and uveal melanomas and the influence of these patterns on metastatic potential in the long-term follow-up of 112 patients with melanocytic uveal tumours. In vivo markers indicating malignancy and metastatic potential have implications for treatment decision. METHODS: Primary diagnosis and work-up included clinical examination, fundus photography, standardized A and B scan echography as well as evaluation of tumour microcirculation patterns via confocal fluorescein and indocyanine green angiography (ICGA). Patient data were collected from the patient files, the tumour registry or personal contact. Statistical analysis was performed with spss 22.0 using chi-square, Fisher's exact test and Kaplan-Meier survival analysis. RESULTS: Forty-three uveal melanocytic lesions remained untreated and were retrospectively classified as benign nevi, whereas 69 lesions were malignant melanomas (T1: 32, T2: 28, T3: 6 and T4: 3). 'Silent' and 'arcs without branching' were found significantly more often in nevi (p = 0.001 and p = 0.010), whereas 'parallel with cross-linking' and 'networks' were significantly more frequent in melanomas (p = 0.022 and p = 0.029). The microcirculation pattern 'parallel with cross-linking' proved significantly more frequent in patients who developed metastases (p = 0.001). CONCLUSIONS: Certain microcirculation patterns may guide us in differentiating uveal nevi from malignant melanomas. A non-invasive prognostic marker can be of great value for borderline lesions in which cytology is less likely taken. 'Parallel with cross-linking' did not only indicate malignancy, but it was also associated with later tumour metastasis.

Reasons reported by African ophthalmologists for staying in Africa and for considering migrating.

In sub-Sahara Africa, the shortage of ophthalmologists is a major obstacle in the struggle of fighting preventable blindness. Migration of well-trained ophthalmologists has an additional negative effect on the low number of caregivers. However, to date, the reasons affecting migration of ophthalmologists have not been completely understood. The present study evaluates reasons reported by ophthalmologists for staying in their current work setting/country and potential reasons why they might consider migrating. In the years 2009-2011, after approval was obtained from the Institutional Review Board, a questionnaire evaluating reasons for and against migration of ophthalmologists was distributed to the participants of 2-week courses in Ethiopia, Cameroon and Kenya providing continuing medical education in the field of ophthalmology. A total of 84 ophthalmologists participated in this survey. The main reasons for staying in their current region/country were good working conditions, commitment to help, possibility of further training, familial ties and general feeling of satisfaction. Professional development elsewhere and better income abroad were named as the main reasons for considering migration. Almost half of the survey participants reported good infrastructure, equipment, and consumables, which is encouraging. Programs aimed at continuing medical education of ophthalmologists to enable professional development may have an appropriate role in the establishment of an ophthalmic infrastructure which can meet patients' needs.

Quality of life in the follow-up of uveal melanoma patients after CyberKnife treatment.

To assess quality of life in uveal melanoma patients within the first and second year after CyberKnife radiosurgery. Overall, 91 uveal melanoma patients were evaluated for quality of life through the Short-form (SF-12) Health Survey at baseline and at every follow-up visit over 2 years after CyberKnife radiosurgery. Statistical analysis was carried out using SF Health Outcomes Scoring Software and included subgroup analysis of patients developing secondary glaucoma and of patients maintaining a best corrected visual acuity (BCVA) of the treated eye of 0.5 log(MAR) or better. Analysis of variance, Greenhouse-Geisser correction, Student's t-test, and Fisher's exact test were used to determine statistical significance. Physical Functioning (PF) and Role Physical (RP) showed a significant decrease after CyberKnife radiosurgery, whereas Mental Health (MH) improved (P=0.007, P<0.0001 and P=0.023). MH and Social Functioning (SF) increased significantly (P=0.0003 and 0.026) in the no glaucoma group, MH being higher compared with glaucoma patients (P=0.02). PF and RP were significantly higher in patients with higher BCVA at the second follow-up (P=0.02). RP decreased in patients with BCVA<0.5 log(MAR) (P=0.013). Vitality (VT) increased significantly in patients whose BCVA could be preserved (P=0.031). Neither tumor localization nor size influenced the development of secondary glaucoma or change in BCVA. Although PF and RP decreased over time, MH improved continuously. Prevention of secondary glaucoma has a significant influence on both SF and MH, whereas preservation of BCVA affects VT. Emotional stability throughout follow-up contributes positively toward overall quality of life. CyberKnife radiosurgery may contribute to attenuation of emotional distress in uveal melanoma patients.

Receiver operating characteristic analysis: calculation for the marker 'melanoma inhibitory activity' in metastatic uveal melanoma patients.

The serological marker melanoma inhibitory activity (MIA) has been shown to be significantly higher in the serum of patients suffering from metastatic uveal melanoma than in progression-free patients. The objective of this study was to calculate a meaningful receiver operating characteristic (ROC) curve for MIA based on a large patient collective and to find an appropriate threshold value. MIA tumor marker levels of 503 outpatients suffering from uveal melanoma were evaluated using enzyme-linked immunosorbent assay. Fifty-four patients had confirmed metastases and 449 patients showed no overt metastatic disease at the time the blood sample was taken. ROC analysis was performed and the area under the curve (AUC) was calculated. Metastatic patients showed significantly higher MIA levels (median 11.69 ng/ml) than patients in the group without overt metastatic disease (median 6.97 ng/ml) (the Mann-Whitney test, P<0.001). The AUC was 0.84 (95% confidence interval: 0.76-0.91). The ROC resulting from our study can be applied for test comparison by means of AUC. The AUC value of 0.84 for MIA demonstrates the accurate performance of the test. On the basis of this ROC curve, we propose a MIA threshold value for uveal melanoma patients of 8.3 ng/ml (with a corresponding sensitivity of 82% and specificity of 77%, positive predictive value of 0.30 and negative predictive value of 0.97). In patients with higher MIA serum levels, further diagnostics should be initiated.

Ocular fat embolism syndrome.

Ocular fat embolism syndrome in the complete absence of any cardiac defects is a rare phenomenon which is not commonly encountered in ophthalmic practice. We present a case of a 16-year-old girl with fat embolism syndrome and involvement of the retina after a tibial fracture without any cardiac defect.

Whole-body F-18-fluoro-2-deoxyglucose positron emission tomography/computed tomography imaging in the follow-up of metastatic uveal melanoma.

Metastasis has been reported in the follow-up of up to 50% of uveal melanoma patients. Established oncological diagnostic modalities in tumor follow-up so far have limited sensitivity and specificity. The diagnostic value of combined positron emission tomography (PET)/computed tomography (CT) scans in the follow-up of patients with metastatic uveal melanoma was assessed. Eleven patients with successfully treated and one patient with suspected uveal melanoma underwent combined PET/CT scan. The indication for PET/CT scan was heterogenous and ranged from suspected metastatic choroidal melanoma in conventional imaging (n=3) to exclusion of further organ involvement before local therapy of liver metastases (n=5) and restaging after local or systemic therapy of metastases (n=4). PET/CT scan showed vital metastases from uveal melanoma in all patients (n=12). Ten patients showed vital hepatic metastases (83%), five osseous (42%), four lymphatic (33%), two pulmonary (17%), one adrenal (8%) and one had muscular metastases (8%). Six patients showed multiple organ involvement (50%). In addition, PET/CT scan correctly identified a primary intraocular tumor and ruled out pulmonary metastatic involvement with suspicious intrapulmonary findings in a CT scan and chest X-ray in two patients. It could also confirm an equivocal intrahepatic finding in an MRI scan as a vital metastasis. PET/CT scan is a very sensitive and specific tool for the detection and localization of metastatic disease in patients with uveal melanoma, assessing both anatomical morphology and cell metabolism in one single examination. With novel therapeutic approaches in evolution, PET/CT scanning can be of great importance for therapy planning and monitoring.

Choroidal pigmented lesions imaged by ultra-wide-field scanning laser ophthalmoscopy with two laser wavelengths (Optomap).

PURPOSE: Clinical differentiation of choroidal pigmented lesions is sometimes difficult. Choroidal melanoma is the most prevalent primary neoplasia among malignant ocular tumors, and metastasis often occurs before the primary tumor is diagnosed. Therefore, early detection is essential. We investigated the imaging properties of clinically diagnosed melanocytic choroidal tumors using a nonmydriatic ultra-wide-field scanning laser ophthalmoscope (SLO) with two laser wavelengths to distinguish benign from malignant lesions. Repeated standardized ultrasound (US) evaluation provided reference standard. METHODS: In a consecutive series of 49 patients with clinically diagnosed melanocytic choroidal tumors in one eye, 29 had established melanoma (defined by proven growth on repeated US follow-up) and 20 had nevi (defined by no malignancy according to clinical, US, and growth characteristics for at least 2 years). All patients underwent clinical examination, undilated Optomap((R)) (Optos PLC, Dunfermline, Fife, Scotland, UK) imaging, standardized US examination, and standard retinal photography. Measurements of the tumor base using the Optomap software were compared with US B-scan measurements. Imaging characteristics from the SLO images were correlated with the structural findings in the two patient groups. RESULTS: Measurements of tumor base correlated well between SLO and US with r = 0.61 (T-direction) and r = 0.51 (L-direction). On SLO imaging, typical malignant lesions appeared dark on the red laser channel and bright on the green laser channel. Based on those simple binary characteristics, a sensitivity of 76% at a specificity of 70% was obtained for a correct classification of lesions. When analogous to clinical examination lesion size, margin touching the optic disc, and existence of subretinal fluid were additionally considered, 90% sensitivity at 82% specificity was obtained. CONCLUSIONS: In this first, limited series, nonmydriatic SLO imaging with two laser wavelengths permitted to differentiate malignant ocular tumors from nonmalignant lesions with high diagnostic accuracy. Additional parameters may further enhance diagnostic properties, but larger patient series are required to validate our findings and prove the diagnostic properties.

Prospective study of risk factors for conjunctival bacterial contamination in patients undergoing intraocular surgery.

PURPOSE: To determine whether a patient's age, gender, local or systemic risk factors affect the rate of preoperative bacterial contamination. METHODS: Consecutive 1,474 patients undergoing intraocular surgery were enrolled in this prospective masked study. Past medical history was noted and examinations were performed. The patients were divided into four groups: a control group (without local or systemic risk factors), those with local risk factors (chronic use of topical medications, contact lens wear, blepharitis, chronic eyelid or conjunctival inflammation), those with systemic risk factors (immunosuppression, diabetes, autoimmune conditions, and asthma), and those with both. Conjunctival cultures were obtained before surgery. RESULTS: Among the 1,474 patients, 914 bacteria were isolated from 214 (14.9%) patients. Advanced age was associated with a higher rate of positive conjunctival cultures (p<0.005). No statistical difference was found with regard to gender (p=0.7173). Among the 282 patients in the control group, 14 (5%) had a positive conjunctival culture. Compared to the control group, positive conjunctival cultures were found in 118 out of 503 patients (23.5%) with local risk factors (p<0.0001), 65 out of 545 patients (11.9%) with systemic risk factors (p=0.0019), and 22 out of 144 (15.3%) with both (p=0.0006). Two patients developed postoperative endophthalmitis (0.14%), one with both local risk and systemic factors and the other with a systemic risk factor. CONCLUSIONS: Patients with local or systemic risk factors or advanced age were found to have a higher rate of bacterial conjunctival contamination before intraocular surgery.

Complex microcirculation patterns detected by confocal indocyanine green angiography predict time to growth of small choroidal melanocytic tumors: MuSIC Report II.

PURPOSE: Multiple independent laboratories have confirmed the histologic observation that some tumor microcirculation patterns (MCPs) in uveal melanomas are associated strongly with death resulting from metastatic disease. Because these patterns are imageable with confocal indocyanine green angiography (ICG), we designed a prospective study to evaluate whether these angiographically detectable MCPs predict time to tumor growth. DESIGN: Observational case series, prospective, non-randomized. PARTICIPANTS: Ninety-eight patients with unilateral, small, choroidal melanocytic tumors. METHODS: The following information and tumor characteristics were recorded for each patient: demographic parameters, best-corrected visual acuity, intraocular pressure, related visual symptoms, location and dimension of tumor, pigmentation, orange pigment, drusen, tumor-associated hemorrhage, subretinal fluid, and confocal ICG angiographically determined microcirculation patterns-silent (avascularity), normal (preexisting normal choroidal vessels within the tumor), straight vessels, parallel without and with cross-linking, arcs without and with branching, loops, and networks. MAIN OUTCOME MEASURES: Time to growth of the tumor, with growth defined as an increase in the maximal apical tumor height of 0.5 mm measured by standardized A-scan ultrasonography, photographic documentation of an increase of the largest basal diameter of at least 1.5 mm, advancement of one tumor border of at least 0.75 mm, or a combination thereof. RESULTS: Twenty-eight of the 98 tumors in this study (29%) met the predetermined criteria for tumor growth. The median time to growth was 127 days (range, 51-625 days). The following tumor characteristics were significantly associated with time to tumor growth: flashes (P = 0.0224), orange pigment (P = 0.012), subretinal fluid (P < 0.001), maximum basal tumor diameter at initial examination (P = 0.015), maximum apical tumor height (P < 0.001), parallel with cross-linking MCP (P < 0.001), arcs with branching MCP (P = 0.006), loops (P < 0.001), and networks (P < 0.001). Of these, the angiographic documentation of any of the complex MCPs (parallel with cross-linking, arcs with branching, loops, networks, or a combination thereof) showed the strongest association with the time to tumor growth in a Cox proportional hazard model. CONCLUSIONS: The characteristics of our patient cohort are comparable by clinical and echographic parameters with cohorts for predicting tumor growth, described previously in the literature. In addition, we detected a novel clinical predictor of tumor growth: the confocal ICG angiographic detection of complex MCPs.

An orthotopic model for human uveal melanoma in SCID mice.

The microcirculation of primary uveal melanomas, their precursors, and their metastases is distinctive. Medium-sized and even large primary uveal melanomas typically lack significant zones of necrosis, suggesting that either these tumors are relatively well perfused or they are capable of growth in a severely blood-deprived microenvironment. In addition to normal choroidal vessels that are incorporated into nevi and most primary uveal melanomas, aggressive primary and metastatic uveal melanomas tend to contain patterns of extracellular matrix that surround spheroidal or cylindrical packets of tumor cells. Some components of this branching, looping, and interconnected system of matrix may be perfused. It is now known that the generation of this patterning is a characteristic of genetically dysregulated melanoma cells (nonaggressive tumor cells do not form these patterns and melanomas lacking branching, looping, or interconnected matrix patterns tend to follow a relatively indolent course). We developed an orthotopic model of an aggressive human uveal melanoma by injecting suspensions of the primary human choroidal melanoma cell line (OCM1) into the subretinal space of one eye of 20 SCID mice. All mice were examined daily for tumor growth and tumors developed in every eye within 3 weeks of injection. The tumors were characterized by extraocular extension and the development of looping matrix patterns characteristic of those seen in aggressive human uveal melanoma. As in human uveal melanomas, these patterns were perfused by blood in areas. The orthotopic injection of human uveal melanoma cells into the SCID mouse eye generates a model reproducing the matrix-associated microcirculatory patterns of aggressive primary human uveal melanomas. This model can be used to explore the molecular pathogenesis and modulation of this novel circulation in vivo, to facilitate our understanding of the blood flow to these tumors providing insight into perfusion and drug delivery, to enable testing of pharmacologic modulation of pattern formation and intratumoral blood flow, and to refine noninvasive methods such as confocal scanning laser ophthalmoscopy to detect the presence of these patterns by which ophthalmologists might assess the biological behavior of tumors as noninvasive substitute for biopsy.