Ann Schalenbourg

Adjuvant intra-arterial hepatic fotemustine for high-risk uveal melanoma patients.

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/m2, 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 ≥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.

Indocyanine Green Angiographic Findings in Choroidal Hemangiomas: A Study of 75 Cases

Indocyanine green (ICG) angiography is a new diagnostic modality that was suggested, in small series, to provide a typical angiographic pattern in cases of choroidal hemangioma. Our study, through an exceptionally large series of 75 patients, assessed in a prospective way whether a typical ICG pattern of choroidal hemangioma exists and what would be its possible variations. The most constant feature is the sequence of the different ICG angiographic phases. The arterial phase demonstrates the filling of intratumoral vessels on a hypofluorescent tumoral background. During the venous phase, the hemangioma reaches a stage of maximal ICG-A fluorescence, with superimposed hyper- and hypofluorescent spots. Sturge-Weber cases have also extratumoral hyperfluorescent spots. The late phase shows a hypofluorescent lesion with residual hyperfluorescent caverns and a well-delineated, but complex border structure.

Comprehensive Genetic Landscape of Uveal Melanoma by Whole-Genome Sequencing

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.

18F-fluorodeoxyglucose positron emission tomography/computed tomography and magnetic resonance imaging in patients with liver metastases from uveal melanoma: results from a pilot study

Purpose18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) and MRI are used for detecting liver metastases from uveal melanoma. The introduction of new treatment options in clinical trials might benefit from early response assessment. Here, we determine the value of FDG-PET/CT with respect to MRI at diagnosis and its potential for monitoring therapy. Material and methodsTen patients with biopsy-proven liver metastases of uveal melanoma enrolled in a randomized phase III trial (NCT00110123) underwent both FDG-PET coupled with unenhanced CT and gadolinium-diethylene triamine pentaacetic acid-enhanced liver MRI within 4 weeks. FDG-PET and MRI were evaluated blindly and then compared using the ratio of lesion to normal liver parenchyma PET-derived standardized uptake value (SUV). The influence of lesion size and response to chemotherapy were studied. ResultsOverall, 108 liver lesions were seen: 34 (31%) on both modalities (1–18 lesions/patient), four (4%) by PET/CT only, and 70 (65%) by MRI only. SUV correlated with MRI lesion size (r=0.81, P<0.0001). PET/CT detected 26 of 33 (79%) MRI lesions of more than or equal to 1.2 cm, whereas it detected only eight of 71 (11%) lesions of less than 1.2 cm (P<0.0001). MRI lesions without PET correspondence were small (0.6±0.2 vs. 2.1±1.1 cm, P<0.0001). During follow-up (six patients, 30 lesions), the ratio lesion-to-normal-liver SUV diminished in size-stable lesions (1.90±0.64–1.46±0.50, P<0.0001), whereas it increased in enlarging lesions (1.56±0.40–1.99±0.56, P=0.032). ConclusionMRI outweighs PET/CT for detecting small liver metastases. However, PET/CT detected at least one liver metastasis per patient and changes in FDG uptake not related to size change, suggesting a role in assessing early therapy response.

Systemic Melanoma Metastatic to the Retina and Vitreous

Purpose: Report of a case of retinal and vitreous metastases of a systemic melanoma, possibly arising in the lung, that responded favourably to radiotherapy. Case Report: Retinal and vitreous metastases were demonstrated in a 57-year-old woman during routine follow-up after surgical resection of a melanoma presumed to be a primary pulmonary melanoma. After a 7-week observation period, which confirmed the progressive nature of the intra-ocular lesions, the patient was treated by external beam radiotherapy at a dose of 35 Gy delivered in 14 fractions of 2.5 Gy. Complete disappearance of the vitreous invasion and progressive elimination of the retinal invasion were observed over a period of 9 months. Final visual function was 20/25. Review of Published Cases: A review of the literature identified 28 cases of melanoma with metastases to the retina and vitreous. In almost all of these cases, the primary tumour was a cutaneous melanoma and the mean patient survival following the diagnosis of intra-ocular metastases was 22 months. Retinal metastases, as in the case reported here, present a vascular tropism and tend to develop around veins. These metastases are generally unilateral and may be either solitary or multiple. Tumour invasion of the vitreous occurred by means of isolated cells forming a suspension of aggregates or spherules. Vitreous haemorrhage and irreducible neovascular glaucoma leading to functional impairment, which requires enucleation, were both the most frequent and the most serious complications of these metastases. Treatment is always palliative and is effective in cases with limited retinal and vitreous invasion, as in the case reported here. Conclusions: Metastatic melanoma in the retina and vitreous is a rare entity and can lead to functional impairment and enucleation because of neovascular glaucoma. As treatment is only effective in cases with limited invasion, systematic screening is recommended in all patients with a metastatic cutaneous melanoma presenting with suggestive ocular symptoms.

Peripheral Exudative Hemorrhagic Chorioretinopathy: Polypoidal Choroidal Vasculopathy and Hemodynamic Modifications

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.

Prophylactic Use of Bevacizumab to Avoid Anterior Segment Neovascularization Following Proton Therapy for Uveal Melanoma

PURPOSE To investigate whether the prophylactic use of bevacizumab reduces the rate of rubeosis after proton therapy for uveal melanoma and improves the possibility to treat ischemic, reapplicated retina with laser photocoagulation. DESIGN Comparative retrospective case series. METHODS Uveal melanoma patients with ischemic retinal detachment and treated with proton therapy were included in this institutional study. Twenty-four eyes received prophylactic intravitreal bevacizumab injections and were compared with a control group of 44 eyes without bevacizumab treatment. Bevacizumab injections were performed at the time of tantalum clip insertion and were repeated every 2 months during 6 months, and every 3 months thereafter. Ultra-widefield angiography allowed determination of the extent of retinal ischemia, which was treated with laser photocoagulation after retinal reapplication. Main outcome measures were the time to rubeosis, the time to retinal reattachment, and the time to laser photocoagulation of ischemic retina. RESULTS Baseline characteristics were balanced between the groups, except for thicker tumors and larger retinal detachments in the bevacizumab group, potentially to the disadvantage of the study group. Nevertheless, bevacizumab prophylaxis significantly reduced the rate of iris rubeosis from 36% to 4% (log-rank test P = .02) and tended to shorten the time to retinal reapplication until laser photocoagulation of the nonperfusion areas could be performed. CONCLUSIONS Prophylactic intravitreal bevacizumab in patients treated with proton therapy for uveal melanoma with ischemic retinal detachment prevented anterior segment neovascularization, until laser photocoagulation to the reapplied retina could be performed.

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

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

The Pediatric Choroidal and Ciliary Body Melanoma Study: A Survey by the European Ophthalmic Oncology Group

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 Melanocytic Tumors

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.