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Background: To determine whether scanning laser ophthalmoscope in the retromode (RM-SLO) is useful to evaluate the extent of diabetic macular edema (DME) and its functional characteristics., Methods: Comparative case series of 37 eyes (27 patients with diabetes). Inclusion criteria were: center involving DME determined by optical coherence tomography; RM-SLO, optical coherence tomography, fluorescein angiography (FA), and microperimetry performed on the same day; no significant media opacities. Two masked retinal specialists independently graded all images. The full extent of DME areas and two grades (small and large) DME areas were separately evaluated. The relationship between the DME extent obtained by RM-SLO and FA was assessed by Pearson correlation coefficient, intraclass correlation coefficient, and Bland-Altman plot. T-test was used to compare DME extent to central retinal thickness and macular sensitivity., Results: The values of RM-SLO from the right and left prospective were highly correlated in the evaluation of the extent of DME (rho = 0.99, P < 0.0001). Mean DME area on RM-SLO was 5.7 + 5.6 mm (range, 0.3-18.2 mm); mean DME area on FA was 6.4 + 5.9 mm (range, 0.3-19.7 mm). The correlation between RM-SLO and FA in the evaluation of DME extent was highly significant (rho = 0.97, P < 0.0001), even when DME extent was divided in 2 major areas (intraclass correlation coefficient >0.8, P < 0.0001). The correlation between retinal sensitivity and DME area (RM-SLO) was significant (rho = -0.61, P = 0.0003)., Conclusion: The extent has become an important parameter for monitoring DME, with or without treatment. The extent of DME well correlates with functional data, mainly retinal sensitivity. Retromode SLO can be reliably and easily used in the evaluation of DME extent, avoiding the use of invasive FA.

Purpose: To compare visual function assessment, optic disc evaluation by indirect ophthalmoscopy, and retinal nerve fiber layer analysis by optical coherence tomography (OCT) for the screening of optic pathway gliomas in pediatric patients (2-15 years old) affected by neurofibromatosis type 1., Methods: Fifty-seven consecutive patients with neurofibromatosis type 1 with recent (<6 months) orbital/brain magnetic resonance images (MRI) were included. Patients underwent visual function assessment (Hyvarinen symbols chart and/or Snellen charts) and optic disc evaluation by indirect ophthalmoscopy performed by experienced, masked pediatric ophthalmologists. Spectral domain OCT was performed to assess retinal nerve fiber layer., Results: Fifteen of 57 enrolled patients (26%) were affected by MRI-proven optic pathway gliomas. Visual function assessment, optic disc evaluation, and retinal nerve fiber layer analysis by OCT were feasible in 84%, 95%, and 88% of patients, respectively. Visual function assessment, retinal nerve fiber layer analysis, and optic disc evaluation results correlated with the presence of optic pathway gliomas (P = 0.007, P < 0.0001, and P = 0.03, respectively). Specificity and negative predictive value of each test were statistically significant in detecting optic pathway glioma (P < 0.0001), whereas only retinal nerve fiber layers analysis reached statistically significant sensitivity and positive predictive value (P = 0.0386)., Conclusions: Retinal nerve fiber layer analysis assessment using spectral domain OCT is superior to visual function assessment and optic disc evaluation as a clinical screening tool for optic pathway gliomas.

Paraneoplastic cerebellar degeneration (PCD) is characterized by subacute development of pancerebellar dysfunction as a remote effect of a systemic cancer and usually develops in patients affected by gynecological tumors. Uveal melanoma is a very rare disease with a severe prognosis. A 58-year-old man affected by uveal melanoma developed anti-Yo positive paraneoplastic cerebellar degeneration (PCD) 42 months after the initial diagnosis. The onset and worsening of the neurological symptoms were parallel to the course of liver metastasis. To our knowledge this is the first case of PCD in a patient with uveal melanoma. We speculate that the cerebellar degeneration-related protein 2 (CDR2), to which the anti-Yo antibodies are directed, may have been expressed in melanoma cells and conferred proliferative advantage to the disease., (© 2013.)

The aim of this study is to report the first case of biphasic solitary fibrous tumor (SFT) of the orbit with documented histological transformation and metastatic diffusion. We describe a case of a 23-year-old Caucasian man with recurrent SFT of the right orbit with intracranial invasion. The patient underwent surgical tumor removal via a right fronto-orbital approach. Histopathological examination showed a biphasic tumor pattern with both spindle cell and epithelioid components. The histopathological re-evaluation of previously removed lesions (1999 and 2004) confirmed the diagnosis of SFT, without any evidence of epithelioid component at that time. The patient developed local recurrence and systemic metastases (occipital foramen and clivus, paravertebral muscles and peritoneum) three years after surgery. We are unaware of previous reports of biphasic solitary fibrous tumor of the orbit with documented histological transformation and metastatic diffusion.

Purpose: To investigate the presence of KIT gene mutations and immunoreactivity in 85 conjunctival melanocytic tumours and to clarify the role of KIT as a potential therapeutic target in this group of patients., Methods: Eighty-five conjunctival pigmented tumours [27 melanomas, 12 primary acquired melanosis (PAMs) and 46 nevi] were immunostained for KIT. Intensity and pattern of expression were evaluated. Molecular analysis to identify KIT mutations was performed in 15 selected cases (tumour-rich areas >50%). KIT immunostaining score and pattern were statistically related to patients' age, sex, diagnostic category, presence of relapse, disease-free survival, presence of metastases, metastasis-free survival, limbal versus nonlimbal tumour location and thickness of melanomas., Results: KIT stains were documented in 48% of melanomas, 50% of PAMs and 24% of nevi. The mean score of KIT staining in the melanomas/PAMs group was significantly different from nevi (p = 0.0076). No statistically significant differences were detected between either c-kit immunostaining score or pattern and each of the other clinico-pathologic parameters considered. No KIT gene mutations were detected in melanomas and nevi. A silent mutation/polymorphism in KIT exon 13 was found in one PAM., Conclusions: Despite the high level of KIT immunostains in PAMs and melanomas, this parameter seems not to be a good predictor of the presence of molecular mutations. KIT-activating mutations should be considered an uncommon event in this tumour., (© 2013 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Objective: To analyze correlation among microperimetry, inner and outer retinal layers, and fundus autofluorescence (FAF) changes in eyes with progressing geographic atrophy (GA) secondary to age-related macular degeneration., Methods: Microperimetry, spectral-domain optical coherence tomography (SD-OCT), standard short-wavelength FAF (SW-FAF), and near-infrared-wavelength FAF (NIR-FAF) were performed for all patients at both baseline and follow-up visits. FAF pattern, integrity of photoreceptor inner segment/outer segment (IS/OS) junction, total retinal thickness (RT), inner retinal layers (IRL), and outer retinal layers (ORL) thickness changes of every microperimetry extrafoveal tested point were analyzed., Results: A total of 366 microperimetry tested points were analyzed (6 patients, 7 eyes). Mean retinal sensitivity significantly decreased (p = 0.0149), and the percentage of dense scotomas significantly increased (p = 0.0125). Mean RT and mean ORL thickness significantly decreased (both p < 0.0001). Mean IRL thickness significantly increased (p = 0.0001). The decrease of ORL thickness was inversely correlated to the IRL thinning (rho = -0.710). FAF pattern at baseline was correlated to RT and ORL thickness (both p < 0.0001) and was significantly correlated to the risk to evolve to dense scotoma during follow-up (p = 0.0001 at SW-FAF, p < 0.0001 at NIR-FAF). Tested points showing at baseline the loss of photoreceptor IS/OS junction had a greater risk for evolving to dense scotoma compared with those with intact photoreceptor IS/OS junction (odds ratio 3.56, 95% CI 2.41-5.27)., Conclusions: Retinal sensitivity changes are correlated to IRL and ORL thickness changes, and to photoreceptor IS/OS junction integrity. FAF patterns remain a relevant factor in predicting GA evolution. Microperimetry, SW-FAF and NIR-FAF, and SD-OCT should be combined to obtain adequate morphologic and functional prospective information., (© 2013 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the effects of various 5-fluorouracil (5-FU) concentrations, exposure times, and application techniques on in vitro-cultured human corneal cells., Methods: Human corneal epithelial cell (HCEC) and human corneal keratocyte (HCK) cultures were exposed to different 5-FU concentrations (0.025%-1%) and incubation durations (5 minutes to 2 hours). The cytostatic effect was evaluated as the percentage of inhibition of migration relative to the control. The evaluation of cytotoxic effect included both phase contrast microscopic observations and viability measures performed using an MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)] colorimetric assay. The results are expressed as ratio of optical density (OD) reduction 24 hours after exposure., Results: The cytostatic effect was time and dose dependent. The 50% inhibiting dose was 0.55% after 1 hour of incubation for HCECs and was 0.5% after 2 hours of incubation for HCKs. A 100% inhibitory effect was never observed at any concentration or incubation duration. No cytotoxic changes were observed using an 5-FU concentration of <1%; 1% 5-FU showed time-dependent cytotoxic changes in HCEC cultures only. MTT analysis showed no OD reduction at 5-FU concentrations of <1%, whereas 1% 5-FU showed OD reduction <50% at any tested exposure time. HCECs showed higher reduction in OD than HCKs., Conclusions: 5-FU formulations topically used in clinical practice showed limited toxicity in normal cultured corneal epithelial cells and keratocytes.

Purpose: To evaluate the efficacy and safety of prompt intravitreal triamcinolone acetonide injection (4 mg/0.1 mL) vs intravitreal bevacizumab injection (1.25 mg/0.05 mL) compared with observation in the management of extensive exudative retinal detachment secondary to posterior uveal melanoma., Design: Retrospective, nonrandomized, interventional case series., Methods: setting: Institutional. patients: Ninety-six patients affected by posterior uveal melanoma with large exudative retinal detachment (>10 mm in largest basal diameter) were included. intervention: Patients received intravitreal triamcinolone acetonide (32 eyes) or intravitreal bevacizumab (32 eyes) at plaque removal. Thirty-two patients served as controls (observation group). All groups were matched for age, sex, initial tumor thickness and largest basal diameter, largest exudative retinal detachment basal diameter, tumor location, and Bruch membrane rupture. Patients underwent monthly follow-up examinations in the first 6 months and every 3 months thereafter. Follow-up was longer than 24 months. main outcome measure: Exudative retinal detachment resolution (B-scan ultrasonography), steroid-induced cataract, steroid-induced increased IOP., Results: Follow-up was 37 ± 7 months. Marked exudative retinal detachment regression was documented in 22 (69%) intravitreal triamcinolone acetonide-treated vs 11 (34%) intravitreal bevacizumab-treated and 9 (28%) untreated eyes (P = .0007 and P = .0001, respectively). No statistical significance was found between intravitreal bevacizumab group vs observation group (P = .45) Steroid-induced cataract was observed in 4 intravitreal triamcinolone acetonide-treated patients (12%). Neither steroid-induced increased IOP nor other short- or long-term side effects were documented., Conclusion: Intraoperative intravitreal triamcinolone acetonide injection induces earlier and marked exudative retinal detachment resolution after brachytherapy of posterior uveal melanoma. Risk and benefit should be balanced vs steroid-induced cataract., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To review the most important metabolic effects and clinical safety data of subthreshold micropulse diode laser (D-MPL) in diabetic macular edema (DME)., Methods: Review of the literature about the mechanisms of action and role of D-MPL in DME., Results: The MPL treatment does not damage the retina and is selectively absorbed by the retinal pigment epithelium (RPE). MPL stimulates secretion of different protective cytokines by the RPE. No visible laser spots on the retina were noted on any fundus image modality in different studies, and there were no changes of the outer retina integrity. Mean central retinal sensitivity (RS) increased in subthreshold micropulse diode laser group compared to standard ETDRS photocoagulation group., Conclusions: MPL is a new, promising treatment option in DME, with both infrared and yellow wavelengths using the less aggressive duty cycle (5%) and fixed power parameters. It appears to be safe from morphologic and functional point of view in mild center involving DME.

The aim of the study was to assess whether ultrasound biomicroscopy (UBM) examination of anterior uveal tumors could help in tissue differentiation. Five anterior uveal tumors in five patients underwent UBM (Paradigm P45, 50 MHz) examination prior to fine needle aspiration (FNA) of the lesion; two melanomas, one nevus, one metastatic carcinoma, and one bilateral iris lymphoma were cytologically diagnosed. Only UBM information was obtained from four small non-growing lesions consistent with iris nevi. Four ciliary body pigmented tumors elevated by 4 to 6 mm were examined both with UBM and immersion standardized echography (Cinescan S, Quantel Medical). UBM showed high reflective iris subsurface in all iris nevi. Of the FNA verified iridociliary pigmented tumors, the iris pigment epithelium was found to be indistinct in iridociliary melanoma only. Iridociliary melanoma, nevus and metastatic carcinoma showed angle invasion and similar acoustic pattern and reflectivity on UBM examination. Multiple iris masses were imaged in lymphoma and metastatic carcinoma. Two ciliary body low to medium reflective and two ciliary body high reflective tumors on standardized echography, consistent with ciliary body melanoma and melanocytoma, were plaqued or observed for four and thirteen years; UBM was informative for superficial margins and angle invasion only. In conclusion, UBM was very useful for location and size of small anterior uveal tumors, but could not help in tissue differentiation of iridociliary tumors. Multiple iris lesions were found in iridociliary lymphoma or metastatic carcinoma only. Standardized echography allowed for tissue differentiation in at least 4-mm thick ciliary body pigmented

The ability to obtain the proper clinical diagnosis in cases of suspected intraocular tumors has greatly advanced during the past 50 years. The clinical characteristics of most intraocular tumors (size, shape, color, and texture) are detectable by skilled ophthalmoscopic examination and, with the use of adjunctive techniques (mainly ultrasonography), the proper diagnosis can be reached without invasive procedures. Notwithstanding, some intraocular tumors need to be biopsied to obtain a reliable diagnosis. In the cytogenetic era, intraocular tumor management is changing, and tumor-sampling procedures are becoming the main prognostic (and theoretically also diagnostic) tools for uveal melanoma. In spite of the widespread use of biopsies in general surgical practice, in ophthalmic oncology, indications and contraindications for biopsy continue to be under debate. The purpose of this paper is to critically evaluate the role of uveal melanoma biopsy in current clinical practice., (Copyright © 2012 S. Karger AG, Basel.)

Purpose: To compare standard versus bolus photodynamic therapy (PDT) in the treatment of symptomatic circumscribed choroidal hemangioma (CCH)., Methods: Twenty consecutive cases of CCH were included in this prospective randomized study. Each patient was randomly assigned to receive either standard PDT (10-minute 6 mg/mq2 verteporfin infusion; treatment at 15 min; 50 J/cm2; 83 s) or bolus PDT (6 mg/mq2 verteporfin infusion bolus in 1 min; treatment at 5 min; 100 J/cm2; 166 s). Best-corrected visual acuity (BCVA), fundus photography, optical coherence tomography, fluorescein, and indocyanine green angiography were performed at baseline and during follow-up. Retinal sensitivity was tested with microperimetry before and after treatment. Follow-up was longer than 32 months., Results: Mean follow-up was 58±11 months. All cases (100%) showed clinical regression of the treated lesion. Neuroretinal and retinal pigment epithelium (RPE) changes were found in 9 (90%) bolus PDT over treated area. No similar RPE changes were found in patients treated with standard PDT. There was a no statistically significant difference in BCVA outcome between the 2 groups (p=0.078). Microperimetry revealed reduced sensitivity over the treated area in 7 bolus PDT vs 1 in standard treated eyes (p=0.008)., Conclusions: Both standard and bolus PDT induce regression of symptomatic CCH. Bolus PDT may cause RPE and retinal changes associated with reduced retinal sensitivity.

Background/aims: The aim of this study was to evaluate the long-term corneal toxicity of topical chemotherapy with 1% 5-fluorouracil (5-FU) as a sole or adjuvant treatment of ocular surface squamous neoplasia (OSSN)., Methods: Forty-one consecutive cases of OSSN were included in this prospective study. Patients underwent topical chemotherapy with 1% 5-FU four times/day for 4&emsp14;weeks (one course). Adjunctive courses were repeated until clinical and cytological tumour regression. Clinical confocal microscopy was used to check for 5-FU long-term corneal toxicity., Results: Mean follow-up was 89.7±14.4&emsp14;months (range 63-122&emsp14;months). Twenty-two patients (53.7%) underwent topical 5-FU as a sole treatment, and 19 patients (46.3%) as adjuvant and/or debulking therapy. The mean number of 5-FU cycles was 1.9 (range 1-5 cycles). Three tumours (7.3%) treated with 5-FU alone recurred during follow-up. Recurrences were successfully treated with additional 5-FU courses. Clinical confocal microscopy showed no long-term difference between the treated eye and fellow (control) eye in: endothelial cells count, pleomorphism and polymegatism, anterior stromal keratocyte density, sub-basal nerve plexus fibre number, density, and beadings and central cornea epithelium thickness (p=NS)., Conclusion: Topical 5-FU, as a sole or combined therapy, must be considered a long-term safe and effective treatment for patients affected by OSSN.

Purpose: To report the technique and the outcome of modified (enlarged) enucleation via lateral orbitotomy for choroidal melanomas with massive extrascleral extension., Methods: 5 patients with choroidal malanoma with massive, circumscribed perioptic/posterior extrascleral extension underwent modified enucleation via lateral orbitotomy. After lateral orbitotomy and orbital mass exposure with direct tumor visualization, a long optic nerve stump was cut and the orbital component of the tumor was completely (macroscopically) removed along with the globe in all cases. After haemostasis and orbital reconstruction an orbital implant was then placed. Follow-up was longer than 12 months., Results: Excellent cosmetic outcome was acheived in all patients (100%) without operative or postoperative complications. At pathologic examination, tumors were completely removed in all cases (100%)., Conclusions: Modified (enlarged) enucleation via lateral orbitotomy for selectd choroidal melanomas with massive, circumscribed perioptic/posterior extrascleral extension allows complete tumor removal and placement of an orbital implant, avoiding the long healing process of orbital exenteration with excellent clinical and cosmetic outcome.

Purpose: To evaluate prospectively, on a long-term range, the clinical outcomes of transpupillary thermotherapy (TTT) as primary treatment of selected choroidal melanoma., Methods: Seventy-seven eyes of 77 patients affected by small posterior choroidal melanoma were treated with TTT as a sole treatment, using an infrared diode laser at 810 nm according to a standard procedure. Follow-up was longer than 36 months., Results: Seventeen tumours (22%) were parapapillary (PP) and 60 tumours (78%) were non-parapapillary (NPP) in location. Mean follow-up was 55.2 ± 17.9 months in PP tumours and 44.3 ± 23.7 months in NPP tumours. Thirteen (76%) PP tumours and 55 (92%) NPP tumours regressed (P > 0.05). Nine tumours recurred: seven were retreated using Iodine-125 brachytherapy and two were enucleated (both parapapillary). Four patients (5%) developed liver metastasis and died during follow-up. Tumour thickness was found to be predictive of recurrence (odds ratio: 4.3). Complications were found in 20 eyes (26%): macular pucker in 11 (14%), macular oedema in three (4%), retinal vein occlusion in six (8%), vitreous and subretinal haemorrhage in two (3%) and neovascular glaucoma in three (4%). PP tumours had more local complications (but this was not statistically significant; P > 0.05). Complications appeared more frequently in tumours treated with more than one TTT session (P = 0.01), and time-risk to develop intraocular complications seems longer in the PP group, without reaching statistical significance (P = 0.07)., Conclusion: TTT may be a clinically effective method for conservative treatment of selected, non-parapapillary, small posterior choroidal melanoma.

Purpose: To compare long-term choroidal vascular changes after iodine-125 brachytherapy (IBT) versus transpupillary thermotherapy (TTT) used as primary treatment of small choroidal melanoma., Methods: Ninety-five small choroidal melanomas were randomized: 49 eyes with TTT and 46 eyes with IBT alone. Fluorescein and indocyanine green angiography (ICGA) were performed at 3-month intervals during the first year, and every 6 months thereafter., Results: Mean follow-up was 56.2 months (range, 24-118 months; SD, 22.6). Tumor regressed in 45 (92%) TTT-treated vs 45 (98%) IBT-treated eyes (p=0.397). Four TTT-treated and one IBT-treated tumor recurred. Occlusion of choriocapillaris was present in all TTT and IBT cases. Closure of medium and large choroidal vessels was observed in 17 (35%) TTT-treated vs 44 (96%) IBT-treated eyes (p<0.001). Choroidal vascular remodeling was detected in 20 (41%) TTT-treated and 16 (35%) IBT-treated eyes (p=0.693). Retinochoroidal anastomosis was present in 4 of the 37 (11%) TTT-treated eyes with patency of medium and large choroidal vessels, but never observed in the IBT-treated eyes, and was associated with tumor recurrence. Among IBT-treated eyes, segments of choroidal vascular wall ICG staining and choroidal aneurysmal changes were detected in 30 (65%) and 7 (15%), respectively. These changes were never detected in TTT-treated cases (p<0.0001 and p=0.015, respectively)., Conclusions: The pattern of tumor choroidal vascular changes following IBT and TTT differs. TTT is less effective in closing all tumor vasculature. The role of long-term choroidal vascular remodeling observed after these two treatments needs longer follow-up.

Purpose: Circumstantial evidence suggests that development of uveal melanoma may be associated to two different pathogenetic pathways, either loss of chromosome 3 or extra copies of 6p (+6p). Chromosome 3 monosomy (-3) is detected in approximately half of uveal melanomas, and is strongly linked to metastatic disease, whereas +6p accounts for one-fourth of uveal melanomas with no clear clinical correlations. The aim of our study was to verify if the analysis of chromosomes 3 and 6 was able to distinguish two groups of patients for translating this approach in the clinical practise as prognostic tool., Methods: Fluorescence in situ hybridisation (FISH) with probes for chromosome 3, 6p and 6q was used to analyze cytological material obtained by fine needle aspiration biopsy (FNAB) from 28 primary uveal melanomas, just before brachytherapy., Results: Abnormalities affecting 6p and 6q were found in 14 tumors (50%), and -3 in 16 cases (57%). Interestingly, -3 and +6p were mutually exclusive in 23 cases (82%), whereas in two cases only (7%) they coexisted. In particular, +6p alone was present in 9 lesions (32%), -3 was the sole aberration in 11 cases (39%), and concomitant -3 and -6q in 3 other cases (11%)., Conclusions: Although the patient cohort is limited, our findings confirm the hypothesis of a bifurcated pathogenetic model of uveal melanoma. Moreover, our results suggest that investigation of both markers on FNAB samples obtained in vivo could provide a clearer clinical picture of genetic lesions when no histological material is available for prognostic evaluation.

Background: Monosomy 3 is a highly specific marker for poor prognosis in posterior uveal melanoma. Unfortunately, cytogenetic prognostication is limited to enucleated eyes or resected tumors. The aim of this study was to evaluate mid-term natural history and safety of in vivo detection of chromosome 3 status in posterior uveal melanomas undergoing plaque brachytherapy., Methods: A 25-gauge transscleral fine needle aspiration biopsy (FNAB) was performed in 32 eyes affected by posterior uveal melanoma undergoing plaque brachytherapy, just before applying the radioactive plaque. Sampled material underwent fluorescence in situ hybridization (FISH) with centromeric probes for chromosome 3. All patients had a follow-up of at least 36 months., Results: Mean follow-up was 47.1 +/- 8.5 months. Mean largest basal diameter and mean thickness of the tumors were 12.5 +/- 2.7 mm and 8 +/- 2.3 mm respectively. FNAB yielded sufficient material in 26 of 32 cases (81.2%). Adequacy of the sample ranged from 91.1% (ciliary body tumors) to 76.8% (choroidal tumors). Seventeen cases had monosomy 3 (65.3%). No correlation was found between monosomy 3 and tumor dimensions or location (ciliary body vs choroidal tumors). No early and mid-term local complications were documented. Seven patients (21.8%) died during follow-up: five (15.6%) of them died due to metastatic disease (all had monosomy 3 tumors)., Conclusions: Posterior uveal melanomas may be adequately and safely sampled, by intra-operative transscleral FNAB, to detect in vivo monosomy 3.