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Objective: To evaluate the outcomes of orbital exenteration with temporalis muscle flap repair of the socket and secondary healing of the anterior surface of the flap in ocular, conjunctival, and eyelid malignancies., Design: Retrospective single-centre study., Participants: Consecutive patients who underwent total exenteration for malignancy with temporal muscle flap repair of the socket between December 2009 and January 2016., Methods: We report the outcomes of this surgical technique in terms of healing without fistula formation and time to epithelialization., Results: Twenty-nine patients underwent surgery using this technique. Diagnoses consisted of 18 conjunctival melanomas, 2 choroidal melanomas, 6 squamous cell carcinomas, 2 sebaceous cell carcinomas, and 1 basal cell carcinoma. Mean age at surgery was 70.7 years and mean follow-up was 27.4 months. On histological analysis, tumour excision was complete in 25 patients, of whom 3 had an orbital recurrence after exenteration (3 conjunctival melanomas). Four patients had incomplete tumour excision, of whom 3 underwent postoperative orbital radiotherapy with no subsequent orbital recurrences. Complete epithelialization of the socket occurred in mean 7.9 weeks (range 2-16 weeks). Flap necrosis occurred in 1 patient after postoperative radiotherapy (with sino-nasal fistula formation); 2 other patients developed sino-orbital fistulas., Conclusion: After orbital exenteration, spontaneous epithelialization of the socket may take up to several months. Use of a temporalis muscle flap can reduce the duration of socket healing postoperatively, even if left to heal by secondary intention. This may facilitate early postoperative radiotherapy when indicated. Aesthetic results are acceptable and local surgical complications are rare., (Copyright © 2021 Canadian Ophthalmological Society. All rights reserved.)

Introduction: The treatment of conjunctival melanoma is most often conservative, but exenteration is sometimes necessary in order to achieve local control of the disease. It can be performed as a primary procedure in cases of locally advanced disease or as a secondary procedure after one or more recurrences. No benefit to secondary exenteration on patient survival has been demonstrated to date for conjunctival melanoma, and it is generally considered a palliative procedure., Patients and Methods: Single-center retrospective study performed in the ocular oncology department of the Institut Curie (Paris, France). We included all patients who underwent secondary orbital exenteration for conjunctival melanoma between January 2008 and January 2016., Results: Twenty-five patients underwent secondary exenteration for conjunctival melanoma. The maximum number of local recurrences prior to exenteration was six. Metastases occurred in 11 patients after exenteration and were more common when there was a greater tumor thickness on histology, if the tumor had not been treated initially in an ocular oncology center, or if there had been a greater number of local recurrences before the secondary exenteration was performed. Seventy-five percent of patients developed metastases when the exenteration was performed after 5 or 6 local recurrences., Conclusion: This study suggests that early secondary exenteration (i.e. after a number of local recurrences less than or equal to 4) may reduce the occurrence of metastases (and therefore improve patient survival) in conjunctival melanoma. Thus, secondary exenteration might be a curative surgery in some patients with recurrent disease., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Purpose: To determine the size at which choroidal melanomas can metastasize and to report the characteristics of small fatal choroidal melanomas (SFCM)., Design: Retrospective case series., Methods: Ten ocular oncology services submitted 45 patients with a choroidal melanoma 3 mm or less in thickness and 9 mm or less in largest basal diameter (LBD), when treated, who developed metastases., Results: Median tumor thickness was 2.4 mm (range, 1.0-3.0 mm) and LBD 7.3 mm (range, 3.0-9.0 mm). Of 14 (31%) tumors that were first observed, 12 grew a median of 0.5 mm (range, 0.1-1.2 mm) in thickness and 1.0 mm (range, 0-3.0 mm) in LBD within a median of 7 months; 3 were initially smaller than 3 mm in LBD. Number of risk factors for growth and metastasis was 0 for 4% of the tumors; 60% were over 2 mm in thickness, 63% had subretinal fluid, 84% caused symptoms, 57% had orange pigment, and 92% were within 3 mm of the disc. Local recurrence occurred in 8 of 31 eyes (26%) treated conservatively. Median metastasis-free survival was 4.5 years (range, 0.8-15.7 years). Kaplan-Meier estimate of metastasis developing was 15% (95% confidence interval [CI], 7-26), 51% (95% CI, 36-64) and 85% (95% CI, 71-92) by 2, 5, and 10 years, respectively. By the time of analysis, 37 patients had died of metastasis after a median of 7 months., Conclusions: Choroidal melanomas less than 3.0 mm in LBD are highly unlikely to metastasize. Risk factors of an SFCM are similar to those for all choroidal melanomas of similar size., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Up to 50% of uveal melanomas (UM) metastasise to the liver within 10 years of diagnosis, and these almost always prove rapidly fatal. As histopathological growth patterns (HGPs) of liver metastases of the replacement and desmoplastic type, particularly from colon and breast carcinoma, may import valuable biological and prognostic information, we have studied HGP in a series of 41 UM liver metastases originating from 41 patients from the period 2006-2017. Twenty patients underwent enucleation while 21 had radiation therapy. Analysis of UM by array comparative genomic hybridisation revealed: 25 (64%) patients with high risk (monosomy3/8q gain); 13 (33%) intermediate risk (M3/8normal or disomy3/8q gain); and 1 low risk (disomy3/8normal). The principal HGP was replacement in 30 (73%) cases and desmoplastic in 11 (27%) cases. Cases with replacement demonstrated striking vascular co-option/angiotropism. With the development of liver metastasis, only the replacement pattern, largest primary tumour diameter, and R2 (incomplete resection) status predicted diminished overall survival (OS; p < 0.041, p < 0.017, p < 0.047, respectively). On multivariate analysis, only HGP (hazard ratio; HR = 6.51, p = 0.008) and resection status remained significant. The genomic high-risk variable had no prognostic value at this stage of liver metastasis. Chi-square test showed no association of HGP with monosomy 3 or 8q gain. Eighteen of 41 (44%) patients are alive with disease and 23 (56%) patients died with follow-up ranging from 12 to 318 months (mean: 70 months, median: 47 months). In conclusion, we report for the first time the frequency of the replacement and desmoplastic HGPs in liver UM metastases resected from living patients, and their potential important prognostic value for UM patients, as in other solid cancers. These results may potentially be utilised to develop radiological correlates and therapeutic targets for following and treating patients with UM metastases., (© 2018 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.)

Uveal melanomas are the most frequent primary malignant eye tumor. Enucleation was historically the gold standard. Since then, several studies showed that conservative treatments did not increase the risk of metastasis or survival. Choroidal melanomas are both radioresistant and located close to visual structures (the optic nerve and macula) of the eye, which may be preserved in some settings without compromising tumor control, as this is the first priority. Different types of radiation therapy may be used for such tumors: brachytherapy and charged particles, including proton beam therapy. If visual prognosis is dependent to the local treatment, the vital prognosis is dependent on the metastatic risk, with a risk of liver involvement in 20 to 50% of patients, depending on tumor size and genomics. Median survival after the discovery of liver metastases is about 15 months. The management of these patients is often complex. Systemic therapies (chemotherapy, targeted therapies, immunotherapy, etc.) yield limited response rates and although local treatments of liver metastases are promising, they are only feasible in selected patients. The mission of the MELACHONAT national network is to improve the management of patients regardless of the stage of the disease. The patient association ANPACO is dedicated to help uveal melanoma patients in their health care path and to promote knowledge dissemination within the patient community. The aim of this review is to focus on the local treatments of uveal melanomas as well as the management of their metastatic evolution., (Copyright © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Background: To evaluate the efficacy of bevacizumab on reduction of the enucleation rate and control of intraocular pressure (IOP) in neovascular glaucoma (NVG)-complicating proton beam therapy for UM and to identify the determinants of the efficacy of bevacizumab., Methods: Retrospective comparative study of patients with rubeosis following proton therapy for uveal melanoma. Patients were divided into two groups: a bevacizumab group and a control group which comprised two subgroups: panretinal photocoagulation (PRP)/cryotherapy and observation subgroups. Bevacizumab was administered by three intravitreal injections at 1-month intervals. A second series of injections was administered when necessary. Data concerning IOP and the secondary enucleation rate were collected and compared between the two groups. Univariate and multivariate analyses were performed to determine predictive factors of response to bevacizumab., Results: A total of 169 patients who developed rubeosis following proton therapy between 2006 and 2016 were included: 44 patients in the bevacizumab group and 125 in the control group (38 in the PRP/cryotherapy subgroup and 87 in the observation subgroup). The two groups presented the same baseline characteristics apart from hypertension, retro-equatorial site, and proximity of the optic disk, which were more frequent in the control group, while initial retinal detachment and larger tumor volume were more frequent in the bevacizumab group. After a mean follow-up of 31 months, IOP was less than 21 mmHg in 54.54% of patients after IVB versus 72.7% before treatment (p = 0.06). Statistical analysis did not reveal any statistically significant reduction of the enucleation rate in the bevacizumab group compared to the observational group, whereas the PRP/cryotherapy group showed better eye retention rate (p = 0.15). No enucleation was performed when IOP was < 21 mmHg before IVB. Multivariate analysis identified initial IOP < 21 mmHg and UM situated away from the macula as predictive factors of good response to bevacizumab., Conclusion: Despite the improvement of IOP level, intravitreal bevacizumab (IVB) did not reduce the overall enucleation rate in NVG following proton beam therapy. Nevertheless, this treatment was effective in the early phases of NVG or as preventive treatment. PRP remains a valid treatment for NVG.

Purpose: To describe the macular features of patients treated with proton beam therapy for choroidal melanoma (CM), using optical coherence tomography angiography (OCTA)., Design: Retrospective case-control study., Methods: This study included patients treated with proton beam radiotherapy (PBR) for a small CM. Only patients who had received 100% of the dose of 60 Gy external beam radiation to the macular area were included in the analysis. All the patients had undergone a full ophthalmologic examination, including visual acuity, optical coherence tomography B-scan, and OCTA. Qualitative and quantitative vascular features of the retinal plexus and the choriocapillaris were analyzed on OCTA and compared with those in healthy subjects matched on age and sex., Results: Thirty-seven patients had undergone an OCTA after PBR for a small CM. Seventeen patients (9 men and 8 women) were included. The mean age of the patients was 56.6 years (range, 28-86). At presentation, the mean tumor thickness was 3.39 mm (range, 1.3-7.0 mm). The mean follow-up duration was 35.8 months (range, 11-72 months). Thirteen patients (76.5%) had a clinical radiation maculopathy; 8 patients (47.1%) had macular cysts on OCT-B scan. All patients (100%) had abnormalities on OCTA. Some "signal void" spots were detected at the level of the choriocapillaris in 15 patients (88.2%). The mean vascular density (regarding the full retina) was significantly lower in the patients treated with PBR than in healthy subjects (P < .0001)., Conclusion: Patients treated with PBR for CM (with 100% of the dose given to the macula) present major changes at both plexuses but also a vascular rarefaction of the choriocapillaris., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Choroidal melanoma is a rare tumour in adults. The mean age at diagnosis is 60, but the tumour can affect women of childbearing age. A negative effect of pregnancy on patients' survival has not been formally excluded to date. The aim of the present study is to evaluate the effect of pregnancy on the prognosis of choroidal melanoma., Methods: We conducted a single-centre retrospective study at the Institut Curie on the population of women of childbearing age who were diagnosed with choroidal melanoma between June 1980 and October 2013. We took a particular interest in the prognosis of those who were pregnant at the time of diagnosis and in the prognosis of those who chose to get pregnant after the treatment., Results: We found 27 pregnant patients at the time of diagnosis and 13 patients who became pregnant after the treatment. There was no difference in the survival between these two groups of patients and the group of other women of childbearing age diagnosed with choroidal melanoma (p = 0.52). There was also no difference in metastasis-free survival (p = 0.91). Most women were able to carry their pregnancies to term (67% had a term pregnancy, and only 7% had an abortion). For women who were pregnant when they were diagnosed with choroidal melanoma, a conservative treatment was chosen in 85% of cases, and proton beam therapy was the most widely used treatment., Conclusions: Survival in women of childbearing age does not appear to be influenced by pregnancy. We show that proton beam therapy can be used to treat women who are pregnant at the time of choroidal melanoma diagnosis., (© 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

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.)

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., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Choroidal melanoma is the most common form of eye cancer in adults. Treatments enabling the tumour to be destroyed or removed while preserving the eye socket are mainly based on surgery, proton therapy and brachytherapy., (Copyright © 2015. Publié par Elsevier Masson SAS.)

Purpose: To report the technical aspects, complications, and outcomes concerning fine needle aspiration biopsy (FNAB) in uveal melanoma., Design: Retrospective cohort study., Methods: Patients with uveal melanoma who underwent transscleral or transvitreal FNAB at an ocular oncology center were retrospectively evaluated. FNAB was performed if the tumor was more than 5 mm in thickness. Array comparative genomic hybridization analysis was performed on biopsy samples with sufficient tissue. The main outcome measures were success (sample that gave a successful result for biomarker analysis) rate, complications, liver metastasis, and overall survival., Results: There were 217 (114 male, 52%) consecutive study patients with a mean age of 56.7 (16-84) years. The mean follow-up period was 31 (range 3.6-61.3) months. Mean tumor thickness was 8.4 (range 5-12) mm. The overall success rate of the procedure was 169 patients (77.9%). Thirty-one patients (14.3%) experienced intravitreal hemorrhage, of whom 9 (4.1%) required vitreal surgery. There was no case of endophthalmitis, orbital dissemination, local recurrence, or rhegmatogenous retinal detachment. Thirty-two patients (14.7%) developed metastasis during the study, of whom 20 (9.2%) died. Of the 169 successful samples, 53 patients (31%) were classified as low risk, 41 (24%) as intermediate risk, and 54 (32%) as high risk. Fifteen patients (9%) did not have any detectable chromosomal abnormality and 6 (4%) could not be classified., Conclusion: FNAB is a relatively safe and successful technique that can be routinely used to obtain tissue for molecular genomic analysis; such analysis helps determine the diagnosis and prognosis in uveal melanoma., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Little information is currently available concerning loco-regional metastases such as satellite and in transit metastases and their natural history in conjunctival melanoma as compared to cutaneous melanoma. Angiotropism, a marker of extravascular migration of melanoma cells along vascular channels, often appears responsible for microscopic satellite, satellite and in transit metastases development in cutaneous melanoma. In addition, diffuse tissue microscopic satellites are correlated with widespread melanoma dissemination and death. Herein we report rapid conjunctival melanoma progression and a fatal outcome in four of five patients following recurrence as satellite in transit metastases. Five patients aged 31, 60, 63, 56, and 67 years developed primary conjunctival melanoma, histologically characterised by tumour thicknesses of 4, 4, 1.1, 3, and 2 mm. Two or more conjunctival melanomas manifested ulceration, significant mitotic rates, necrosis, angiotropism, and intralesional transformation. The conjunctival melanoma recurred in a matter of months as one or more discrete satellite in transit lesions in the vicinity of the primary melanoma. Histological examination revealed well-defined micronodules containing atypical melanocytes in the subepithelial connective tissue stroma. All lesions were extravascular and most appeared angiotropic. Four of five patients subsequently developed parotid or other loco-regional nodal disease and rapidly ensuing widespread metastases and death. The time course from diagnosis to the demise of the patients averaged about 13 (range 7-20) months. Our findings suggest that satellite in transit metastases constitute an important new risk marker for possible rapid metastatic disease progression and death in patients with conjunctival melanoma. This finding appears to take on even greater significance if such lesions develop rapidly, i.e., in a matter of weeks or months following diagnosis of primary conjunctival melanoma, and if the primary melanoma manifests additional high-risk features. Additional studies are underway in order to further elucidate the mechanism of these metastases., (Copyright © 2016. Published by Elsevier B.V.)

The past few years have witnessed major advances in the understanding of the molecular landscape of uveal melanoma (UM). The discovery of a mutational background that is completely different from the one of skin melanoma has granted to UM a stand-alone status. The absence of effective therapy for metastatic disease offers now a chessboard for targeted therapy but at the same time urges preclinical science to develop accordingly, to guide the use of economical resources to the best profit of patients. This review describes the current knowledge on the biology of this disease and discusses the challenges that must be undertaken to translate this knowledge into real benefit for patients.

Despite advances in the local treatment of UM, half of patients develop metastases typically to the liver with poor survival. Microscopic complete surgical resection (R0) of liver metastases improves survival in high selected patients. Early identification of high-risk patients might allow detection of asymptomatic metastases, and increase R0 liver surgery rate. From October 2006 to December 2009, we conducted a prospective study to detect early minimal lesions with 6-monthly liver function tests (LFTs) and liver MRI in 100 high-risk patients. High risk was defined by primary tumor clinical or genomic criteria: thickness>8mm or diameter>15 mm, or extra-scleral extension, or monosomy 3 by FISH or aCGH. With a median follow-up of 49 months, the 5-year metastasis-free survival and overall survival were 47 and 33%, respectively. Of the 60 patients who became metastatic, 50 (83%) had exclusive liver metastasis. LFTs screening had no sufficient accurary, but biannual MRI showed high predictive value to detect metastasis and select patients eligible for curative surgery: 25/50 underwent laparotomy and among them, 8/25 (32%) had a R0 surgery. Median survival after metastasis was 14 months, mean survival reached 40 months in the R0 resected population. Six-monthly liver MRI screening is recommended in patients with large tumors or genomic high risk in order to detect early patient candidates to complete resection of liver metastases., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Cutaneous melanoma is a multifactorial disease resulting from both environmental and genetic factors. Five susceptibility genes have been identified over the past years, comprising high-risk susceptibility genes (CDKN2A, CDK4, and BAP1 genes) and intermediate-risk susceptibility genes (MITF, and MC1R genes). The aim of this expert consensus was to define clinical contexts justifying genetic analyses, to describe the conduct of these analyses, and to propose surveillance recommendations. Given the regulatory constraints, it is recommended that dermatologists work in tandem with a geneticist. Genetic analysis may be prescribed when at least two episodes of histologically proven invasive cutaneous melanoma have been diagnosed before the age of 75 years in two 1st or 2nd degree relatives or in the same individual. The occurrence in the same individual or in a relative of invasive cutaneous melanoma with ocular melanoma, pancreatic cancer, renal cancer, mesothelioma or a central nervous system tumour are also indications for genetic testing. Management is based upon properly managed photoprotection and dermatological monitoring according to genetic status. Finally, depending on the mutated gene and the familial history, associated tumour risks require specific management (e.g. ocular melanoma, pancreatic cancer). Due to the rapid progress in genetics, these recommendations will need to be updated regularly., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Uveal melanoma (UM) is the most common primary tumor of the eye in adults. There is no standard adjuvant treatment to prevent metastasis and no effective therapy in the metastatic setting. We have established a unique panel of 7 UM cell lines from either patient's tumors or patient-derived tumor xenografts (PDXs). This panel recapitulates the molecular landscape of the disease in terms of genetic alterations and mutations. All the cell lines display GNAQ or GNA11 activating mutations, and importantly four of them display BAP1 (BRCA1 associated protein-1) deficiency, a hallmark of aggressive disease. The mTOR pathway was shown to be activated in most of the cell lines independent of AKT signaling. mTOR inhibitor Everolimus reduced the viability of UM cell lines and significantly delayed tumor growth in 4 PDXs. Our data suggest that mTOR inhibition with Everolimus, possibly in combination with other agents, may be considered as a therapeutic option for the management of uveal melanoma., (Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Objective: This study investigated the capacity of genetic analysis of uveal melanoma samples to identify high-risk patients and discusses its clinical implications., Methods: Patients with posterior uveal melanoma were prospectively enrolled. Tumour samples were derived from enucleated globe, fine-needle aspirates or endoresection. Chromosome 3 and 8 status was determined by array comparative genomic hybridisation (array-CGH). Patients were followed after treatment to detect metastasis., Results: Four groups were classified by array-CGH. Patients were divided into disomy 3 and normal chromosome 8 (D3/8nl), disomy 3 and 8q gain (D3/8g), monosomy 3 and normal chromosome 8 (M3/8nl) and monosomy 3 and 8 or 8q gain (M3/8g). Median follow-up was 28 months (range: 1-147 months). At the end of the study, 128 patients (33.7%) had developed metastasis and 96 patients had died. Univariate Cox proportional hazard analysis showed that factors associated with metastasis included basal tumour diameter p=0.0007, tumour thickness p=0.01, mixed/epithelioid cell type p=0.0009 and genomic data p<0.0001. High-risk profile was more strongly associated with metastasis than the other prognostic factors p<0.001. Multivariate Cox modelling analysis showed that the status of chromosomes 3 and 8 were the only two variables that independently contributed to prognosis: monosomy 3 alone p=0.001 and monosomy 3 and 8q gain p<0.0001., Conclusions: Array-CGH allowed identification of three prognostic groups with low, intermediate and high risk of developing metastasis. Array-CGH is a reliable and inexpensive method for uveal melanoma prognosis. This method is now currently used in France., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) have been recently investigated in several cancer types, but their respective clinical significance remains to be determined. In our prospective study, we compared the detection rate and the prognostic value of these two circulating biomarkers in patients with metastatic uveal melanoma. GNAQ/GNA11 mutations were characterized in archived tumor tissue. Using a highly sensitive and mutation-specific bidirectional pyrophosphorolysis-activated polymerization (bi-PAP) technique, GNAQ c.626A>T, GNAQ c.626A>C and GNA11 c.626A>T copy numbers were quantified in plasma from 12 mL of blood. CTCs were detected at the same time in 7.5 mL of blood by the CellSearch technique. Patient characteristics and outcome were prospectively collected. CTCs (≥1) were detected in 12 of the 40 included patients (30%, range 1-20). Among the 26 patients with known detectable mutations, ctDNA was detected and quantified in 22 (84%, range 4-11,421 copies/mL). CTC count and ctDNA levels were associated with the presence of miliary hepatic metastasis (p = 0.004 and 0.03, respectively), with metastasis volume (p = 0.005 and 0.004) and with each other (p < 0.0001). CTC count and ctDNA levels were both strongly associated with progression-free survival (p = 0.003 and 0.001) and overall survival (p = 0.0009 and <0.0001). In multivariate analyses, ctDNA appeared to be a better prognostic marker than CTC. In conclusion, ctDNA and CTC are correlated and both have poor prognostic significance. CTC detection can be performed in every patient but, in patients with detectable mutations, ctDNA was more frequently detected than CTC and has possibly more prognostic value., (© 2013 UICC.)

Purpose: Uveal melanoma (UM) is associated with a high risk of metastases and lack of efficient therapies. Reduced capacity for apoptosis induction by chemotherapies is one obstacle to efficient treatments. Human UM is characterized by high expression of the anti-apoptotic protein Bcl-2. Consequently, regulators of apoptosis such as Bcl-2 family inhibitors may constitute an attractive approach to UM therapeutics. In this aim, we have investigated the efficacy of the Bcl-2/Bcl-XL inhibitor S44563 on 4 UM Patient-Derived Xenografts (PDXs) and derived-cell lines., Experimental Design: Four well characterized UM PDXs were used for in vivo experiments. S44563 was administered alone or combined with fotemustine either concomitantly or after the alkylating agent. Bcl-2, Bcl-XL, and Mcl-1 expressions after S44563 administration were evaluated by immunohistochemistry (IHC)., Results: S44563 administered alone by at 50 and 100 mg/kg i.p. induced a significant tumour growth inhibition in only one xenograft model with a clear dose effect. However, when S44563 was concomitantly administered with fotemustine, we observed a synergistic activity in 3 out of the 4 tested models. In addition, S44563 administered after fotemustine induced a tumour growth delay in 2 out of 3 tested xenografts. Finally, IHC analyses showed that Bcl-2, Bcl-XL, and Mcl-1 expression were not modified after S44563 administration., Conclusion: The novel anti-apoptotic experimental compound S44563, despite a relative low efficacy when administered alone, increased the efficacy of fotemustine in either concomitant or sequential combinations or indeed subsequent to fotemustine. These data support further exploration of potential therapeutic effect of Bcl-2/Bcl-xl inhibition in human UM.

Unlabelled: Uveal melanoma, the most common eye malignancy, causes severe visual morbidity and is fatal in approximately 50% of patients. Primary uveal melanoma can be cured by surgery or radiotherapy, but the metastatic disease is treatment refractory. To understand comprehensively uveal melanoma genetics, we conducted single-nucleotide polymorphism arrays and whole-genome sequencing on 12 primary uveal melanomas. We observed only approximately 2,000 predicted somatic single-nucleotide variants per tumor and low levels of aneuploidy. We did not observe an ultraviolet radiation DNA damage signature, but identified SF3B1 mutations in three samples and a further 15 mutations in an extension cohort of 105 samples. SF3B1 mutations were associated with good prognosis and were rarely coincident with BAP1 mutations. SF3B1 encodes a component of the spliceosome, and RNA sequencing revealed that SF3B1 mutations were associated with differential alternative splicing of protein coding genes, including ABCC5 and UQCC, and of the long noncoding RNA CRNDE., Significance: Our data show that despite its dismal prognosis, uveal melanoma is a relatively simple genetic disease characterized by recurrent chromosomal losses and gains and a low mutational burden. We show that SF3B1 is recurrently mutated in uveal melanoma, and the mutations are associated with aberrant alternative splicing.

Purpose: To refine the anatomic classification and staging of ciliary body and choroidal melanomas in the TNM classification., Patients and Methods: Tumor largest basal diameter and thickness of 7,369 patients were analyzed based on registry data from five ocular oncology centers. T categories were derived empirically by dividing data into blocks representing 3- × 3-mm fractions. Blocks with similar survival were grouped together so that no T category comprised a large majority of tumors, and each was uniform in survival, using randomly drawn 60% building and 40% validation data sets. Presence of ciliary body involvement (CBI) and extraocular extension (EXE) was analyzed among 5,403 patients to define T subcategories. Stages were generated by iteratively combining subcategories with similar survival., Results: Of the 7,369 tumors analyzed, 24% were classified as T1, 33% as T2, 31% as T3, and 12% as T4. Ten-year Kaplan-Meier survival estimates for the T categories were 89%, 77%, 58%, and 39%, respectively (P < .001). Survival of patients in four subcategories based on presence or absence of CBI and EXE differed significantly within each T category (P = .018 for T1; P < .001 for T2 to T4). EXE exceeding 5 mm in largest diameter carried a worse prognosis than smaller extensions (P < .001) and was assigned a separate subcategory. Ten-year Kaplan-Meier survival estimates for stages I, IIA to IIB, and IIIA to IIIC were 88%, 80%, 67%, 45%, 27%, 10%, respectively (P < .001)., Conclusion: This evidence-based anatomic classification provides a basis for staging ciliary body and choroidal melanomas in the seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer.

Purpose: To evaluate the efficacy of endoresection after proton beam radiotherapy to prevent neovascular glaucoma (NVG) in patients treated for choroidal melanoma., Methods: From a series of 4,867 patients treated for choroidal melanoma were prospectively recorded in the database (Macro Infermed 3.075). One hundred and seventy-one patients presenting a tumor diameter >10 mm and thickness >5 mm treated with proton beam (PB) radiotherapy were selected. One group of 63 patients was treated with PB therapy followed by endoresection (PE) of the scar. This group was compared with 2 historical matched controlled groups: 57 patients treated with PB therapy alone (P) and 51 patients treated with PB therapy followed by transpupillary thermotherapy of the scar (PTTT). Main outcome measures are as follows: age, gender, tumor diameter, tumor thickness, pre- and posttreatment visual acuity, NVG rate, secondary enucleation rate, and 5-year survival. Statistical analysis was performed using R version 2.5.1 software., Results: Correlations between the 3 groups were P = 0.29 for age, P = 4.7×10 for tumor diameter, and P = 6.44×10 for tumor thickness. Comparison between the 3 groups showed that 2-year survival without secondary enucleation was 96.2% for PE, 88.8% for P, and 98% for PTTT (P = 0.203) (95% confidence interval). Two-year survival without NVG (95% confidence interval) was 92.7% (85.1-1.00) for PE, 54.6% for P, and 62.1% for PTTT (P = 0.0001). The difference between the endoresection (PE) group and the PB radiotherapy (P) and PB radiotherapy + TTT (PTTT) groups in terms of reduction of the NVG rate was statistically significant. Relative risk of developing NVG was calculated with the P group as reference, relative risk = 1. The relative risk of the PTTT group was 0.79 (20% reduction of the risk), and the relative risk of the PE group was 0.18 (82% reduction of the risk of developing NVG)., Conclusion: This study shows that endoresection of the necrotic scar after PB radiotherapy reduces the risk of NVG and secondary enucleation for selected choroidal melanoma patients.

We have previously developed a new method for the development and maintenance of uveal melanoma (UM) xenografts in immunodeficient mice. Here, we compare the genetic profiles of the primary tumors to their corresponding xenografts that have been passaged over time. The study included sixteen primary UMs and corresponding xenografts at very early (P1), early (P4), and late (P9) in vivo passages. The tumors were analyzed for mutation status of GNAQ, GNA11, GNAS, GNA15, BAP1, and BRAF, chromosomal copy number alterations using Affymetrix GeneChip(®) Genome-Wide Human SNP6.0 arrays, gene expression profiles using GeneChip(®) Human Exon 1.0 ST arrays, BAP1 mRNA and protein expression, and MAPK pathway status using Reverse Phase Protein Arrays (RPPA). The UM xenografts accurately recapitulated the genetic features of primary human UMs and they exhibited genetic stability over the course of their in vivo maintenance. Our technique for establishing and maintaining primary UMs as xenograft tumors in immunodeficient mice exhibit a high degree of genetic conservation between the primary tumors and the xenograft tumors over multiple passages in vivo. These models therefore constitute valuable preclinical tool for drug screening in UM., (Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Purpose: To determine the incidence and to discuss pathogenic mechanisms of sympathetic ophthalmia in patients treated for choroïdal melanoma., Design: Retrospective., Methods: We analyzed the clinical and pathological data of 4867 patients, treated for choroïdal melanoma at Institute Curie-Orsay, between 1998 and 2011. Were involved patients with uveitis of the adelphe eye filling clinical and angiographic criteria of sympathetic ophthalmia. Extensive work-up was undertaken to rule out another etiology of the inflammation., Results: Three patients developed sympathetic ophthalmia respectively 7, 4 and 3 years after protontherapy.The incidence of this complication was 6.1 per 10000 patients treated by proton beam radiation. Ocular perforating injury was ruled out and radioactive effect of treatment was incriminated in the occurrence of sympathetic ophthalmia., Conclusion: Sympathetic ophthalmia remains a rare complication which must be treated promptly and aggressively to prevent blindness.Proton beam irradiation could induce disruption of uveal tissue which enhances auto immune reactions.

Purpose: To develop a molecular tool to detect circulating tumor-derived DNA (ctDNA) in the plasma from patients with uveal melanoma as a marker of tumor burden and monitor treatment efficacy., Experimental Design: A real-time PCR was developed on the basis of bidirectional pyrophosphorolysis-activated polymerization (bi-PAP) for the quantification of ctDNA using 3'blocked primer pairs specific for the 3 recurrent mutually exclusive mutations of Gα subunits GNAQ and GNA11., Results: Sensitivity and specificity of bi-PAP were assessed on serial dilutions of tumor DNA in normal DNA for the 3 recurrent mutations. Each assay could detect a single mutated molecule per reaction, whereas 10(4) copies of normal DNA were not detected. The ctDNA was readily detected in plasma of mice bearing uveal melanoma xenografts in amounts proportional to circulating human DNA. Finally, plasma was almost always found positive (20 of 21 tested patients) in a prospective analysis of patients with metastatic uveal melanoma., Conclusions: Bi-PAP assays detect and quantify ctDNA in patients with metastatic uveal melanoma. A prospective study is ongoing to assess the clinical usefulness of ctDNA level in uveal melanoma.

Proton beam irradiation of uveal melanoma has great advantages compared to brachytherapy because of the homogenous dose delivered to the tumor and the possibility of sparing normal tissue close to the tumor. We describe the technique of proton beam therapy including the surgical technique of clip positioning, the radiotherapy delivery technique and the dose administered (60 Gy cobalt relative biological effectiveness in 4 fractions). Indications of proton beam are given and the follow-up procedure is described. An inactive residual tumor scar is observed after 2-3 years. Results are given comparing the most recent series of patients treated at the Institut Curie-Orsay proton therapy center with the data published in the literature. The metastasis rate at 10 years varies between 25 and 30%. Local control is excellent. The local recurrence rate at 10 years is usually around 5%. Secondary enucleation is performed in 10-15% of patients either due to complications or local recurrence. Complications such as retinal detachment, maculopathy, papillopathy, cataract, glaucoma, vitreous hemorrhage and dryness are described. The severest complication that usually leads to secondary enucleation is neovascular glaucoma and it is encountered after irradiation of large to extra-large tumors. The toxic tumor syndrome has recently been described. It is hypothesized that the residual tumor scar may produce proinflammatory cytokines and VEGF leading to intraocular inflammation and neovascular glaucoma. Additional treatments after proton beam such as transpupillary thermotherapy, endoresection of the tumor scar or intravitreal injections of anti-VEGF may reduce the rate of these complications., (Copyright © 2012 S. Karger AG, Basel.)

Unlabelled: Treatments for choroidal melanoma (CM) generate largely unknown consequences on the level of the quality of life (QoL) and psychological state. Prospective published work is relatively rare and their results are not consistent. The objective of this study is to describe the QoL and psychological state's evolution in patients treated by conservative treatment for CM., Population: Sixty-nine patients treated for CM by conservative treatment (proton beam irradiation or iodine plaques). QoL (EORTC-QLQ-C30 + QLQ-OPT-30), anxiety and depression (HADS, STAI-B-trait)., Data Collection: Prospective study comprising four evaluations T0: before the beginning of the treatment, T1: one month, T2: six month, T3: one year after the treatment. The preliminary results of the first two evaluations showed that the level of the QoL remained relatively good and stable with an exception for the social functioning, which decreased after the treatment. More than half of the patients had a moderated rate of anxiety before the beginning of the treatment, which decreased significantly a month later. The depressive symptoms were lower and remained stable one month after the treatment. These results confirmed the importance of exploration and screening the fear of cancer recurrence among choroidal melanoma patients.

Uveal melanoma arises from melanocytes of the uveal tract (iris, ciliary body and choroid) and represents the most common intraocular malignancy in adults. Some rare clinical situations (young age at diagnosis, bilateral or multifocal forms, association with cutaneous malignant melanoma and/or familial aggregations of melanomas) are suggestive of genetic susceptibility. The aim of this study was to evaluate the contribution of CDKN2A/P16INK4A, P14ARF and CDK4 gene germline mutations in a series of patients with uveal melanoma recruited in a single institution with a clinical presentation indicative of genetic predisposition. Molecular analyses were proposed to 36 patients and were performed in 25 cases. The contribution of BRCA1/2 gene germline mutations in patients with uveal melanoma and a personal and/or family history of breast/ovarian cancers was also evaluated. Molecular analysis of BRCA1/2 genes was proposed to 35 patients and was performed in 25 patients. No deleterious germline mutation was identified in either group of patients. These results indicate that the CDKN2A/P16INK4A, P14ARF, CDK4 genes are not responsible for the vast majority of genetic susceptibility to uveal melanoma. They also suggest that one case of uveal melanoma in a family with a history of breast cancer is not sufficient to justify BRCA1/2 genetic testing when the classical criteria for molecular analysis are not present. International studies are ongoing in melanoma-prone families in an attempt to identify uveal melanoma susceptibility loci and genes.

BACKGROUND Extraocular spread is thought to be a negative prognostic factor on the survival in patients with uveal melanoma. Enucleation was the standard treatment in these patients. Today, depending on the size of the tumour and the type of extraocular extension, eye-preserving irradiation treatments, such as proton beams or radioactive plaques, may be employed. METHODS 2256 patients were treated between 2000 and 2007 at the Institut Curie, Paris, France for a uveal melanoma. 67 patients (3.0%) presented an extraocular extension. A retrospective study was performed to evaluate the patients' outcomes with regard to tumour recurrence and survival. RESULTS Eye-conserving treatment was employed in 38 (52.8%) patients. Enucleation was performed in 29 (47.2%) patients. The median follow-up was 38 (range 7 to 79) months with an overall survival rate at 5 years of 40.4% in enucleated patients and 79.3% in the eye-conserving treatment group (protons n=19, iodine-125 plaque n=19) (p=0.01; Kaplan-Meier analysis). No tumour recurrence was observed in any group. The degree of extraocular spread as well as the clinical characteristics tumour location, retinal detachment, ciliary body involvement (p<0.01; chi(2) test) and tumour thickness (p=0.04; chi(2) test) influenced the choice of treatment. Age, tumour diameter, involvement of optic nerve, vitreous haemorrhage and the amount of pigment did not have any influence. CONCLUSIONS Tumour recurrence rates and survival rates were not adversely affected in patients receiving conservative eye treatment. This may thus represent a therapeutic option in certain patients with extraocular spread.

Purpose: Uveal melanoma is the most common primary intraocular malignant tumor in adults and is defined by a poor natural outcome, as 50% of patients die from metastases. The aim of this study was to develop and characterize a panel of human uveal melanoma xenografts transplanted into immunodeficient mice., Experimental Design: Ninety tumor specimens were grafted into severe combined immunodeficient mice, and 25 transplantable xenografts were then established (28%). Relationship between tumor graft and clinical, biological, and therapeutic features of the patients included were investigated. Characterization of 16 xenografts included histology, molecular analyses by immunohistochemistry, genetic alteration analysis (single-nucleotide polymorphism), and specific tumor antigen expression by quantitative reverse transcription-PCR. Pharmacologic characterization (chemosensitivity) was also done in four models using two drugs, temozolomide and fotemustine, currently used in the clinical management of uveal melanoma., Results: Take rate of human uveal melanoma was 28% (25 of 90). Tumor take was independent of size, histologic parameters, or chromosome 3 monosomy but was significantly higher in metastatic tumors. Interestingly, in vivo tumor growth was prognostic for a lower metastasis-free survival in patients with primary tumors. A high concordance between the patients' tumors and their corresponding xenografts was found for all parameters tested (histology, genetic profile, and tumor antigen expression). Finally, the four xenografts studied displayed different response profiles to chemotherapeutic agents., Conclusions: Based on these results, this panel of 16 uveal melanoma xenografts represents a useful preclinical tool for both pharmacologic and biological assessments.

Background: Microscopically complete (R0) resection of metastases from uveal melanoma prolongs median overall survival compared to incomplete surgery. The aim of this study was to compare the sensitivity of dynamic-enhanced magnetic resonance imaging (MRI) with fluorodeoxyglucose-positron emission tomography (FDG-PET) in the preoperative diagnosis of liver metastases from uveal melanoma., Patients and Methods: Fifteen consecutive patients (mean age: 56 years) underwent FDG-PET and liver MRI. Extrahepatic metastatic disease was excluded by whole body computed tomography and bone scintigraphy. MRI and FDG-PET were performed with a mean of 19 days (range: 1-30) before surgery. Imaging findings were compared with surgical (including intraoperative ultrasonography) and histological findings on a lesion by lesion analysis., Results: R0 resection was performed in 12 patients. A total of 28 lesions were resected with 27 histologically proven metastases. Nine lesions were smaller than 5mm, 7 measured 5-10mm and 11 were larger than 10mm. Sensitivity and positive predictive value were 67% and 95% for MRI compared to 41% and 100% for FDG-PET. The difference between the two modalities was statistically significant (p=0.01; McNemar test). In remaining 3 patients, diffuse miliary disease (>10 capsular lesions) was discovered intraoperatively, and was suspected on preoperative MRI in 2 cases. Only one extrahepatic lesion identified by FDG-PET was falsely positive., Conclusions: In this preliminary study, MRI was superior to FDG-PET for staging of liver metastases from uveal melanoma. Although miliary disease was suggested by MRI in some cases, preoperative confirmation remains imperfect., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)

Background: The RAS/RAF/MEK/ERK pathway is involved in the balance between melanocyte proliferation and differentiation. The same pathway is constitutively activated in cutaneous and uveal melanoma (UM) and related to tumour growth and survival. Whereas mutant BRAF and NRAS are responsible for the activation of the RAS/RAF/MEK/ERK pathway in most cutaneous melanoma, mutations in these genes are usually absent in UM., Methods: We set out to explore the RAS/RAF/MEK/ERK pathway and used mitogen-activated protein kinase profiling and tyrosine kinase arrays., Results: We identified Src as a kinase that is associated with ERK1/2 activation in UM. However, low Src levels and reduced ERK1/2 activation in metastatic cell lines suggest that proliferation in metastases can become independent of Src and RAS/RAF/MEK/ERK signalling. Inhibition of Src led to the growth reduction of primary UM cultures and cell lines, whereas metastatic cell line growth was only slightly reduced., Conclusion: We identified Src as an important kinase and a potential target for treatment in primary UM. Metastasis cell lines seemed largely resistant to Src inhibition and indicate that in metastases treatment, a different approach may be required.

Purpose: Incurable metastases develop in approximately 50% of patients with uveal melanoma (UM). The purpose of this study was to analyze genomic profiles in a large series of ocular tumors and liver metastases and design a genome-based classifier for metastatic risk assessment., Methods: A series of 86 UM tumors and 66 liver metastases were analyzed by using a BAC CGH (comparative genomic hybridization) microarray. A clustering was performed, and correlation with the metastatic status was sought among a subset of 71 patients with a minimum follow-up of 24 months. The status of chromosome 3 was further examined in the tumors, and metastases with disomy 3 were checked with an SNP microarray. A prognostic classifier was constructed using a log-linear model on minimal regions and leave-one-out cross-validation., Results: The clustering divides the groups of tumors with disomy 3 and monosomy 3 into two and three subgroups, respectively. Same subgroups are found in primary tumors and in metastases, but with different frequencies. Isolated monosomy 3 was present in 0% of metastatic ocular tumors and in 3% of metastases. The highest metastatic rate in ocular tumors was observed in a subgroup defined by the gain of 8q with a proximal breakpoint, and losses of 3, 8p, and 16q, also most represented in metastases. A prognostic classifier that included the status of these markers led to an 85.9% classification accuracy., Conclusions: The analysis of the status of these specific chromosome regions by genome profiling on SNP microarrays should be a reliable tool for identifying high-risk patients in future adjuvant therapy protocols.

Aims: To describe the evolution and management over time of scleral necrosis as a complication after radiation therapy for uveal melanomas., Design: Retrospective nonrandomized case series., Methods: Twenty-three patients (12 male, 11 female; median age 56.4 years; range, 30-73 years) treated with a single plaque therapy (cobalt-60 (Co(60)) or iodine-125 (I(125)) (1.5% of treated patients) or proton beam radiotherapy (0.45% of treated patients) for choroidal or ciliary body melanoma, presenting scleral necrosis as a post-radiation complication, were studied. Tumor characteristics, intraocular pressure, location and size of scleral necrosis were recorded during visits after radiation therapy., Results: The median maximal tumour base and thickness at diagnosis were 14.6 +/- 4.4 mm and 7.2 +/- 2.3 mm respectively. Median radiation dose to tumor base and tumor apex was 223 Gy and 88.3 Gy respectively. The mean time of scleral necrosis onset after radiation therapy was 70.4 months (range 11-257 months); the mean scleral necrosis diameter at its onset was 4.4 mm (range 1-10 mm). Out of 23 affected eyes, 17 presented a stability of scleral necrosis; in three cases there was partial regression of scleral necrosis; in two cases there was a progressive extension of scleral necrosis until a pre-perforation stade. In two cases, a secondary enucleation was necessary due to a severe neovascular glaucoma., Conclusions: Scleral necrosis is a rare complication of radiotherapy for uveal melanomas. Relapse with extrascleral extension of the primary tumor has to be ruled out in order to avoid unnecessary enuclations. In most patients, the scleral necrosis remains stable and does not need any further treatment.

Quantitative ultrasonic characterization yields information that is correlated to the tissue microstructure and increases the diagnostic potential of ultrasound. The measurement of acoustic properties of melanomas in vivo has not yet been reported after proton-beam irradiation. This prospective study was conducted on a cohort of 50 patients diagnosed with primary malignant melanoma to assess in vivo the ability of quantitative echography to detect changes in choroidal malignant melanomas after proton-beam irradiation and to follow the ultrasonographic changes during 24 months posttreatment. Echographic evaluations of these patients were performed at diagnosis and repeated every 6 months after treatment over a 2-y period. The acoustic parameters included in this work are derived from the calibrated tissue backscatter spectra (spectral slope, spectral intercept and apparent integrated backscatter) of a selected tumor volume after correction of the apparatus transfer function and beam diffraction. Clinical parameters resulting from conventional echography were also quantified and included mainly tumor height, tumor vascularity and internal reflectivity. Spectral intercept and apparent integrated backscatter were found to be the most useful to evaluate changes in melanomas after treatment. Significant (p < 0.05) differences of these parameter values were observed between pre- and postproton therapy. In particular, significant changes (compared with baseline) were observed for these parameters, even when the tumor size after treatment was not significantly different from baseline. The results suggest that quantitative spectrum analysis of frequency-dependent backscatter can provide information about the structural modifications of choroidal malignant melanomas as a result of proton-beam irradiation.

Aims: To describe the results in terms of local control, eye preservation and systemic evolution of iris melanomas treated by proton beam irradiation., Methods: Retrospective review of the charts of patients with iris melanoma treated by proton beam therapy between April 1998 and September 2002. Ciliary body melanomas with iris involvement or tumours with extrascleral invasion were excluded. Treatment consisted of 60 Gy of proton beam irradiation delivered in four fractions to the tumour volume., Results: A total of 21 patients were treated, median follow-up of 33 months (8-72 months). 15 patients presented a lesion with documented growth. The median clinical diameter was 5 mm (2-8 mm), the median ultrasound diameter 4.8 mm (2-7.7 mm) The patients were 6% T1, 57.1% T2, and 14.3% T3 all N0M0. The iridocorneal angle was invaded by the tumour in 71.4% of patients. At the end of follow-up, all patients were alive with no proven metastatic disease except one patient with suspicious liver lesions. None of the patients showed tumour progression or ocular relapse. The tumour response at 2 years was a flat lesion for 6.3% of cases, partial regression in 75% and stable in 18.8%. None of the patients required secondary enucleation. The main complication was cataract (45% within 24 months of treatment). Raised intraocular pressure was observed in 15% of patients but no neovascular glaucoma., Conclusions: Proton beam therapy shows potential utility for selected cases of localised iris melanomas allowing excellent local tumour control and eye preservation. Further follow-up on larger series is needed to confirm these results.

Introduction: We conducted a retrospective study on the clinical factors influencing the local and general prognosis of patients treated for uveal melanoma with a preliminary analysis of the prognostic value of monosomy 3., Patients: and method: The patients sent to Curie Institute for uveal melanoma have a complete initial clinical evaluation, conservative management by radiotherapy or enucleation, and local and general long-term follow-up. Over the last 5 years, the status of chromosome 3 has been assessed by FISH in the tumors of enucleated patients. Findings concerning the initial workup, treatment, and follow-up are recorded prospectively. We conducted a retrospective study with multivariate analysis of the clinical factors influencing local recurrence, ocular conservation metastasis, and survival and studied the effect of monosomy 3., Results: A total of 2241 patients were registered with a median follow-up of 72 months. Of these patients, 92.8% had conservative management with iodine 125 brachytherapy or proton beam therapy and 7.2% of the patients had enucleation (n=160). Tumors from 120 patients were studied for the status of chromosome 3 by FISH. The overall survival rate was 76.3% and the metastatic rate was 19.5%. The clinical factors influencing survival were the size and location of the tumor, age of the patient, gender, and initial treatment. The factors influencing the metastatic risk were the same plus retinal detachment and local recurrence. Monosomy 3 was a significant risk factor for metastatic disease., Discussion: This study found the usual risk factors with the difference that location on the equator seems to be of worse prognosis than ciliary body involvement for survival and metastasis. In addition, the initial retinal detachment appears to be a risk factor for local recurrence and metastasis. At present, the evaluation of chromosome 3 is available for enucleated tumors but it could probably be done on needle biopsy performed during conservative management as well., Conclusion: This study confirms previous results on the prognostic factors of uveal melanoma and on the value of monosomy 3. The increasingly precise identification of a group of high-risk patients should allow us to propose adjuvant therapy and to adapt follow-up.

Purpose: This study reports the results of proton beam radiotherapy based on a retrospective series of patients treated for uveal melanoma at the Orsay Center., Methods and Materials: Between September 1991 and September 2001, 1,406 patients with uveal melanoma were treated by proton beam radiotherapy. A total dose of 60 cobalt Gray equivalent (CGE) was delivered in 4 fractions on 4 days. Survival rates were determined using Kaplan-Meier estimates. Prognostic factors were determined by multivariate analysis using the Cox model., Results: The median follow-up was 73 months (range, 24-142 months). The 5-year overall survival and metastasis-free survival rates were 79% and 80.6%, respectively. The 5-year local control rate was 96%. The 5-year enucleation for complications rate was 7.7%. Independent prognostic factors for overall survival were age (p < 0.0001), gender (p < 0.0003), tumor site (p < 0.0001), tumor thickness (p = 0.02), tumor diameter (p < 0.0001), and retinal area receiving at least 30 CGE (p = 0.003). Independent prognostic factors for metastasis-free survival were age (p = 0.0042), retinal detachment (p = 0.01), tumor site (p < 0.0001), tumor volume (p < 0.0001), local recurrence (p < 0.0001), and retinal area receiving at least 30 CGE (p = 0.002). Independent prognostic factors for local control were tumor diameter (p = 0.003) and macular area receiving at least 30 CGE (p = 0.01). Independent prognostic factors for enucleation for complications were tumor thickness (p < 0.0001) and lens volume receiving at least 30 CGE (p = 0.0002)., Conclusion: This retrospective study confirms that proton beam radiotherapy ensures an excellent local control rate. Further clinical studies are required to decrease the incidence of postirradiation ocular complications.

Epidemiologic studies have reported an association between lymphoid neoplasia and melanoma. However, the clinical characteristics, medical history and outcome of patients presenting both diseases have not been clearly described. Patients who developed both lymphoma and melanoma at the Institut Curie between 1970 and 2005 were included in this retrospective study. Patient characteristics were analysed and a review of all previously published cases was then performed. The eight patients of our series and those derived from a review of the literature resulted in a population of 70 patients. The male/female sex ratio was greater than 1. Patients were older than 50 years. The mean interval to the second malignancy was 5 years and 13 years for lymphoma and melanoma, respectively. Most patients had an indolent B-cell lymphoma and localized melanoma. Frequent skin involvement was reported for T-cell lymphoma. Chemotherapy or external radiation therapy frequently preceded the second malignancy. Patients with lymphoma and melanoma should be closely monitored to detect the appearance of a second malignancy. Further studies are therefore warranted to elucidate this peculiar association.

Uveal melanoma is very rare in children, and in both adults and children it can in rare cases develop intralesional cavities resembling an intraocular cyst. The presence of a solid mass at the base and a thick wall surrounding the cavity can assist in differentiating cavitary melanoma from a benign cyst. We report the case of a 5-year-old girl who presented with a large intraocular pigmented mass in the left eye, showing multiple hollow cavities on ocular ultrasonography, CT scan, and MRI. The patient was treated by enucleation and the pathology confirmed the diagnosis of choroidal melanoma. FISH revealed no aberration in chromosome 3.

Introduction: Exudation from the tumour scar and glaucoma can be major problems after proton beam irradiation of uveal melanoma and can sometimes lead to secondary enucleation. We conducted a randomized study to determine whether systematic transpupillary thermotherapy (TTT) after proton beam radiotherapy could have a beneficial effect., Patients and Method: Between February 1999 and April 2003, all the patients treated by proton beam radiotherapy for uveal melanomas >/=7 mm thick or >/=15 mm in diameter were included in this study after giving their informed consent. One half of the patients received proton beam radiotherapy alone (60 Gy in 4 fractions) and the other half received the same dose of proton beam radiotherapy followed by TTT at 1, 6 and 12 months. All the information concerning the initial tumour parameters, treatments and follow-up was recorded and a statistical analysis was performed., Results: We randomized 151 patients. The median follow-up was 38 months. The 2 groups of patients were similar in terms of age, gender and tumour characteristics. The patients treated with TTT showed a greater reduction of tumour thickness (p = 0.06), less retinal detachment at the latest follow-up (p = 0.14) and a lower secondary enucleation rate (p = 0.02)., Discussion: The present study is the first randomized analysis to demonstrate a significant decrease in the secondary enucleation rate in patients treated with TTT after proton beam radiotherapy. Further studies should be performed to determine whether TTT could be beneficial to smaller tumours and to define its optimal dose., (Copyright (c) 2006 S. Karger AG, Basel.)

Purpose: We analyzed the long-term results of uveal melanoma treatment with proton beam irradiation in a series of patients with a follow-up of at least 10 years., Patients and Methods: The patients were treated with proton beam radiation between September 1991 and December 1992. They had an initial examination including visual acuity, funduscopy, A and B scan ultrasonography of the eye, fundus photographs and fluorescein angiography. General examination included chest radiography and B scan ultrasonography of the liver. All tumors received a total dose of 60 cobalt-Gray equivalents (applied in four daily fractions) at the Orsay proton therapy center., Results: A total of 167 patients were treated with a median follow-up of 116 months. Their median age was 59 years. Thirteen tumors were anterior to the equator, 76 overlapped the equator and 78 were posterior to the equator. An initial retinal detachment was present in 41 cases. The optic disk was invaded in 10 cases. The median tumor diameter was 12 mm and the median tumor thickness was 5.8 mm. The mean initial acuity was 20/50. The survival rate was 62.93% at 10 years; 72.9% of deaths resulted from metastasis. Statistically significant risk factors for death identified in the multivariate analysis were tumor diameter greater than 12 mm (p=0.0004) and age over 60 years (p=0.0001). The metastasis rate at 10 years was 31%. The liver was affected in 97.8% of these patients. Risk factors for metastasis were the anterior site of the tumor, its volume greater than 0.4 cc and the presence of retinal detachment at diagnosis. The secondary enucleation rate at 10 years was 13.23%, mainly attributable to secondary neovascular glaucoma. The local recurrence rate was 6%. The visual acuity rate in 42.1% of patients was better than 20/100 at 10 years. Visual loss was mainly due to postradiation maculopathy and neuropathy., Conclusion: Our study confirms the long-term results found in the literature on proton beam radiation. This therapy allows good tumor control, an excellent eye retention rate, and good final visual acuity for approximately half of the patients.

The molecular and cellular basis of human choroidal malignant melanoma progression has remained largely unknown. However, choroidal melanoma is the most important primary intraocular tumor in adults. Developmentally, choroidal melanocytes are of neural crest origin similar to cutaneous melanocytes. However, there are some significant differences between cutaneous and uveal melanocytes that have yet to be fully assessed. The purpose of this study is to describe choroidal melanocytes. We will describe the significant differences between cutaneous and uveal melanocytes as well as the congenital and acquired diseases of uveal melanocytes. We will then describe the cellular and molecular mechanisms involved in melanoma progression.

Ocular melanoma is a rare tumour with a poor prognosis when initial tumour burden is large. In France, the disease incidence is estimated to 7/1,000,000 persons. Except for the presence of an Ota's naevus, no risk factor has been clearly identified. In many patients, radiotherapy offers an alternative local therapy to surgery. No adjuvant treatment has demonstrated any benefit. Treatment of metastatic disease has to be precised.