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A letter tot the editor is presented related to the successful treatment of longstanding vasospastic central retinal artery occlusion.

Simple Summary: This study assesses for the first time the clinical outcomes in a group of adolescent and young adult (AYA: 15–39 years old) uveal melanoma (UM) patients (n = 270) treated with proton therapy, comparing them with matched elder adults (>40 years). Ocular outcomes, local tumor control, metastasis incidence, and overall survival were similar in both groups, in contrast with the better survival rates in previous, pediatric UM series. Moreover, when compared with the general population, the AYAs had reduced relative survival, while the elder adults had better relative survival. Objective: The aim of this study was to compare the clinical outcomes of adolescents and young adults (AYAs) with those of elder adult patients treated with proton therapy (PT) for uveal melanoma (UM). Material and Methods: A retrospective, comparative study was conducted in UM patients who underwent PT at the Ocular Oncology Unit of the Jules-Gonin Eye Hospital (University of Lausanne, Lausanne, Switzerland) and the Paul Scherrer Institute (PSI); (Villigen, Switzerland) between January 1997 and December 2007. Propensity score matching (PSM) was used to select for each AYA (between 15–39 years old) an elder adult patient (≥40 years) with similar characteristics. We assessed ocular follow-up, local tumor control, metastasis incidence, and overall and relative survival (OS and RS). Non-terminal outcomes were then compared between the two groups using competing risk survival analysis. Results: Out of a total of 2261 consecutive UM patients, after excluding 4 children (<15 years) and 6 patients who were metastatic at presentation, we identified 272 AYA patients and matched 270 of them with 270 elder adult patients. Before PSM, the AYA patients had a higher incidence of primary iris melanoma (4.0% vs. 1.4%; p = 0.005), while the elder patients were more likely to have other neoplastic diseases at presentation (9% vs. 3.7%; p = 0.004). Ocular outcomes and local tumor control were similar in both groups. Cumulative metastasis incidence for the AYA and elder adult groups was 13% and 7.9% at 5 years and 19.7% and 12.7% at 10 years, respectively, which was not significantly different between the groups (p = 0.214). The OS was similar in the two groups (p = 0.602), with estimates in the AYA and elder adult groups of 95.5% and 96.6% at 5 years and 94.6% and 91.4% at 10 years, respectively. However, the relative survival (RS) estimation was worse in the AYA group than the elder group (p = 0.036). Conclusion: While AYAs treated with PT for UM have similar ocular outcomes and present the same metastasis incidence and OS as elder adults, their RS is worse than that in elder adults, when compared with the population in general. [ABSTRACT FROM AUTHOR]

Purpose: The aim of our study was to describe the clinical presentation of an unusual evanescent, exudative, choroidal pseudo-tumor with acute painful onset, and propose a pathogenesis. Methods: We carried out a retrospective, observational study using the case series of three patients presenting with an evanescent, exudative, choroidal pseudo-tumor with acute painful onset. Ultra-widefield fluorescein and indocyanine green angiography (ICGA) using the Heidelberg Retina Angiograph and the Staurenghi 230 SLO Retina Lens were used to propose a pathogenesis of this unusual entity. Results: In all three cases, acute ocular pain led to discovery of an exudative, partially hemorrhagic choroidal mass (thickness 2.4 mm-4.1 mm on ultrasound) that quickly regressed within weeks. In the subacute phase, all patients showed choroidal circulation abnormalities on dynamic wide-field ICGA in the affected quadrant, with delayed arterio-venous filling in two patients, and a poorly-defined vortex vein in the third. The choroidal circulation abnormalities resolved within 8-12 weeks, simultaneously with the spontaneous resolution of the choroidal pseudo-tumor. The findings evoked a self-resolving vortex vein occlusion in the corresponding quadrants with acute, painful choroidal exudation. Conclusions: An evanescent, exudative, hemorragic choroidal pseudo-tumor with acute painful onset may be caused by a vortex vein occlusion. Future patients need to be studied with ICGA in the acute phase to confirm this hypothesis. [ABSTRACT FROM AUTHOR]

Purpose: Retinal pigment epithelium (RPE) tear is an extremely rare complication in patients with classic neovascular membranes without RPE detachment. We evaluate their incidence and functional outcome following treatment with intravitreal ranibizumab. Methods: Observational study of 72 consecutive patients (74 eyes) treated at Jules Gonin University Eye Hospital, Lausanne, with intravitreal ranibizumab 0.5 mg for classic choroidal neovascularization (CNV) between March 2006 and February 2008. Best-corrected visual acuity (BCVA), fundus examination and optical coherence tomography were recorded monthly; fluorescein angiography was performed at baseline and repeated at least every 3 months. Results: RPE tears occurred in four (5.4%) eyes temporal to the fovea, after a mean of four injections (range 3-6). Mean baseline BCVA was 0.25 decimal equivalent (logMAR 0.67) and improved despite the RPE tear to 0.6 decimal equivalent (logMAR 0.22). Conclusion: RPE tears following intravitreal ranibizumab injections for classic CNV can occur in about 5% of patients, even in the absence of baseline RPE detachment. Nevertheless, vision may improve provided the fovea is not involved. [ABSTRACT FROM AUTHOR]

Purpose: To determine the types and incidence of caruncular lesions and to investigate the correlation between clinical and histologic diagnosis. Design: Retrospective, observational case series. Methods: Records of patients with a lesion of the caruncle that was excised and submitted to our ocular pathology department between January 1979 and May 2005 were reviewed. Lesions were classified by histologic type and correlated with patient age, gender, and preoperative clinical diagnosis. Results: A total of 195 consecutive caruncular lesions from 191 patients were identified. Twenty-four different types of lesions were identified; the most common were nevi (n = 92, 47%) and papillomas (n = 29, 15%). One keratoacanthoma was identified. One hundred eighty-three lesions (93.8%) were benign, six (3.1%) were premalignant, and five (2.6%) were malignant. Preoperative clinical diagnosis corresponded to postexcision histologic diagnosis in 73 cases (37.4%). Suspected malignancy was a common reason for excision (61 cases, 31.3%), but malignancy was confirmed in only three (4.9%) of 61 cases. Two of the five malignant lesions were clinically thought to be benign. Conclusions: We hereby report the first caruncular keratoacanthoma. The rarity and variety of caruncular lesions make clinical diagnosis difficult. Malignancy is clinically overestimated, and some malignant lesions can take a benign aspect, justifying close photographic follow-up of all lesions. Because caruncular malignant melanoma is associated with poor prognosis, pigmented lesions should be monitored carefully. In the absence of clear criteria for malignancy, any change in color, size, or vascularization of a caruncular lesion should hasten excision. [Copyright &y& Elsevier]

The article presents a case study of a 68-year old woman who was brought to a hospital for choroidal pigmental tumour in the left eye. During eye examination, it was revealed that the tumour was asymptomatic, parapillary and is covered with drusen and with the absence of any orange pigment. The visual acuity of the patient was 0.7 in the right eye relative to hypermetropic amblyopia since her childhood.

A letter to the editor is presented regarding the efficacy of ranibizumab, which was administered intravitreally, in treating a 56-year-old woman with progressive visual loss associated with proliferative idiopathic juxtafoveal retinal telangiectasia (PIJRT).

Conjunctival melanoma (CJM) is a rare but potentially lethal and highly-recurrent cancer of the eye. Similar to cutaneous melanoma (CM), it originates from melanocytes. Unlike CM, however, CJM is relatively poorly characterized from a genomic point of view. To fill this knowledge gap and gain insight into the genomic nature of CJM, we performed whole-exome (WES) or whole-genome sequencing (WGS) of tumor-normal tissue pairs in 14 affected individuals, as well as RNA sequencing in a subset of 11 tumor tissues. Our results show that, similarly to CM, CJM is also characterized by a very high mutation load, composed of approximately 500 somatic mutations in exonic regions. This, as well as the presence of a UV light-induced mutational signature, are clear signs of the role of sunlight in CJM tumorigenesis. In addition, the genomic classification of CM proposed by TCGA seems to be well-applicable to CJM, with the presence of four typical subclasses defined on the basis of the most frequently mutated genes: BRAF, NF1, RAS, and triple wild-type. In line with these results, transcriptomic analyses revealed similarities with CM as well, namely the presence of a transcriptomic subtype enriched for immune genes and a subtype enriched for genes associated with keratins and epithelial functions. Finally, in seven tumors we detected somatic mutations in ACSS3, a possible new candidate oncogene. Transfected conjunctival melanoma cells overexpressing mutant ACSS3 showed higher proliferative activity, supporting the direct involvement of this gene in the tumorigenesis of CJM. Altogether, our results provide the first unbiased and complete genomic and transcriptomic classification of CJM. Author summary: Conjunctival melanoma is an extremely rare form of cancer of the eye that arises from melanocytes–the cells producing the protective pigment melanin–in the outmost layer of the eye: the conjunctiva. This tissue, similarly to the skin, can also be exposed to UV light radiation from the sun. We investigated the genetic background of this rare form of cancer in samples from fourteen patients, by global DNA and RNA sequencing. Our results showed that conjunctival melanoma is genetically very similar to cutaneous melanoma. More precisely, in tumor DNA we detected signs of damage caused by UV light, as well as mutations in the genes BRAF, NF1 and NRAS/HRAS, previously described to be involved in cutaneous melanoma. Analysis of tumor gene expression also revealed similarities between these two types of cancer, some of which could be used as prognostic factors or as indicators of a patients' response to therapy. In addition, we identified frequent somatic mutations in ACSS3, a gene not yet associated with either conjunctival or cutaneous melanoma, which represents a potential key player in oncogenesis of conjunctival melanoma. [ABSTRACT FROM AUTHOR]

Purpose To collect comprehensive data on choroidal and ciliary body melanoma (CCBM) in children and to validate hypotheses regarding pediatric CCBM: children younger than 18 years, males, and those without ciliary body involvement (CBI) have more favorable survival prognosis than young adults 18 to 24 years of age, females, and those with CBI. Design Retrospective, multicenter observational study. Participants Two hundred ninety-nine patients from 24 ocular oncology centers, of whom 114 were children (median age, 15.1 years; range, 2.7–17.9 years) and 185 were young adults. Methods Data were entered through a secure website and were reviewed centrally. Survival was analyzed using Kaplan-Meier analysis and Cox proportional hazards regression. Main Outcome Measures Proportion of females, tumor-node-metastasis (TNM) stage, cell type, and melanoma-related mortality. Results Cumulative frequency of having CCBM diagnosed increased steadily by 0.8% per year of age between 5 and 10 years of age and, after a 6-year transition period, by 8.8% per year from age 17 years onward. Of children and young adults, 57% and 63% were female, respectively, which exceeded the expected 51% among young adults. Cell type, known for 35% of tumors, and TNM stage (I in 22% and 21%, II in 49% and 52%, III in 30% and 28%, respectively) were comparable for children and young adults. Melanoma-related survival was 97% and 90% at 5 years and 92% and 80% at 10 years for children compared with young adults, respectively ( P = 0.013). Males tended to have a more favorable survival than females among children (100% vs. 85% at 10 years; P = 0.058). Increasing TNM stage was associated with poorer survival (stages I, II, and III: 100% vs. 86% vs. 76%, respectively; P = 0.0011). By multivariate analysis, being a young adult (adjusted hazard rate [HR], 2.57), a higher TNM stage (HR, 2.88 and 8.38 for stages II and III, respectively), and female gender (HR, 2.38) independently predicted less favorable survival. Ciliary body involvement and cell type were not associated with survival. Conclusions This study confirms that children with CCBM have a more favorable survival than young adults 18 to 25 years of age, adjusting for TNM stage and gender. The association between gender and survival varies between age groups. [ABSTRACT FROM AUTHOR]

Purpose: To examine the metastatic and survival rates, eye retention probability, and the visual outcomes of juvenile patients after proton beam radiotherapy (PBRT) for uveal melanoma (UM). Design: Retrospective case-factor matched control study. Participants and Controls: Forty-three patients younger than 21 years treated with PBRT for UM were compared with 129 matched adult control patients. Methods: Information on patient demographics and clinical characteristics were recorded before and after treatment from patients' files. The control group was composed of adult patients (>21 years) matched for tumor size (largest tumor diameter, ±2 mm; height, ±2 mm) and anterior margin location (iris, ciliary body, pre-equatorial or postequatorial choroid). For each juvenile patient, 3 adults were selected. Main Outcome Measures: Comparing outcomes of juvenile and adult patients in terms of metastatic and eye retention rates using the log-rank statistic, relative survival using the Hakulinen method, as well as their visual outcomes. Results: Forty-three juvenile and 129 control cases were reviewed. The metastatic rate at 10 years was significantly lower in juvenile UM patients than in adult controls (11% vs. 34%; P <0.01), with an associated relative survival rate of 93% versus 65% (P = 0.02). Six juvenile patients (14%) demonstrated metastases. One patient underwent enucleation because of a presumed local tumor recurrence and 4 additional patients underwent enucleation because of complications (9.3%). In the adult control group, 27% (n = 35) of matched patients demonstrated metastases, there were 2 cases of local recurrence, and 16% (n = 21) underwent enucleation because of complications. A visual acuity of more than 0.10 was maintained in most cases, without any significant differences before or after treatment observed between both groups. Conclusions: After PBRT, metastatic and survival rates are significantly better for juvenile than for adult patients with UM. Clinically, juvenile and adult eyes react similarly to PBRT, with patients having a comparable eye retention probability and maintaining a useful level of vision in most cases. This is the largest case-control study of proton therapy in juvenile eyes to date and further validates PBRT as an appropriate conservative treatment for UM in patients younger than 21 years. [ABSTRACT FROM AUTHOR]

Purpose: To investigate choroidal vascular abnormalities in peripheral exudative hemorrhagic chorioretinopathy, using dynamic ultrawide-field fluorescein angiography (FA) and indocyanine green angiography (ICGA). Design: Prospective observational case series. Methods: This institutional study comprised a consecutive series of 40 patients (48 eyes) with peripheral exudative hemorrhagic chorioretinopathy. Choroidal vascular abnormalities were assessed with dynamic ultrawide-field (150-degree) FA and ICGA, using the Staurenghi 230 SLO Retina Lens and the Heidelberg scanning laser ophthalmoscope. The main outcome measures were morphologic descriptions of structural vascular abnormalities and choroidal hemodynamics (comparison with 30 normal eyes). Results: The peripheral mass lesions were highly exudative and hemorrhagic, and usually associated with a pigment epithelium detachment. FA revealed nonspecific alterations corresponding to the visible fundoscopic changes (window defects, blockage, staining), but no neovascular membrane. However, despite frequent masking, ICGA showed hyperfluorescent polyp-like structures in the choroid of the lesion area in 33 eyes (69%) and an abnormal choroidal vascular network in 24 eyes (50%). The abnormal choroidal vascular network filled in the arterial or early venous phase, while the polyp-like structures filled some seconds later. Optical coherence tomography revealed the typical dome-shaped elevation of the pigment epithelium over the vascular polyps. Peripheral choriocapillaris closure was observed as well as dilated shunting vessels. Conclusion: Peripheral exudative hemorrhagic chorioretinopathy shares many characteristics (polyp-like choroidal telangiectases, abnormal choroidal vascular networks, exudative and hemorrhagic presentation) with polypoidal choroidal vasculopathy. Clarification of the precise role of these abnormalities requires further studies. [Copyright &y& Elsevier]

Purpose: To describe the clinical and angiographic characteristics of peripheral exudative hemorrhagic chorioretinopathy, an uncommon chorioretinal mass lesion, important for its differential diagnosis to choroidal melanoma, but only rarely described in the literature. Design: Retrospective, institutional chart review. Methods: Institutional chart review of 45 patients (56 eyes) diagnosed with peripheral exudative hemorrhagic chorioretinopathy to describe the clinical findings and those obtained by fluorescein angiography (FA) and indocyanine green angiography (ICGA), in addition to a review of the histologic findings of an enucleated eye. Results: Peripheral exudative hemorrhagic chorioretinopathy typically was characterized by increased age of the patient (mean, 77 years; range, 60 to 91 years), female preponderance (69%), frequent pigment epithelium detachment, temporal equatorial location, and a highly hemorrhagic and exudative presentation, sometimes extending to the macula. Bilateral involvement (24%) was associated with multiples lesions in the same eye (P < .001) and with nasal extension (P < .001). A neovascular origin was suspected on FA, but was more evident on ICGA. Histologic examination of the enucleated eye did not reveal a neovascular network. Conclusions: Peripheral exudative hemorrhagic chorioretinopathy is a characteristic peripheral degenerative disorder, frequently with benign outcome, although it can be vision threatening because of hemorrhage or exudation. Clinical features are helpful for its diagnosis. FA and ICGA contribute valuable evidence to the hypothesis of a neovascular origin, but further histologic studies are needed to prove this hypothesis. [Copyright &y& Elsevier]

Introduction Melanoma of the iris and ciliary body may be associated with secondary glaucoma. Treatment with proton beam radiotherapy (PBRT) to the anterior segment can also elevate intraocular pressure (IOP), resulting in uncontrolled glaucoma, often requiring enucleation. This is the first prospective study of Baerveldt aqueous shunts in irradiated eyes with anterior uveal melanoma (AUM; affecting the iris or ciliary body). Methods Thirty-one eyes with uncontrolled IOP following anterior segment PBRT treatment for AUM were prospectively recruited to undergo Baerveldt shunt implantation. Postoperative examinations were performed on day 1; weeks 1, 3, 6, 9; months 3, 6, 9, 12 and annually thereafter. Surgical success was defined as IOP 21 mm Hg or less and 20% reduction from baseline. All complications were recorded. Results Mean follow-up was 15.7 months (SD 68.3 months). Mean interval from irradiation to shunt implantation was 2.5 years. Mean preoperative IOP was 31.0 (610.3) mm Hg; mean IOP at last visit was 15.0 (65.0) mm Hg; mean pre-operative glaucoma medications were 3.3 (61.3); postoperatively 0.7 (61.3) glaucoma medications. Surgical success rate was 86% using glaucoma medications. Four eyes had minor postoperative complications, none of which were sight threatening. There were no local tumour recurrences or systemic metastases. There were no enucleations caused by ocular hypertension. Conclusions Baerveldt shunts were effective in lowering IOP, with few complications, in eyes treated with total anterior segment irradiation for AUM. [ABSTRACT FROM AUTHOR]

Purpose: To report the first case of choroidal schwannoma in a patient affected by PTEN hamartoma tumor syndrome (PHTS) and investigate the molecular involvement of the phosphatase and tensin homolog (PTEN) and neurofibromin 2 (NF2) genes in this rare intraocular tumor. Design: Observational case report. Participant: A 10-year-old girl diagnosed with PHTS. Methods: The enucleated specimen underwent histologic, immunohistochemical, and transmission electronic microscopy. The expression of PTEN and NF2 and their protein products were evaluated by reverse transcription-polymerase chain reaction and immunohistochemistry. Somatic mutations of PTEN and NF2, as well as allelic loss, were investigated by direct sequencing of DNA extracted from the tumor. PTEN epigenetic silencing was investigated by pyrosequencing. Main Outcome Measures: Histopathologic and molecular characterization of a choroidal pigmented schwannoma. Results: Histopathologic, immunohistochemical, and electron microscopic analysis demonstrated features consistent with a pigmented cellular schwannoma of the choroid. We found no loss of heterozygosity at the genomic level for the PTEN germline mutation and no promoter hypermethylation or other somatic intragenic mutations. However, we observed an approximate 40% reduction of PTEN expression at both the mRNA and the protein level, indicating that the tumor was nonetheless functionally deficient for PTEN. Although DNA sequencing of NF2 failed to identify any pathologic variants, its expression was abolished within the tumor. Conclusions: We report the first description of a pigmented choroidal schwannoma in the context of a PHTS. This rare tumor showed a unique combination of reduction of PTEN and absence of NF2 expression. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. [Copyright &y& Elsevier]

Purpose: To describe a patient with metastatic choroidal paraganglioma that was locally controlled with radiotherapy. Design: Interventional clinicopathologic case report. Participant: One patient with metastatic choroidal paraganglioma. Methods: Interventional clinicopathologic case report and systematic search of the literature. Main Outcome Measures: Description of clinicopathologic features, treatment methods, and outcome. Results: A 50-year-old man had a nonpigmented atypical choroidal mass with secondary retinal detachment in the left eye. After incisional biopsy, the diagnosis of paraganglioma was established. Metastatic work-up revealed vertebral, mediastinal, and pulmonary metastases of a nonsecretory, malignant paraganglioma without tracer uptake. The primary tumor was not identified. The ocular tumor regressed after stereotaxic radiotherapy. Two years later, recurrent lesions developed in the contralateral eye, which also was irradiated. Conclusions: Malignant paraganglioma can metastasize in the choroid and should be included in the differential diagnosis of a nonpigmented choroidal mass. Stereotaxic radiation therapy is an effective treatment method. To the authors'' knowledge, this is the first report of a patient with choroidal paraganglioma. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. [ABSTRACT FROM AUTHOR]

Retinal angiomatous proliferation (RAP) is a distinct variant of neovascular age-related macular degeneration (AMD). The aim of this study is to evaluate the functional and anatomic outcome after intravitreal ranibizumab (Lucentis) treatment in patients with RAP. Prospective study of consecutive patients with newly diagnosed or recurrent RAP treated with intravitreal ranibizumab at the Jules Gonin Eye Hospital between March 2006 and December 2007. Baseline and monthly follow-up visits included best-corrected visual acuity (BCVA), fundus exam and optical coherence tomography. Fluorescein and indocyanine green angiography were performed at baseline and repeated at least every 3 months. Thirty-one eyes of 31 patients were treated with 0.5 mg of intravitreal ranibizumab for RAP between March 2006 and December 2007. The mean age of the patients was 82.6 years (SD:4.9). The mean number of intravitreal injections administered for each patient was 5 (SD: 2.4, range 3 to 12). The mean follow up was 13.4 months (SD: 3, range 10 to 22). The baseline mean logMAR BCVA was 0.72 (SD: 0.45) (decimal equivalent of 0.2). The mean logMAR BCVA was improved significantly ( P < 0.0001) at the last follow-up to 0.45, SD: 0.3 (decimal equivalent 0.35). The visual acuity (VA) improved by a mean of 2.7 lines (SD 2.5). Mean baseline central macular thickness (CMT) was 376 μm, and decreased significantly to a mean of 224 μm ( P < 0.001) at the last follow-up. Mean reduction of CMT was 152 μm (SD: 58). An average of 81.5% of the total visual improvement and 85% of the total CMT reduction occurred during the first post-operative month after one intravitreal injection of ranibizumab. During follow-up, an RPE tear occurred in one eye (3.2%) of the study group. No injection complications or systemic drug-related side-effects were noted during the follow-up period. Intravitreal ranibizumab injections appeared to be an effective and safe treatment for RAP, resulting in visual gain and reduction in macular thickness. Further long-term studies to evaluate the efficacy of intravitreal ranibizumab in RAP are warranted. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficacy of 106Ru plaque brachytherapy for the treatment of retinoblastoma. Methods and Materials: We reviewed a retrospective, noncomparative case series of 39 children with retinoblastoma treated with 106Ru plaques at the Jules-Gonin Eye Hospital between October 1992 and July 2006, with 12 months of follow-up. Results: A total of 63 tumors were treated with 106Ru brachytherapy in 41 eyes. The median patient age was 27 months. 106Ru brachytherapy was the first-line treatment for 3 tumors (4.8%), second-line treatment for 13 (20.6%), and salvage treatment for 47 tumors (74.6%) resistant to other treatment modalities. Overall tumor control was achieved in 73% at 1 year. Tumor recurrence at 12 months was observed in 2 (12.5%) of 16 tumors for which 106Ru brachytherapy was used as the first- or second-line treatment and in 15 (31.9%) of 47 tumors for which 106Ru brachytherapy was used as salvage treatment. Eye retention was achieved in 76% of cases (31 of 41 eyes). Univariate and multivariate analyses revealed no statistically significant risk factors for tumor recurrence. Radiation complications included retinal detachment in 7 (17.1%), proliferative retinopathy in 1 (2.4%), and subcapsular cataract in 4 (9.7%) of 41 eyes. Conclusion: 106Ru brachytherapy is an effective treatment for retinoblastoma, with few secondary complications. Local vitreous seeding can be successfully treated with 106Ru brachytherapy. [Copyright &y& Elsevier]

Historically, retinoblastoma was treated with external beam radiotherapy (EBR) and for many years this was the accepted standard of care. With greater knowledge of radiation-induced morbidity and mortality, the trend over the past decade has shifted towards primary chemotherapy for most globe conservative treatments. Such a radical change in treatment modalities has restrained EBR to second-line and salvage indications with little consensus regarding dose, timing and techniques. New radiotherapy options now allow for more focused radiation to the globe with further sparing of adjacent structures in such a way that their role in the management of retinoblastoma need to be reappraised. In this perspective paper, first the historical techniques of using EBR primarily with linear accelerated photons are reviewed. Then modern approaches are described, such as stereotactic conformal radiotherapy using a micromultileaf collimator, and proton therapy using a fixed horizontal beam and tantalum localization, or a rotating ganthry with spot scanning. For the first time, to the authors' knowledge, the benefits of these new irradiation modalities over conventional EBR are illustrated with six successfully treated pilot cases. Finally, some guidelines are provided regarding indications to modern radiation therapy in patients requiring second-line or salvage treatment for intraocular retinoblastoma, as well as adjuvant therapy for orbital involvement. [ABSTRACT FROM AUTHOR]

François­Neetens fleck corneal dystrophy (CFD) is a rare, autosomal dominant corneal dystrophy characterized by numerous small white flecks scattered in all layers of the stroma. Linkage analysis localized CFD to a 24-cM (18-Mb) interval of chromosome 2q35 flanked by D2S2289 and D2S126 and containing PIP5K3. PIP5K3 is a member of the phosphoinositide 3-kinase family and regulates the sorting and traffic of peripheral endosomes that contain lysosomally directed fluid phase cargo, by controlling the morphogenesis and function of multivesicular bodies. Sequencing analysis disclosed missense, frameshift, and/or protein-truncating mutations in 8 of 10 families with CFD that were studied, including 2256delA, 2274delCT, 2709C↵T (R851X), 3120C↵T (Q988X), IVS19-1G↵C, 3246G↵T (E1030X), 3270C↵T (R1038X), and 3466A↵G (K1103R). The histological and clinical characteristics of patients with CFD are consistent with biochemical studies of PIP5K3 that indicate a role in endosomal sorting. [ABSTRACT FROM AUTHOR]

Simple Summary: This study aims to assess cancer control and preservation of the eye and visual acuity after proton therapy abroad for eye melanoma. For this, medical files were reviewed of Dutch uveal melanoma patients who were treated in Switzerland with proton therapy from 1987 to 2019. The tumours of these patients were too large and/or localised too close to the optic nerve to be treated with local plaque irradiation. There were 103 patients, of whom one had a uveal melanoma in both eyes. The tumours were relatively large and often localised around the central part of the retina. At five years after treatment, proton therapy had controlled the uveal melanomas of 94% of the patients and 81% had preserved their eye. Spread of the cancer beyond the eye was observed in 30% of the patients. Most patients (79%) became blind or had severe visual impairment after proton therapy; a small group of patients had mild or no visual impairment (17%). The size of the tumour, its localisation and the dose of proton therapy were important for the risk of decline in visual acuity. This study shows that proton therapy abroad for uveal melanoma is feasible and yields good results. Objective: To assess oncological and ophthalmological outcomes after international referral of uveal melanoma patients for proton therapy. Materials and Methods: This is a retrospective study among Dutch uveal melanoma patients who were treated in Switzerland with 60.0 CGE proton therapy (in 4 fractions) from 1987 to 2019. All patients were ineligible for brachytherapy due to tumour size and/or proximity to the optic nerve. Time-to-event analyses were performed using Kaplan–Meier's methodology and Cox proportional hazards models. Results: There were 103 patients (104 eyes) with a median largest tumour diameter of 19 mm (range 6–26 mm). Tumours were localised centrally (11%), mid-peripherally (65%) or peripherally (34%). Median follow-up was 7 years. Five-year local control, distant metastasis-free survival and eye preservation rates were 94%, 70% and 81% respectively. At five years, severe, moderate and mild visual impairment was observed in respectively 79%, 4% and 6% of the patients. Larger tumour volumes and more central tumour localisation were associated with severe visual impairment. After correction for these factors, dose to the macula, optic disc and retina, but not optic nerve was significantly associated with severe visual impairment. Conclusion: International referral for proton therapy yielded good tumour control and eye preservation rates, but risk of distant metastasis and severe visual impairment were substantial, possibly due to the selection of advanced tumour stages and/or central localisation. Dose to the macula may be more relevant than dose to the optic nerve for preservation of visual acuity, which is relevant for the treatment planning of proton therapy. [ABSTRACT FROM AUTHOR]

Purpose: To describe a unique unilateral association between an iris stromal tumor and a macular focal choroidal excavation., Case Description: A 40-year old patient presented with a small iris tumor associated with a unilateral macular lesion disclosed during a routine ophthalmologic examination. The patient was asymptomatic and visual function was not affected. After clinical and instrumental evaluation, a diagnosis of nonmelanocytic undefined stromal tumor of the iris associated with macular focal choroidal excavation was made. The size and shape of the two lesions remained stable during a 7-year follow-up and the patient did not develop other signs., Conclusion: The concurrent presence of a stromal iris tumor associated with focal choroidal excavation has never been reported. Further reports of this association are required in order to understand its exact pathogenesis.

Purpose: To evaluate 18 months' results of a strict anti-vascular endothelial growth factor protocol for radiation maculopathy following proton therapy in choroidal melanoma., Methods: Retrospective, comparative, nonrandomized study of 74 radiation maculopathy patients presenting macular lipid deposits, hemorrhages, microaneurysms, cystoid edema, nerve layer infarction, telangiectasia, or capillary nonperfusion. The study group included 52 consecutive patients injected with intravitreal anti-vascular endothelial growth factors (bevacizumab/ranibizumab: 46/6) every two months for the first and every 3 months for the second year, with minimum 12 months' follow-up. The control group consisted of 22 patients having declined this treatment. Best-corrected visual acuity, spectral domain-optical coherence tomography and optical coherence tomography angiography were recorded at baseline, 6, 12, and 18 months. The foveal avascular zone and capillary density were measured at the superficial capillary plexus., Results: Radiation maculopathy was diagnosed at 2 years (1.5-3.5) after proton therapy. Best-corrected visual acuity at baseline, 12 and 18 months improved in the study group from 0.45, 0.3 to 0.2 logarithm of the minimum angle of resolution, but decreased in the control group from 0.5, 0.9 to 1.0 logarithm of the minimum angle of resolution respectively (P < 0.001 at 12 months). Simultaneously, foveal avascular zone enlargement was less in the study (from 0.377, 0.665 to 0.744 mm2) than control group (from 0.436, 1.463 to 2.638 mm2) (P = 0.05 at 12 months). CMT (280 and 276 µm) and capillary density (37% and 38%, at baseline, respectively) did not evolve significantly different., Conclusion: Intravitreal anti-vascular endothelial growth factors, every 2 months for the first and every 3 months for the second year, slow down, over up to 18 months, vision loss and anatomical degradation in radiation maculopathy following proton therapy for choroidal melanoma., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

Purpose: To report the case of a small pigmented tumor in the macular region investigated using optical coherence tomography angiography (OCT-A) in the context of a multimodal approach., Methods: Case report., Results: A 24-year-old man was referred for evaluation of an asymptomatic unilateral round comma-shaped pigmented tumor located in the macular region of his right eye. Spectral-domain OCT revealed an irregular hyperreflective mass within the retina, with a thickened hyaloid membrane and abrupt margins, and a complete posterior shadowing effect. On fluorescein angiography, early hyperfluorescence without leakage in the middle and late phases and a subtle halo of hyperfluorescence in the late phase were observed. OCT-A revealed the presence of intrinsic vascularization at the level of the inner capillary plexus, with signal intensity present at the level of the outer capillary plexus. In the superficial scans, the retinal vessels were oriented radially to the lesion and were in continuity with the vascular network within the tumor mass. No choroidal vessels could be identified., Conclusion: We report the case of a congenital simple hamartoma of the retinal pigment epithelium investigated using OCT-A as part of multimodal imaging. OCT-A provided a new insight in the assessment of the lesion, differential diagnosis, and follow-up of the patient. This imaging modality could be an important non-invasive tool in the management of congenital hamartomas of the retinal pigment epithelium.

Purpose: To evaluate why small- and certain medium-sized parapapillary choroidal melanoma (pcM) patients treated with hypo-fractionated proton therapy (PT) retain excellent long-term visual acuity (VA) and assess the negative predictive factors for retaining good vision (≤ 0.2 logMAR (≥ 0.6 decimal) after 5 years., Methods: This single-center, retrospective, comparative study recruited consecutive pcM patients that were treated with PT. Between 1984 and 2005, 609 patients received a total of 60 CGE, of whom 310 met the following inclusion criteria: posterior tumor border ≤ 2.5 mm from the optic disc, largest tumor diameter ≤ 17.9 mm, tumor thickness ≤ 5.2 mm and available follow-up data for at least 5 years., Results: Mean follow-up was 120.8 ± 48.8 months (54.0-295.0). Out of 310 patients, 64 (21%) maintained a VA ≤ 0.2 logMAR (≥ 0.6 decimal) for at least 5 years following PT and were allocated to the "good visual outcome" (GVO) group, while the remaining 246 (79%) constituted the "poor visual outcome" (PVO) group, subdivided into 70 (22%) with a VA of 0.3-1.0 logMAR (0.1-0.5 decimal) and 157 (57%) patients with a VA > 1.0 logMAR (< 0.1 decimal). On multivariate analysis, older age (P = 0.04), tumor localization ≤ 0.5 mm to the fovea (P < 0.03), volume of the optic disc and macula receiving 50% of dose (30 CGE) (P = 0.02 and P < 0.001, respectively) were independent negative predictors of GVO., Conclusions: Of 310 small- to medium-sized pcM patients successfully treated with PT, 21% retained a VA ≤ 0.2 logMAR (≥ 0.6 decimal) for at least 5 years. Strongest negative predictive factor for retaining good long-term vision was the volume of the macula irradiated with at least 30 Gy.

Purpose: To report, with the aid of original imaging, an unusual differential diagnosis of an iris tumor., Observations: A 60-year-old Caucasian man visited our clinic with a large amelanotic iris mass in the left eye in the absence of concomitant extraocular inflammation or neoplastic evidence. The patient reported an ocular trauma caused by a wire 5 years prior to his visit, which resolved after a short course of antibiotic eye drops. Orbital magnetic resonance imaging with contrast enhancement was consistent with an iris tumor; ultrasound biomicroscopy indicated a semi-solid, mid-stromal iris formation continuous with the lens. Surgical inspection was performed. Surgery showed the presence of a hypermature cataract with a fine break in the anterior capsule of the lens covered by the iris surface. The liquefied cortex infiltrated the iris without diffusing into the aqueous humor., Conclusions and Importance: A so-called morgagnian cataract developed, likely following a penetrating ocular wound. The progressive, slow infiltration of the iris stroma by the crystalline matrix mimicked the appearance of an amelanotic iris tumor., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article., (© 2020 The Authors.)

Purpose: The exact cellular types that form the human fovea remain a subject of debate, and few studies have been conducted on human macula to solve this question. The purpose of this study was to perform immunohistochemistry on fresh human samples to characterize the glial cells that form the human fovea., Methods: Immunohistochemistry was performed using antibodies against proteins expressed in astrocytes or in retinal Müller glial cells or both types of cells on six human macula obtained from eyes enucleated for peripheral intraocular tumors and on two postmortem eyes from healthy donors. The posterior poles of the enucleated eyes were cryosectioned and stained with antibodies against the glial proteins GFAP, vimentin, CRALBP, glutamine synthetase, and connexin 43., Results: A population of cells positive for GFAP and negative for glutamine synthetase and CRALBP that express connexin 43 were identified at the roof of the foveal pit. These cells are distinct from the Müller cone cells described by Yamada and Gass, suggesting that another type of foveal glial cells, most likely astrocytes, are present in the human fovea., Conclusions: This study showed that in humans, astrocytic glial cells cover the foveal pit. Their roles in macula homeostasis and mechanisms of macular diseases disease remain to be determined., (Copyright © 2020 Molecular Vision.)

Purpose: To evaluate, in eyes with radiation maculopathy, the effect of 2-month-interval anti-vascular endothelial growth factor therapy on best-corrected visual acuity and foveal avascular zone (FAZ) enlargement using optical coherence tomography angiography., Methods: Consecutive treatment-naive patients with radiation maculopathy after proton beam irradiation for choroidal melanoma were retrospectively included. Clinical and optical coherence tomography angiography data at baseline and the 6-month visit were recorded. Two independent observers measured FAZ area manually on 3 × 3-mm optical coherence tomography angiography images of the superficial capillary plexus and deep capillary plexus. Patients were encouraged to follow strictly a 2-month-interval intravitreal anti-vascular endothelial growth factor treatment by either bevacizumab or ranibizumab. Findings were analyzed based on the adherence to the treatment scheme., Results: According to the adherence to the bimonthly anti-vascular endothelial growth factor treatment protocol, patients were categorized into 3 groups: treatment protocol (n = 19, strict adherence), variable intervals (n = 11, intervals other than 2 months), and no treatment (n = 11). The estimated radiation dose to the foveola in each group was 49 ± 16, 46 ± 17, and 46 ± 18 cobalt gray equivalent, respectively (P = 0.85). For the entire cohort, best-corrected visual acuity loss (P < 0.02) and FAZ enlargement (P < 0.0001) were observed over 6 months. Best-corrected visual acuity loss was significantly less pronounced in the treatment-protocol group than in the variable-interval and no-treatment groups (P = 0.007 and P = 0.004). The FAZ enlargement was lower in the treatment-protocol group compared with the variable-interval group for both superficial capillary plexus (P = 0.029) and deep capillary plexus (P = 0.03), and to the no-treatment group for the deep capillary plexus only (P = 0.016)., Conclusion: Decrease in best-corrected visual acuity and FAZ enlargement on optical coherence tomography angiography occurred over 6 months in eyes with radiation maculopathy and were significantly reduced under 2-month-interval anti-vascular endothelial growth factor therapy.

Purpose: To report the clinical and histopathologic features of two cases of eyelids metastases from uveal melanoma diagnosed in a metachronous and synchronous fashion., Methods: Monocentric retrospective case series of histopathologically proven eyelids metastases from uveal melanoma at our institution., Results: Two patients were presented to our hospital for upper eyelids pigmented and firm lesions. Patient 1 had an history of left uveal melanoma treated conservatively with proton beam therapy 5 years earlier. Examination revealed bilateral upper eyelids lesions. Patient 2 had no malignancy history but was incidentally diagnosed with a cerebral nodule few months earlier. Examination revealed a right upper eyelid nodule and a previously unknown right uveal melanoma. Excisional biopsy was performed for both patients. Pathological assessment allowed the presence of melanoma cells. The lack of BAP1 nuclear expression on immunohistochemistry as well as the absence of cutaneous or mucosal melanoma were consistent with an uveal origin. Diffuse metastatic spread was noted for both patients. Systemic therapies were prescribed. Patient 1 died from metastatic spread (62 months and 4 months after uveal melanoma diagnosis and eyelids metastases removal, respectively) whereas patient 2 was still alive (14 months follow up)., Conclusions: Eyelids metastases from uveal melanoma is an exceptional finding. Excisional biopsy and pathological assessment are of main importance to confirm the diagnosis and to identify genetic mutations for further targeted therapies. Currently, prognosis remains poor.

Purpose: To validate a staging system for metastatic uveal melanoma that will facilitate planning, reporting, and interpreting the results of clinical trials., Design: Reliability and validity study., Methods: The performance index, the largest diameter of the largest metastasis and alkaline phosphatase level at the time of diagnosis of metastases, and overall survival of 249 patients from 7 ocular oncology centers who died of dissemination were analyzed. Predicted median survival time calculated according to the Helsinki University Hospital Working Formulation was used to assign patients to stages IVa, IVb, and IVc, which correspond to predicted survival times of ≥12, <12-6, and <6 months, respectively. The predictions were compared against observed survival., Results: The 3 variables used to assign stage were independent predictors of survival in the validation dataset. Of the 249 patients, 110 (44%), 109 (44%), and 30 (12%) were classified to Working Formulation stages IVa, IVb, and IVc, respectively. Corresponding median observed survival times were 18.6, 10.7, and 4.6 months and worsened by increasing stage (P < .001). Of 201 patients managed without surgical resection of metastases, 83 (41%), 89 (44%), and 29 (15%) were classified to stages IVa, IVb, and IVc, respectively, and their median observed survival times were 17.2, 10.0, and 4.6 months (P < .001). Survival of 47 patients who underwent resection did not differ by working formulation stage (P = .69)., Conclusions: This multicenter study confirms that the Working Formulation is a reliable and valid, repeatable system for dividing metastatic uveal melanoma into distinct prognostic subgroups, especially for stage-specific reporting of survival in prospective clinical trials., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aim: To describe the incidence of retinocytomas, their variability at presentation and their growth patterns both before and after regression., Methods: Medical notes of the 525 patients of the Jules-Gonin Eye Hospital Retinoblastoma Clinic between 1964 and 2008 were reviewed and the charts of 36 patients with retinocytomas and/or phthisis bulbi were selected., Results: The proportion of patients with retinocytomas and/or phthisis bulbi was 3.2%. The mean age at diagnosis was 28.7 ± 17 years. Five tumours presented a cystic pattern (5.8%). Evidence of aggressive exophytic disease prior to spontaneous regression was documented in two eyes, and of invasive endophytic disease (regressed vitreous seeding or internal limiting membrane disruption) in three eyes. Twenty patients were followed with a mean follow-up of 44 ± 60 months. Tumour growth was observed in 16% cases, benign cystic enlargement in 4% and malignant transformation in 12%., Conclusion: This large study of retinocytomas substantially expands the published features of retinocytoma by describing the cystic nature of some retinocytomas as well as clinical characteristics of the endophytic and exophytic preregression growth patterns. The authors report two different patterns of reactivation: benign cystic enlargement and malignant transformation with or without cystic growth. Higher than previously reported frequency of growth and possible life-threatening complications impose close lifetime follow-up of retinocytoma patients.

Purpose: We evaluate the functional and anatomic outcome after intravitreal ranibizumab treatment in patients with choroidal neovascularization (CNV) related to chronic central serous chorioretinopathy (CSC)., Methods: This is a small case series of 5 eyes with CNV associated with chronic CSC treated with intravitreal injection of 0.5 mg ranibizumab in the Jules Gonin University Eye Hospital from July 2007 to July 2009. Baseline and monthly follow-up visits included best-corrected visual acuity (BCVA), fundus examination, and optical coherence tomography (OCT). Fluorescein and indocyanine green angiography (ICG) were performed at baseline and repeated at least every 6 months., Results: We studied 5 eyes of 4 patients with a mean age of 66 years. Mean follow-up was 21 months (SD 1.9). The mean number of intravitreal injections administered for each patient was 10 (SD 4.6). The mean initial BCVA was 0.23 (decimal equivalent) (logMAR 0.64, SD 0.13). At the last follow-up, mean BCVA was 0.44 decimal equivalent (logMAR 0.36, SD 0.31). Mean central macular thickness (CMT) measured with OCT was 330 microm (SD 43) at baseline and decreased at the final follow-up to 243 microm (SD 44 ). Persistent intraretinal or subretinal fluid on OCT and/or multifocal areas of increased choroidal permeability on ICG angiographies were present in all patients at the last follow-up visit., Conclusions: Intravitreal ranibizumab appeared to be an effective treatment of CNV related to chronic CSC. However, residual intraretinal or subretinal fluid and increased choroidal permeability persisted. Prospective controlled studies are warranted to evaluate the long-term safety and efficacy of intravitreal ranibizumab.

Background: Macular choroidal neovascularization (CNV) is one of the most vision-threatening complications of myopia, which can lead to severe vision loss. The purpose of this study was to evaluate the safety and efficacy of intravitreal ranibizumab in the treatment of myopic CNV., Methods: We conducted a prospective, consecutive, interventional study of patients with subfoveal or juxtafoveal CNV secondary to pathologic myopia (PM) treated with intravitreal injection of ranibizumab in the Jules Gonin University Eye Hospital from June 2006 to February 2008. Best-corrected visual acuity (BCVA), optical coherence tomography (OCT), and fluorescein angiography (FA) were performed at baseline and monthly for all patients. Indications for retreatment were loss in BCVA associated either with persistent leakage from CNV shown on FA, and/or evidence of CNV activity on OCT., Results: The study included 14 eyes of 14 patients. The mean spherical equivalent refractive error was -12.5 (range, -8.0 D to -16.0 D). Mean time of follow-up was 8.4 months (range from 3 to 16 months, SD: 3). The mean number of intravitreal injections administered for each patient was 2.36 (SD 1.5). The mean initial visual acuity (VA) was 0.19 decimal equivalent (log-MAR: 0.71, SD: 0.3). A statistically significant improvement to a mean VA of 0.48 decimal equivalent (log-MAR:0.32, SD: 0.25) was demonstrated at the final follow-up. VA improved by a mean of 3.86 (SD 2.74) lines. Nine patients (64%) demonstrated a gain of 3 or more lines. Mean central macular thickness (CMT) measured with OCT was 304 microm (SD: 39) at the baseline, and was reduced significantly at the final follow-up to 153 microm (SD: 23). Average CMT reduction was 170 microm (SD: 57). No injection complications or drug-related side effects were noted during the follow-up period., Conclusions: In this small series of eyes with limited follow-up, intravitreal ranibizumab was a safe and effective treatment for CNV secondary to PM, resulting in functional and anatomic improvements.

Background: Melanocytoma of the optic disc is a benign melanocytic tumor that rarely causes visual impairment. We report a case of a melanocytoma of the optic disc with a decreased vision related to a peripapillary choroidal neovascular membrane (PCNVM) that was successfully treated by submacular surgery., Methods: A 45-year-old southern European patient had a melanocytoma of the optic disc in his left eye with vision of 20/100. Fluorescein angiography demonstrated a PCNVM impeding the fovea associated with a subretinal hemorrhage., Results: The patient underwent a complete vitrectomy and removal of the PCNVM. Subsequently, the subretinal hemorrhage disappeared and visual acuity improved to 20/25. Visual acuity remained good for a period of 14 months' follow-up without any recurrence of neovascular membrane., Conclusions: Submacular surgery is a potentially effective treatment for large PCNVM associated with a melanocytoma of the optic disc.

RAF proteins are serine/threonine kinases that mediate cellular responses to growth signals by activating the mitogen-activated protein kinase pathway. Mutations in the BRAF gene causing a V599E amino acid substitution that enhance the kinase activity have been described in >60% of cutaneous melanomas and premalignant melanocytic lesions. We have investigated the frequency of BRAF mutations at the expression level in melanomas of the uveal tract. None of the 30 metastases and 10 primary uveal melanomas tested expressed the V599E mutation. In contrast, this mutation was expressed by 65% of cutaneous melanoma samples, confirming previous results. In addition, a double mutation resulting in V599K substitution was detected in two suspect ocular metastases of cutaneous melanoma. Analysis of exon 11, the second common site of BRAF mutations, revealed only wild-type sequences in uveal melanomas. Analysis of tumor lysates showed the presence of phosphorylated mitogen-activated protein kinase, kinase, and mitogen-activated protein kinase in 50% of uveal and 100% of cutaneous melanoma metastases. Taken together, these results suggest that although the common BRAF mutations found in cutaneous melanoma do not play a role in tumorigenesis of uveal tract melanocytes, activation of the RAF/mitogen-activated protein kinase pathway may nevertheless play an important role in uveal melanoma.