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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 (P = 0.04), tumor localization ≤ 0.5 mm to the fovea (P P = 0.02 and P 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 our 14-year experience with orbital exenteration and assess risk factors for poor prognosis by focusing on conjunctival melanoma. Patients and method A retrospective study was conducted in our tertiary care centre (Jules Gonin Eye Hospital, Lausanne, Switzerland) between 2003 and 2017. Inclusion criteria were patients aged ≥18 years with a follow-up >12 months, without metastatic spread at the time of surgery. Data recorded were age, gender, tumour histology, surgical technique, postoperative complications, surgical margin status, local recurrence, postoperative radiation beam therapy and metastatic status. Results Twenty-five patients with a mean age of 63.2 years (38–92) were included. Conjunctival melanoma was the most frequently identified tumour (n = 14, 56%) followed by conjunctival squamous cell carcinoma (n = 4, 16%), sebaceous carcinoma (n = 3, 12%), choroidal melanoma (n = 2, 8%) and basal cell carcinoma (n = 2, 8%). Eighteen tumours (72%) originated from the conjunctival tissue. Clear surgical margins were achieved in 21 (84%) patients. Fourteen (56%) patients experienced distant metastases and died from metastatic spread after a mean follow-up of 52.3 months (6–120). The 1-, 3- and 5-year overall survival (OS) was 96%, 72% and 60%, respectively. In the univariate analysis, positive surgical margins, local recurrence and metachronous metastases were associated with a decreased OS (p = 0.002, p = 0.005 and p = 0.007, respectively). In the multivariate analysis, positive surgical margins and metachronous metastases were also associated with a decreased OS (p = 0.02 and p = 0.042, respectively). Conjunctival melanoma was not associated with a poorer prognosis (p = 0.280). Conclusion Free surgical margins are needed to increase OS. To achieve clearer surgical margins, neoadjuvant targeted therapies/immunotherapies may be considered.

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, 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.

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.

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.

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 2.4mm-4.1mm 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 8-12weeks, 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.

The clinical presentation of uveal melanoma is influenced by its site of origin (iris, ciliary body, or choroid), pigmentation, size, extent of secondary retinal detachment, hemorrhage or inflammation, or any extrascleral extension.

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.

Uveal melanoma (UM) is a rare intraocular tumor that, similar to cutaneous melanoma, originates from melanocytes. To gain insights into its genetics, we performed whole-genome sequencing at very deep coverage of tumor-control pairs in 33 samples (24 primary and 9 metastases). Genome-wide, the number of coding mutations was rather low (only 17 variants per tumor on average; range 7–28), thus radically different from cutaneous melanoma, where hundreds of exonic DNA insults are usually detected. Furthermore, no UV light-induced mutational signature was identified. Recurrent coding mutations were found in the known UM drivers GNAQ, GNA11, BAP1, EIF1AX, and SF3B1. Other genes, i.e., TP53BP1, CSMD1, TTC28, DLK2, and KTN1, were also found to harbor somatic mutations in more than one individual, possibly indicating a previously undescribed association with UM pathogenesis. De novo assembly of unmatched reads from non-coding DNA revealed peculiar copy-number variations defining specific UM subtypes, which in turn could be associated with metastatic transformation. Mutational-driven comparison with other tumor types showed that UM is very similar to pediatric tumors, characterized by very few somatic insults and, possibly, important epigenetic changes. Through the analysis of whole-genome sequencing data, our findings shed new light on the molecular genetics of uveal melanoma, delineating it as an atypical tumor of the adult for which somatic events other than mutations in exonic DNA shape its genetic landscape and define its metastatic potential.

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.

To analyze the activity of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinases/mechanistic target of rapamycin (PI3K/mTOR) pathways in benign and malignant conjunctival melanocytic proliferations and explore whether specific inhibitors can suppress growth of conjunctival melanoma (CJM) cells.; The presence of a BRAF V600E mutation and activation of ERK, MEK, S6, and AKT were assessed with immunohistochemistry in 35 conjunctival nevi and 31 melanomas. Three CJM cell lines were used: CRMM1, carrying the BRAF V600E mutation; CRMM2, harboring the NRAS Q61L mutation; and T1527A, with a BRAF G466E mutation. WST-1 assays were performed with a BRAF inhibitor (vemurafenib), two MEK inhibitors (trametinib, selumetinib), a PI3K inhibitor (pictilisib), and a dual PI3K/mTOR inhibitor (dactolisib). The phosphorylation of ERK, MEK, and S6 were tested with western blots and apoptosis with cleaved caspase-3 immunostaining.; A BRAF V600E mutation was detected in 42.6% of nevi and in 35.5% of CJM. MEK and ERK activation were higher in CJM, occurring in 62.9% and 45.7% of the nevi and 90.3% and 96.8% of the CJM, respectively. There was also a significant increase in S6 activation in CJM (90.3%) compared with the nevi (20%). CRMM1 was sensitive to trametinib and the PI3K inhibitors but only marginally to vemurafenib. CRMM2 was moderately sensitive to pictilisib, whereas T1527A was resistant to all drugs tested.; The MAPK pathway activity in CJM is increased, not only as a consequence of the BRAF V600E mutation. Targeted therapy may be useful for patients with CJM, especially those with activating BRAF mutations, whereas NRAS-mutated melanomas are relatively resistant.

L'utilisation de faisceaux de protons acceleres dans le traitement des melanomes de l'uvee a ete utilisee pour la premiere fois en Suisse (et par ailleurs en Europe) en 1984. Depuis, la protontherapie a constamment evolue avec des logiciels toujours plus performants et precis pour devenir a l'heure actuelle le traitement de reference pour ce type de tumeurs. Ainsi, jusqu'a ce jour, l'Institut Paul Scherrer a Villigen a traite plus de 7000 cas de tumeurs oculaires. Mais la protontherapie, aussi efficace soit-elle avec un taux de guerison de plus de 98%, comporte malheureusement un certain nom bre d'effets secondaires et indesirables pouvant parfois mener le patient jusqu'a l'enucleation secondai re. De la simple dermatite actinique a l'hemorragie intravitreenne massive, les complications induites sont pour la plupart bien connues et documentees mais leurs prises en charge, notamment sur un organe prealablement irradie different. Alors que nous avons beaucoup de recul sur la protontherapie, la gestion de ses complications reste propre a chaque centre de soin et n'est que tres peu documentee. Les complications majeures de la protontherapie qui ont necessite une prise en charge par le chirurgien vitroretinien representent souvent un defi majeur. Bien que rares, puisqu'elles ne representent que 2% de notre collectif, celles-ci peuvent avoir de lourdes consequences. Pa r exemple, une hemorragie intravitreenne massive, complication la plus frequente dans notre serie, compromet l'observation de la tumeur au fond d'oeil et empeche le bon suivi oncologique. La chirurgie vitroretinienne a alors pour mission, de restaurer la transparence des milieux, element indispensable a l'ophtalmologue pour le suivi clinique, iconographique et radiologique des melanomes de l'uvee. Secondairement, cette chirurgie permet parfois d'augmenter l'acuite visuelle de l'oeil malade. La chirurgie vitroretinienne est un precieux atout pour l'oncologue et permet d'eviter une enucleation secondaire. Elle participe ainsi a la prise en charge globale du patient atteint de melanome de l'uvee.

The differential diagnosis of melanocytic choroidal tumors includes choroidal nevus, optic disk melanocytoma and choroidal melanoma. A typical choroidal nevus is an asymptomatic, oval, grey, benign tumor with a thickness of usually less than 2.5 mm. In most cases, retinal pigment epithelial changes at its surface, such as drusen, are present. The statistical risk of malignant transformation increases with the number of certain risk factors. Optic disk melanocytoma (nevus magnocellularis) is a dark nevus carrying risks of visual field damage through nerve compression and of malignant transformation into melanoma. Choroidal nevus and optic disk melanocytoma both require lifelong periodic observation. Choroidal melanoma is a rare malignant tumor. Its degree of pigmentation can vary, as can its size and shape (dome or mushroom shaped, flat, multinodular or small). It usually becomes symptomatic when it affects surrounding visual anatomic structures, such as the retina or lens, causing retinal detachment or cataract. While enucleation is still performed for extended, ill-defined tumors, conservative radiation therapy using radioactive plaques or a proton beam has become the preferred method. Survival depends on the risk of liver metastases, which is enhanced in the presence of tumoral cytogenetic mutations, such as monosomy 3.

The majority of retinal pigment epithelial (RPE) tumors are considered to be congenital and benign. They are classified as either congenital hypertrophy of the RPE (CHRPE) or RPE hamartoma. CHRPE most frequently presents as an isolated, flat, darkly pigmented and well-delineated fundus lesion. Occasionally, multiple CHRPE (grouped pigmentation) can resemble bear tracks. Multifocal pigmented ocular fundus lesions are frequently associated with familial adenomatous polyposis. RPE hamartomas are rare RPE malformations subdivided into simple RPE hamartoma, combined hamartoma of the retina and RPE, and unilateral RPE dysgenesis. Acquired RPE tumors include reactional RPE hyperplasia, RPE adenoma and RPE adenocarcinoma. These three entities are clinically and histopathologically difficult to separate and might represent stages along one continuous pathophysiologic spectrum. They are often secondary to trauma, inflammation or sometimes CHRPE and do not have metastatic potential.

UV light signature in conjunctival melanoma; not only skin should be protected from solar radiation

Intraocular vascular tumors are rare and are often associated with various ophthalmic or systemic anomalies. Choroidal vascular tumors encompass circumscribed and diffuse choroidal hemangiomas, with t

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 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.

To describe a probable case of bilateral diffuse uveal melanocytic proliferation (BDUMP) with unusual manifestations and prognosis.Case report.Clinical follow-up of the patient lasting 50 months with recurrent fundus examination using color photographs, angiography, ultrasound, and optical coherence tomography. Serological and radiological investigations were performed to assess possible extraocular alterations.In both eyes patch-shaped pigmented alterations of the fundus were revealed. Fluorescein and indocyanine angiography evidenced corresponding areas of hyperfluorescent pinpoints and subtle serous detachment of the neurosensory retina, respectively. Ten months after the initial evaluation, flat pigmentary lesions appeared in the superior scleral surface of the right eye and underwent histological examination. After an initial decrease in visual acuity, the patient experienced a spontaneous recovery. He did not develop cataracts or any systemic malignancies.Although not all the criteria for the diagnosis were fulfilled, clinical findings were compatible with BDUMP. The presence of scleral pigmented lesions and the good visual prognosis may widen the spectrum of this rare disease.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 microm, and decreased significantly to a mean of 224 microm (P < 0.001) at the last follow-up. Mean reduction of CMT was 152 microm (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. CONCLUSIONS: 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.

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.

Purpose To evaluate the efficacy of 106 Ru plaque brachytherapy for the treatment of retinoblastoma. Methods and Materials We reviewed a retrospective, noncomparative case series of 39 children with retinoblastoma treated with 106 Ru 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 106 Ru brachytherapy in 41 eyes. The median patient age was 27 months. 106 Ru 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 106 Ru brachytherapy was used as the first- or second-line treatment and in 15 (31.9%) of 47 tumors for which 106 Ru 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 106 Ru brachytherapy is an effective treatment for retinoblastoma, with few secondary complications. Local vitreous seeding can be successfully treated with 106 Ru brachytherapy.

Uveal melanoma metastases occur most commonly in the liver. Given the 50% mortality rate in patients at high risk of developing liver metastases, we tested an adjuvant intra-arterial hepatic (i.a.h.) chemotherapy with fotemustine after proton beam irradiation of the primary tumour. We treated 22 high-risk patients with adjuvant i.a.h. fotemustine. Planned treatment duration was 6 months, starting with four weekly doses of 100 mg/m(2), and after a 5-week rest, repeated every 3 weeks. The survival of this patient group was compared with that of a 3 : 1 matched control group randomly selected from our institutional database. Half of the patients experienced > or =grade 3 hepatotoxicity (one patient developing cholangitis 8 years later). Catheter-related complications occurred in 18%. With a median follow-up of 4.6 years for the fotemustine group and 8.5 years for the control group, median overall survival was 9 years [95% confidence interval (CI) 2.2-12.7] and 7.4 years (95% CI 5.4-12.7; P=0.5), respectively, with 5-year survival rates of 75 and 56%. Treatment with adjuvant i.a.h. fotemustine is feasible. However, toxicities are important. Although our data suggest a survival benefit, it was not statistically significant. Confirming such a benefit would require a large, internationally coordinated, prospective randomized trial.

BACKGROUND: Combined hamartoma of the retina and retinal pigment epithelium (CHRRPE) are rare, benign tumours that typically appear slightly elevated and are characterised by varying amounts of pigmentation, vascular tortuosity, and epiretinal membrane formation that can be related to macular distortion. The importance of changes at the vitreoretinal interface in this condition as a risk for visual loss was early recognised but controversy exists concerning the benefits of surgical removal of the tractional component. We describe 2 cases of CHRRPE who demonstrated significant visual acuity improvement after pars plana vitrectomy and epiretinal membrane peeling. HISTORY AND SIGNS: A 12-year-old girl and a 14-year-old boy presented with progressive unilateral visual loss related with a CHRRPE. In both instances the hamartoma was associated with a thickened posterior hyaloid and epiretinal membrane inducing considerable vitreomacular traction as shown by optical coherence tomography (OCT). Best-corrected pre-operative visual acuity was 0.2 in both cases. THERAPY AND OUTCOME: Vitrectomy and epiretinal membrane peeling were performed in both cases. Relief of vitreomacular traction and macular distortion was achieved and documented on OCT. Visual acuity at the latest follow up was 0.5 and 0.8, respectively. CONCLUSIONS: Surgical dissection can be effective in the treatment of vitreomacular traction associated with CHRRPE with a good functional and anatomical outcome.

Correction: Volume: 211 Pages: 233-233 DOI: 10.1016/j.ajo.2019.11.027 Published:‏ MAR 2020 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

Purpose As loss of cyclin dependent kinase inhibitors p27 and p21 have been identified in cutaneous melanoma and associated with a poorer prognosis, we decided to assess the expression of p27 and p21 in benign and malignant conjunctival melanocytic proliferations. Methods The expression of p27 and p21 was assessed by immunohistochemistry in 35 conjunctival naevi and 32 conjunctival melanomas. Statistical analysis was performed with JUMP 8.0 software. Immunohistochemistry was evaluated independently by two observers. Results There was a concordance in 94.02% and 92.54% of the cases in the evaluation of the expression of p27 and p21, respectively. Discrepant cases were simultaneously reviewed to achieve complete agreement. There were 13 subepithelial nevi and 22 compound nevi. There were 14 females and 21 males with a mean age was 36.9 ± 3.6 yo (SEM). Nuclear expression of p27 was found in all the nevi. p21 was identified in only 4 nevi (11.4%). The melanoma group was composed of 18 females and 14 males with a mean age of 65.9 ± 3.38 yo (SEM). p27 and p21 were respectively lost in 18 cases (56.25%) and in 24 cases (75%). There was a significant downregulation of p27 in conjunctival melanoma compared to benign conjunctival nevi (p > 0.0001). In the melanomas, there was a correlation between loss of p27 expression and depth of invasion (p = 0.0141) as well as non-bulbar tumor localization (p = 0.0279). Although the proliferation index was more elevated in melanomas with p27 loss, this was not significant. Conclusions The downregulation of p21 in benign melanocytic proliferations identified in the skin appears also to occur in the conjunctiva. Our results also demonstrate in vivo a significant downregulation of p27 in conjunctival melanoma. Restauration of p27 function in conjunctival melanoma might represent a potential therapeutical option for this tumor.

Purpose To evaluate the outcomes following stereotactic radiation therapy of diffuse choroidal hemangioma related to Sturge-Weber syndrome (STW) and associated with secondary retinal detachment (RD) Methods Retrospective case series of STW patients with diffuse choroidal hemangioma associated with RD, that were treated with stereotactic radiation therapy. The technique consisted of applying 19.8–25.2 Gray in 10–14 fractions, at the posterior pole Results Between June 2001 and August 2013, 13 patients (M/F ratio: 6/7) with a median age of 8.5 years (range: 3.0–32.0 years) were irradiated. Before, five of them had been unsuccessfully treated with PDT, silicone oil or propranolol in an attempt to reattach the RD. Median visual acuity at baseline was reduced to HM (range: NPL-0.7) with a median tumor thickness of 4.4 mm (range: 3.1–7.2). During radiation treatment, one patient complained of minor, transient conjunctival irritation. Mean follow-up (FU) was 39 months (range: 0–141 months). Complete retinal reattachment was observed in 9 cases, partial retinal reattachment in 1 case (FU 3 months) and no response in 1 case (RD duration of 3 years).Two patients were lost to follow-up. Four patients received panretinal photocoagulation for retinal ischemia. At the last control examination, median visual acuity was 0.04 (range: NPL-0.8), mainly related to pre-existing amblyopia, secondary retinal changes or glaucoma-associated optic atrophy. Median tumor thickness was 2.0 mm (range: 1.3–2.5) Conclusions Stereotactic radiation therapy with 20–25 Gray is an efficient treatment for reapplying secondary RD in STW patients with diffuse choroidal hemangioma. No major complications were noted. However, visual outcomes remained poor, because of the complex ocular problems these young patients present, with often a delay in diagnosis and treatment.

BACKGROUND Cyclitic retrolental membranes (CRM) in children are usually associated with chronic uveitis or genetic syndromes. We report two rare cases of idiopathic CRM. PATIENTS AND METHODS Two girls aged 9 and 13 years with visual acuities (VA) of 0.05 underwent lensectomy and anterior vitrectomy with dissection of the central part of the retrolental membrane and intraocular lens (IOL) implantation. RESULTS The clinical evolution was excellent for the 9 year old girl who recovered 1.0 VA after 2 months. Histological examination revealed a fibroelastic tissue of unknown origin without inflammatory components. The 13 year old girl showed VA of 0.6 within 1 month. However, a recurrent CRM developed with retinal detachment and proliferative vitreoretinopathy (PVR). Vitrectomy, complete excision of the CRM and 360 degrees retinotomy with silicon oil tamponade attached the retina with limited visual recovery. Histology showed fibrovascular tissue with inflammatory components infiltrating the CRM. CONCLUSIONS Idiopathic CRM in children are rare and can be composed of different histological tissues with very different clinical outcomes.

Resume La maladie de Coats, ou telangiectasie retinienne primaire, est une retinopathie exsudative rare, generalement unilaterale, affectant le plus souvent des garcons dans la premiere decennie, non familiale, probablement congenitale, sans evidence de maladies systemiques associees, constituee de telangiectasies primaires et d'exsudats pouvant conduire a un decollement de retine, a des hemorragies vitreoretiniennes, a un glaucome neovasculaire et finalement a la perte de la vision. La lesion primitive est vraisemblablement une anomalie localisee et evolutive de developpement des vaisseaux retiniens. L'origine precise n'est pas connue mais la maladie pourrait etre liee a une mutation somatique du gene NDP (Norrie Disease Protein) . Les telangiectasies idiopathiques juxtafoveolaires constitueraient une seconde forme clinique de telangiectasies primaires de la retine limitee a la region maculaire. Il existe egalement des telangiectasies secondaires a des affections locales ou generales pouvant provoquer, comme dans la maladie de Coats, des exsudations retiniennes importantes. C'est le cas par exemple d'une occlusion de branche veineuse, d'une retinopathie actinique ou du diabete.

Purpose Evaluation of a large series of choroidal nevi inducing the formation of a neovascular membrane in order to more clearly define the clinical presentation and to evaluate the efficacy of various treatment options. METHOD Retrospective study of 22 clinical cases. Results All nevi were situated in the posterior choroid. They had a mean diameter of 3.8 mm and a mean thickness of 1.4 mm. Neovascular membranes were classic in all cases, extrafoveal in 13 cases (59%), and subfoveal in 9 cases (41%). A serous retinal detachment was present in every case, hemorrhages were present in 13 cases (59%), and lipid deposits were present in 16 cases (73%). All extrafoveal neovascular membranes were successfully treated by thermal laser photocoagulation. Initial visual acuity was 0.1 in three cases, 0.2–0.4 in five cases, 0.5–0.8 in four cases, and 1.0 or more in two cases. Final visual acuity was 0.1 in one case, 0.2–0.4 in one case, 0.5–0.8 in four cases, and 1.0 or more in seven cases. Five subfoveal neovascular membranes were treated either by thermal laser, photodynamic therapy, or irradiation. No treatment was applied in four cases and in one of these cases, spontaneous resolution of the neovascular membrane was observed. No growth of the pigmented tumor was observed with a mean follow-up of 4.8 years. CONCLUSIONS Proliferation of a neovascular membrane on the surface of a pigmented choroidal tumor is a rare complication and is considered to be a relative indicator of a benign nature of the lesion. In the authors' experience, neovascular membranes are extrafoveal in more than half of cases and are accessible to laser photocoagulation. In contrast, the various modalities used to treat subfoveal neovascular membrane were ineffective and functional prognosis was unfavorable in these cases.

Resume La choroide peut etre le siege de nombreuses tumeurs benignes et malignes ainsi que de diverses formations pseudotumorales d'aspect clinique tres proche. Les progres de l'ophtalmo-oncologie moderne realises grâce a la generalisation de l'utilisation de l'ophtalmoscopie indirecte binoculaire, a l'utilisation systematique de l'ultrasonographie, de l'angiographie fluoresceinique, de l' indocyanine green et de l'imagerie par resonance magnetique ainsi qu'a la mise en commun d'une large experience acquise dans les centres specialises, ont abaisse les erreurs de diagnostic clinique a moins de 2 %. Les developpements considerables des moyens de traitement conservateurs et plus particulierement de la radiotherapie circonscrite ont par ailleurs permis, dans la grande majorite des cas, d'eviter l'enucleation, et d'atteindre un taux de controle local de la tumeur superieur a 98 %. La recherche actuelle a pour but d'ameliorer la fonction visuelle, de preserver la vue et d'ameliorer la survie des patients grâce a des therapies systemiques novatrices.

Resume Le complexe iridociliaire est constitue d'elements tissulaires d'origine embryogenique exo- et mesodermique, pouvant etre a l'origine de tumeurs benignes et malignes et de formations pseudotumorales. Ces diverses lesions peuvent etre situees en chambre anterieure, en chambre posterieure et dans l'espace peri- et retrocristallinien. Elles peuvent etre diffuses ou nodulaires et etre a l'origine de diverses complications telles une reaction inflammatoire majeure, des synechies, un glaucome, une cataracte et une subluxation du cristallin. L'aspect clinique etant souvent non specifique, le diagnostic differentiel et le choix de la meilleure attitude therapeutique sont par consequent difficiles.