20-year assessment of metastatic latency and subsequent time to death after proton therapy for uveal melanomas.

The aim of this study was to evaluate metastatic latency and survival after the occurrence of metastases in patients with choroidal/ciliary body melanoma treated with proton therapy. This was a retrospective cohort study. All consecutive patients with choroidal/ciliary body melanoma treated with proton therapy between 1991 and 2010 were included. Overall survival, specific survival (SS), local recurrence-free interval, and metastasis-free interval (MFI) were calculated. There were 508 patients. The mean follow-up was 239.4 months. Overall survival and SS rates were 57.2 and 67.6% at 10 years. Pre-equatorial tumor location, advanced tumor stage, and initial exudative retinal detachment were associated independently with SS. Thirty-three percent of the patients (n = 169) had metastases. Local recurrence-free interval and MFI were 91.3 and 65.7% at 10 years, respectively. MFI was shorter in pre-equatorial, large tumors, and/or tumors with exudative retinal detachment. After the occurrence of metastases, the median survival time was 1.25 years and survival probabilities were 62.1% at 1 year, 26.0% at 2 years, and 6.0% at 5 years. Except for age, none of the baseline clinical factors was associated with survival after metastasis occurrence. SS after metastasis occurrence was longer for metastasis occurring more than 10 years after tumor diagnosis (P =0.010). Death after metastasis is independent of initial tumor characteristics. Small tumors still have a risk for metastases after 10 years. Thus, lifelong follow-up is necessary for uveal melanoma patients. Larger series of metastatic patients are needed to evaluate aggressive multimodal treatments of metastases. Death after metastasis is independent of the initial tumor characteristics. Small tumors contraintuitively have a long-life risk of metastases. MFI is associated independently with pre-equatorial location, tumor stage, and retinal detachment.

The Small Fatal Choroidal Melanoma Study. A Survey by the European Ophthalmic Oncology Group.

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.

Intravitreal dexamethasone implant (Ozurdex®) for exudative retinal detachment after proton beam therapy for choroidal melanoma.

PURPOSE: To evaluate the efficacy and safety of intravitreal 0.7-mg dexamethasone implant (DEX-I) (Ozurdex®) in the treatment of extensive exudative retinal detachment (RD) associated with uveal melanoma treated using proton beam therapy (PBT). METHODS: Data from 10 patients with exudative RD after PBT treated with intravitreal injection of 0.7-mg DEX-I were reviewed retrospectively. The main outcome measures were resolution of exudative RD, visual acuity, and safety profile. RESULTS: Mean age was 55.6 years (range 34-85). Mean time between PBT and DEX-I was 12.4 months (range 3-25). Mean follow-up was 9.9 months (range 4-15). Intravitreal Ozurdex® reduced exudative RD in 7 cases (70%) on average 3.1 months after injection with complete resolution of RD in 6 of these (60%). For half of the patients, their level of vision remained stable; the other half experienced a deterioration in visual acuity at the end of follow-up. No adverse effects were observed. CONCLUSIONS: In this small case series, treatment with intravitreal DEX-I reduced exudative RD in the majority of cases and had an acceptable safety profile.

Validation of a Prognostic Staging for Metastatic Uveal Melanoma: A Collaborative Study of the European Ophthalmic Oncology Group.

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.

Visual Outcomes of Parapapillary Uveal Melanomas Following Proton Beam Therapy.

PURPOSE: In parapapillary melanoma patients, radiation-induced optic complications are frequent and visual acuity is often compromised. We investigated dose-effect relationships for the optic nerve with respect to visual acuity after proton therapy. METHODS AND MATERIALS: Of 5205 patients treated between 1991 and 2014, those treated using computed tomography (CT)-based planning to 52 Gy (prescribed dose, not accounting for relative biologic effectiveness correction of 1.1) in 4 fractions, with minimal 6-month follow-up and documented initial and last visual acuity, were included. Deterioration of ≥0.3 logMAR between initial and last visual acuity results was reported. RESULTS: A total of 865 consecutive patients were included. Median follow-up was 69 months, mean age was 61.7 years, tumor abutted the papilla in 35.1% of patients, and tumor-to-fovea distance was ≤3 mm in 74.2% of patients. Five-year relapse-free survival rate was 92.7%. Visual acuity was ≥20/200 in 72.6% of patients initially and 47.2% at last follow-up. A wedge filter was used in 47.8% of the patients, with a positive impact on vision and no impact on relapse. Glaucoma, radiation-induced optic neuropathy, maculopathy were reported in 17.9%, 47.5%, and 33.6% of patients, respectively. On multivariate analysis, age, diabetes, thickness, initial visual acuity and percentage of macula receiving 26 Gy were predictive of visual acuity. Furthermore, patients irradiated to ≥80% of their papilla had better visual acuity when limiting the 50% (30-Gy) and 20% (12-Gy) isodoses to ≤2 mm and 6 mm of optic nerve length, respectively. CONCLUSIONS: A personalized proton therapy plan with optic nerve and macular sparing can be used efficiently with good oncological and functional results in parapapillary melanoma patients.

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.

Somatic DICER1 gene mutation in sporadic intraocular medulloepithelioma without pleuropulmonary blastoma syndrome.

Germline DICER1 gene mutation has been described in ocular medulloepithelioma associated with pleuropulmonary blastoma family tumor and dysplasia syndrome. We present a case of sporadic ocular medulloepithelioma in an 18-year-old woman with D1709N somatic mutation in DICER1 gene, which has not been previously described. This case highlights the potential use of DICER1 gene sequencing to resolve the diagnostic challenge in recurrent and metastatic malignant medulloepithelioma, when morphology and immunohistochemistry are inconclusive. Further studies in larger series of this type of tumor are needed to confirm the relevance of this molecular abnormality in the tumorigenesis of this embryonic-type ocular tumor.

Small metastasizing choroidal melanomas.

PURPOSE: Small choroidal melanomas have a better prognosis than large tumours. However, these small tumours can spread, often late in their course. The aim of the study was to analyse survival and tumour characteristics of six cases of late metastatic diseases after conservative treatment. METHODS: A retrospective study was conducted at the Croix-Rousse University Hospital of Lyon among 523 patients treated between 1991 and 2010 by proton beam therapy (508) or brachytherapy with 106 (Ru/Rh) (15) for uveal melanomas. We have selected patients with small choroidal melanoma (thickness≤3 mm and diameter≤9 mm) (59 patients), who have developed hepatic metastases (six of 59). RESULTS: At the time of diagnosis, median age was 57 years (range, 37-82 years). The mean tumour thickness was 2.9 mm (range 2.5-3 mm), and the mean diameter was 7 mm (5-8 mm). Orange pigment was observed in four cases, subretinal fluid was observed in two cases, and one tumour touched the optic disc. Five patients had proton beam therapy. One patient had beta brachytherapy (106 Ru/106 Rh). Average follow-up was 8.3 years (range 4.2-11.8 years). None of the six patients developed local tumour recurrence. The mean survival time after diagnosis of melanoma was 9.8 years (range, 4.9-14.6 years). The average time from treatment of primary tumour to detection of liver metastasis was 7 years (range 3.9-12 years). The mean survival time from the diagnosis of metastasis was 35.2 months (range 9-101 months). Small melanoma-related death was 0% at 3 years, 1.7% at 5 years, 5.1% at 10 years and 10.2% at 15 years in our series. CONCLUSIONS: Despite a small tumoral size and an early and effective local treatment, six of 59 small choroidal melanomas have developed metastasis after local treatment. Small tumours represent a significant risk of metastasis.

Proton beam therapy for presumed and confirmed iris melanomas: a review of 36 cases.

BACKGROUND: To report the clinical features and outcomes of iris melanomas treated by proton beam therapy. MATERIALS AND METHODS: A retrospective study was conducted at the Croix-Rousse University Hospital of Lyon, Department of Ophthalmology, in 36 patients treated by proton beam therapy for presumed (n = 29) and confirmed (n = 7) iris melanomas between July 1997 and October 2010. Ciliary body melanomas with iris involvement were excluded. The patients' mean age was 54.4 years (range, 22-82 years). The average tumor diameter was 3.8 mm (range, 2.5-8.0). The iridocorneal angle was invaded by the tumor in 47% of cases (n = 17), the ciliary body in 17% of cases (n = 6), and the sclera in 3% (n = 1). Raised intraocular pressure was present before treatment in 11.1 % of cases (n = 4). Tumor biopsy was performed in 19% of cases (n = 7). Four patients had undergone an initial incomplete surgical excision of tumor before radiotherapy. Surgical preparation of the eye with tantalum ring positioning had been performed in all cases 3-4 weeks before irradiation. The prescribed dose was 60 Cobalt Gray Equivalent (CGE) of proton beam radiotherapy delivered in four fractions on four consecutive days. RESULTS: The median follow-up was 50 months (mean 60.5, range 15-136). One patient (2.7%) was lost to follow-up. None of the patients showed tumor progression, local recurrence, or metastasis. None of the patients required secondary enucleation. Cataract was developed in 62% of patients, glaucoma in two cases (6%) after irradiation, and hyphema with the aggravation of pre-existing glaucoma in one patient. No patients developed neovascular glaucoma. CONCLUSIONS: Proton beam therapy appears to be the treatment of choice for the conservative treatment of iris melanomas with excellent tumor control and an acceptable rate of complications. Longer follow-up studies on a larger series is necessary to consolidate these results.

(123)I-BZA2 as a melanin-targeted radiotracer for the identification of melanoma metastases: results and perspectives of a multicenter phase III clinical trial.

UNLABELLED: Our group has developed a new radiopharmaceutical, (123)I - N-(2-diethylaminoethyl)-2-iodobenzamide ((123)I-BZA2), a benzamide derivative able to bind to melanin pigment in melanoma cells. In a prospective and multicentric phase III clinical study, the value of (18)F-FDG PET/CT and (123)I-BZA2 scintigraphy was compared for melanoma staging. METHODS: Patients with a past history of cutaneous or ocular melanoma were included from 8 hospitals. (18)F-FDG imaging was performed according to a standard PET protocol. Whole-body, static planar, and SPECT/CT (if available) images were acquired 4 h after injection of a 2 MBq/kg dose of (123)I-BZA2. (18)F-FDG and (123)I-BZA2 sensitivity and specificity for the diagnosis of melanoma metastasis were calculated and compared on both a lesion basis and a patient basis. True-positive and true-negative lesion status was determined after 6 mo of clinical follow-up or according to lesion biopsies (if available). Melanin content in biopsies was evaluated with the standard Fontana-Masson silver method and was correlated with (123)I-BZA2 uptake. Based on statistical analysis, the number of inclusions was estimated at 186. RESULTS: In all, 87 patients were enrolled from 2008 to 2010. Of these, 45 (52%) had metastases. A total of 338 imaging abnormalities were analyzed; 86 lesions were considered metastases, and 20 of 25 lesion biopsies found melanoma metastases. In a patient-based analysis, the sensitivity of (18)F-FDG for diagnosis of melanoma metastases was higher than that of (123)I-BZA2, at 87% and 39%, respectively (P < 0.05). For specificity, (18)F-FDG and (123)I-BZA2 were not statistically different, at 78% and 94%, respectively. In a lesion-based analysis, the sensitivity of (18)F-FDG was statistically higher than that of (123)I-BZA2 (80% vs. 23%, P < 0.05). The specificity of (18)F-FDG was lower than that of (123)I-BZA2 (54% vs. 86%, P < 0.05). According to biopsy analysis, only 9 of 20 metastatic lesions (45%) were pigmented with high melanin content. (123)I-BZA2 imaging was positive for 6 of 8 melanin-positive lesions, fairly positive for 3 of 10 melanin-negative lesions, and negative for 7 of 10 melanin-negative lesions. The sensitivity and specificity of (123)I-BZA2 for the diagnosis of melanin-positive lesions were 75% and 70%, respectively. Because of a low (123)I-BZA2 sensitivity, this clinical trial was prematurely closed after 87 patients had been included. CONCLUSION: This study confirms the value of (18)F-FDG PET/CT for melanoma staging and strengthens the high accuracy of (123)I-BZA2 for diagnosis of melanin-positive metastatic melanoma. Moreover, benzamide derivatives radiolabeled with therapeutic radionuclide may offer a new strategy for the treatment of metastatic melanoma patients harboring melanin-positive metastases.

Staging of ciliary body and choroidal melanomas based on anatomic extent.

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.

Transretinal uveal melanoma biopsy with 25-gauge vitrectomy system.

PURPOSE: To evaluate the efficacy and the safety of uveal melanoma transretinal biopsy using 25-gauge vitrectomy system. METHODS: At the patient's request of a tissue diagnosis, nine posterior uveal melanomas treated by proton-beam therapy were biopsied during the insertion of tantalium markers. RESULTS: The diagnosis was uveal melanoma, confirmed in all cases using cytological (7 of 9) and histological analysis (2 of 9). Immunocytochemistry was performed on all samples (9 of 9). In eight of nine patients, minor postoperative vitreous haemorrhages were seen, which resolved in 1 day. No other ocular complications were noticed. CONCLUSION: Uveal melanoma biopsy using 25-gauge vitrectomy system is a valuable procedure to confirm the diagnosis, with adequate sample and low ocular morbidity.

Intraocular sarcoidosis: association of clinical characteristics of uveitis with findings from 18F-labelled fluorodeoxyglucose positron emission tomography.

AIMS: To assess specific clinical criteria in patients with uveitis that are related to signs of sarcoidosis on (18)F-labelled fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET). METHODS: Retrospective study of 54 consecutive patients with chronic uveitis for whom a PET scan was done because of suspected sarcoidosis, between July 2004 and December 2009. All the patients underwent a clinical examination, biological tests and a high-resolution CT of the chest. RESULTS: 17 of the 54 patients (31.5%) presented hypermetabolic foci on (18)F-FDG-PET scan consistent with sarcoidosis. Among them eight patients (14.8%) underwent biopsy showing non-caseating granuloma. At the end of the study, 10 patients (18.5%) were considered as having a presumed sarcoidosis and seven patients (12.9%) as having indeterminate sarcoidosis. The increasing age at the diagnosis of uveitis (p=0.01), the presence of posterior synechiae (p=0.01) and a positive high-resolution CT of the chest (p=0.01) were significantly related to an abnormal PET scan. CONCLUSIONS: Increasing age at the diagnosis of uveitis, the presence of posterior synechiae and the positivity of high-resolution chest CT are associated with (18)F-FDG PET scan signs consistent with sarcoidosis.

Diagnosis of a multicentric extranodal nasal-type natural killer T-cell lymphoma made with an anterior chamber tap.

PURPOSE: To report the case of an unusual multicentric Epstein-Barr virus (EBV)-associated extranodal nasal-type natural killer T-cell lymphoma masquerading as unilateral panuveitis, diagnosed with an anterior chamber tap. METHODS: The clinical history and the morphological, immunohistochemical, and molecular features of a 51-year-old white man with left severe panuveitis were retrospectively evaluated. RESULTS: The patient initially presented with a 3-month history of recalcitrant sinusitis and new onset of unilateral loss of vision. Clinical examination revealed right peripheral facial nerve palsy, severe panuveitis of the left eye, and nasopharyngeal obstruction. Anterior chamber aspirates were examined. The combination of the presence of small- to intermediate-size lymphocyte proliferation, moderate elevation of the interleukin-10 level on cytokine profiling, and slightly positive polymerase chain reaction for EBV in the aqueous humor indicated an EBV-induced nasal-type natural killer T-cell lymphoma. Transnasal biopsy revealed the presence of numerous irregular lymphoma cells with positive staining for CD3, CD56, EBV-encoded RNA in situ hybridization, and negative staining for CD4, CD8, and CD1a. Lumbar puncture, cerebral magnetic resonance imaging, thoracoabdominal computed tomography, and upper digestive tract endoscopy revealed meningeal, renal, adrenal, and digestive involvement. Massive hemorrhage of the upper digestive tract caused rapid death. CONCLUSION: Extranodal nasal-type natural killer T-cell lymphoma is a very uncommon disease that may present acutely, sometimes as pseudouveitis. Simple investigations such as anterior chamber aspirates for cytological examination, reinforced by cytokine profiling and viral polymerase chain reaction looking for EBV, may provide a rapid diagnosis, necessary given the poor prognosis of the disease. To our knowledge, and after extensive review of the literature, we did not find another case report diagnosing this entity by anterior chamber paracentesis.

Sturge-Weber syndrome: decrease in intraocular pressure after transpupillary thermotherapy for diffuse choroidal haemangioma.

PURPOSE: To report intraocular pressure (IOP) reduction after selective and partial destruction of diffuse choroidal haemangioma (DCH) by transpupillary thermotherapy (TTT) using an 810 nm infrared diode laser in two patients with Sturge-Weber syndrome (SWS) having late-onset juvenile glaucoma (LOJG). METHODS: An interventional small case series. Laser spots (diameter, 1 mm) were applied to the tumour surface located outside the posterior pole. Energy level (600-1700 mW) and exposure time (1-4 seconds) were increased stepwise until the tumour exhibited a greyish discoloration. The treatment was split into 2-4 sessions. RESULTS: Before TTT, both patients had uncontrolled LOJG with an IOP of 23 mmHg (Case 1) and 45 mmHg (Case 2) in spite of topical medications. In both cases, TTT led to normalization of IOP to 15 mmHg and 24 mmHg, respectively, and stopped the progression of LOJG during a follow-up period of 6 years (Case 1) and 1 year (Case 2). Visual loss or other complications were not observed. CONCLUSIONS: Our study highlights the close link that exists between LOJG and DCH in SWS. A single treatment modality such as TTT may both reduce IOP in LOJG and help to prevent exudative retinal detachment in DCH. We believe that TTT is a good therapeutic option for SWS patients who have both DCH and LOJG.

Primary transpupillary thermotherapy for 18 small posterior pole uveal melanomas.

PURPOSE: To evaluate transpupillary thermotherapy (TTT) for the treatment of small uveal melanomas of the posterior pole. DESIGN: Prospective, nonrandomized interventional case series. METHODS: Eighteen patients underwent TTT for small uveal melanomas located in the posterior pole of the eyes. Tumors were between 2.5 and 4 mm in thickness. TTT was performed with a diode laser at 810 nm. Patients had between one and three TTT sessions, with an intensity adapted to the coloration of the fundus impact. Biomicroscopic examination, ultrasonographic measurements, and angiography were performed before and two months, four months, and six months after treatment, then regularly during follow-up. RESULTS: Eight of the 18 tumors regressed and 10 recurred. The one- and two-year metastasis-free survival rates calculated by the Kaplan-Meier method were, respectively, 61.11% to 44.44% (95% confidence interval). Recurrences were managed with enucleation (three patients), proton beam therapy (six), or additional thermotherapy (one). After treatment, visual acuity was maintained or improved for the eight patients with nonrecurrent tumors. Pathologic analysis of the three enucleated eyes revealed scleral invasion. CONCLUSIONS: Despite encouraging initial short-term results obtained with TTT for the management of small choroidal melanomas, the occurrence of severe complications, especially recurrences and insufficient local tumor control, should raise concern about indications for primary TTT given as isolated treatment for small melanomas of the posterior pole.

Characterization of the typical multidrug resistance profile in human uveal melanoma cell lines and in mouse liver metastasis derivatives.

Uveal melanoma is the most common intraocular malignancy. To study its biology, stable cell lines provide a useful tool, but these are very difficult to obtain. A stable and rapidly growing human choroidal melanoma cell line composed of pure epithelioid cells was established and maintained for at least 4 years. In vivo transplantation into BALB/cByJ nude mice induced vascularized tumours at the injection sites. Interestingly, two of three cases produced a liver metastasis. Other uveal melanoma cell lines displaying different morphological aspects were also obtained. To avoid the bias due to uncertain immunologically based staining approaches, several methods were juxtaposed to establish the multidrug resistance (MDR) profile. All the uveal melanomas studied expressed significant levels of the MDR-related MDR1, MRP1 (MDR-related protein 1) and LRP/MVP (lung resistance protein/major vault protein) messenger RNAs (mRNAs), produced their corresponding proteins and were able to functionally extrude daunomycin. When compared with the established MEWO skin melanoma cell line, our data showed that both primary and metastatic uveal melanomas intrinsically expressed the typical MDR phenotype, which precludes the use of any anticancer drugs known to be substrates of MDR-related proteins to treat the disease. Moreover, it appears that the metastasizing process does not change the status of the MDR phenotype.

Major cytogenetic aberrations and typical multidrug resistance phenotype of uveal melanoma: current views and new therapeutic prospects.

Uveal melanoma is the most frequent intra-ocular cancer. The recent development of new chromosome-related technologies have permitted the elucidation of both the cytogenetics and the natural history of this disease. Fifty to 60% of uveal melanomas are linked to a monosomy 3, which appears as an early and determinant event in tumor progression. Tumors with this anomaly have a very poor prognosis. Recent work suggests that this category of uveal melanoma represents a distinct pathologic entity from that associated with normal disomy 3. Chromosome 6 aberrations probably constitute a second entry point into the process of cancerogenesis, while gains in 8q seem to appear later in the natural history of uveal melanomas due to their higher frequency in larger tumors. Other anomalies will be reviewed. In spite of significant improvements in the local treatment of uveal melanoma, many patients die due to tumor metastasis. This disease is characterized by a constitutive chemoresistance whose typical multidrug resistance phenotype (MDR) is particularly complex since different combinations of several resistance proteins are simultaneously produced. Regulation of the expression of these proteins is a research priority, increasingly so as gene therapy-dependent chemosensitization strategies expand. Therefore, the development and improvement of methods to determine the chemoresistance profile become a crucial objective today in the therapeutic strategies against uveal melanoma.