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Background: We evaluated the control rate of choroidal melanomas treated with ¹⁰⁶Ru plaque brachytherapy to identify the risk factors associated with local recurrence and lack of response., Methods: A retrospective review of ¹⁰⁶Ru plaque brachytherapy for patients with choroidal melanoma treated at St Bartholomew's Hospital, London. Survival analysis was used to assess associations between evaluated age, sex, location, foveal proximity, tumour base and height, presence of lipofuscin and subretinal fluid, apex dose, radiation rate and type of plaque with time to local recurrence. Logistic regression analysis was used to assess to evaluate the association between the same set of variables and lack of tumour response., Results: From January 2002 to December 2006 189 patients were treated. The follow-up ranged from 12 to 78 (median 33) months. None of the patients received adjuvant diode laser thermotherapy. The control rate was 85.7% (14 recurred while 13 did not respond). Of the patients who had local recurrence, univariate survival analysis demonstrated an association with younger patients, foveal proximity, preoperative subfoveal fluid and tumour base >11 mm. Age and foveal proximity remained significant in a Cox multiple variable model (p=0.03). Of the patients who did not respond, logistic regression analysis showed that lack of response was associated with a tumour height >5 mm, confirmed through multiple variable analysis (p=0.027)., Conclusions: Tumours that are close to the fovea in young patients appear more likely to show local recurrence. Tumour height >5 mm was the only prognostic factor that determined lack of response. These results may be used to select which tumours require adjuvant therapy.

Choroidal melanoma has a high mortality rate and responds poorly to existing chemotherapy, but unexpected ex vivo sensitivity of a subset of these tumours to topoisomerase II inhibitors has been noted. Since chemoresistance may be mediated by the molecular phenotype of tumours, immunohistochemistry has been used to study the expression of both isoforms of topoisomerase II (alpha and beta) in 29 choroidal melanomas for which chemosensitivity assay data for doxorubicin or mitoxantrone are also available. Of these, eight tumours were topoisomerase II beta-positive and 11 were topoisomerase II alpha-positive. Recent studies showing genetic abnormality (often monosomy of chromosome 3) in choroidal melanoma suggest that loss of immunostaining could be due to genomic loss rather than down-regulation of topoisomerase II beta in these tumours. There was no convincing excess of anthracycline resistance in the topoisomerase II beta-negative group. Addition of topoisomerase II alpha, MDR1 (11/17 positive), LRP (16/28 positive), and MRP (5/29 positive) data in multivariate analysis did not reliably predict sensitivity or resistance. Vincristine chemosensitivity showed no relation to MDR1, LRP or MRP in 18 tumours tested. While it is possible that some tumours which do express topoisomerase II beta may respond to anthracyclines, the molecular basis of resistance or sensitivity to anthracyclines or vincristine in uveal melanoma is complex and remains incompletely understood., (Copyright 2000 John Wiley & Sons, Ltd.)

Purpose: To compare the efficacy of iodine-125 (125I) and ruthenium-106 (106Ru) episcleral plaque radiation therapy and proton beam radiation therapy (PBRT) in the treatment of choroidal melanoma., Design: A retrospective, nonrandomized comparative study., Methods: Charts of patients treated with 125I, 106Ru, and PBRT for choroidal melanoma between January 1988 and June 1996 at St. Bartholomew's Hospital and Moorfields Eye Hospitals were reviewed., Main Outcome Measure: Local control of choroidal melanomas after 125I, 106Ru, or PBRT., Results: A total of 597 patients were identified (125I = 190, 106Ru = 140, PBRT = 267). Patients treated with 106Ru had a significantly greater risk of local tumor recurrence than did patients treated with either 125I (P = 0.0133; confidence interval [CI], 1.26-7.02; risk ratio, 2.97) or PBRT (P = 0.0097; CI, 1.30-6.66; risk ratio, 2.94). A stepwise Cox proportional hazard model found maximal basal diameter to be a significant covariate (P = 0.0033)., Conclusion: Patients treated with 106Ru had a significantly greater risk of local tumor recurrence than did those patients treated with either 125I or PBRT.

Treatment of choroidal melanoma by chemotherapy is usually unsuccessful, with response rates of less than 1% reported for dacarbazine (DTIC)-containing regimens which show 20% or more response rates in skin melanoma. Recently, we reported the activity of several cytotoxic agents against primary choroidal melanoma in an ATP-based tumour chemosensitivity assay (ATP-TCA). In this study, we have used the same method to examine the sensitivity of choroidal melanoma to combinations suggested by our earlier study. Tumour material from 36 enucleated eyes was tested against a battery of single agents and combinations which showed some activity in the previous study. The combination of treosulfan with gemcitabine or cytosine arabinoside showed consistent activity in 70% and 86% of cases, respectively. Paclitaxel was also active, particularly in combination with treosulfan (47%) or mitoxantrone (33%). Addition of paclitaxel to the combination of treosulfan + cytosine analogue added little increased sensitivity. For treosulfan + cytosine arabinoside, further sequence and timing experiments showed that simultaneous administration gave the greatest suppression, with minor loss of inhibition if the cytosine analogue was given 24 h after the treosulfan. Administration of cytosine analogue 24 h before treosulfan produced considerably less inhibition at any concentration. While we have so far been unable to study metastatic tumour from choroidal melanoma patients, the combination of treosulfan with gemcitabine or cytosine arabinoside shows activity ex vivo against primary tumour tissue. Clinical trials are in progress.

Background: Macular and juxtapapillary circumscribed choroidal haemangiomas (CCH) have always posed a diagnostic and therapeutic challenge. Proton beam therapy has been advocated by Zografos and associates as optimal for treating these tumours in this critical region as charged particles have a highly localised and uniform dose distribution., Patients: We present 3 cases of CCH treated with proton beam therapy. Two patients developed radiation optic neuropathy and maculopathy, and one had a persistent exudative macular detachment following treatment., Conclusion: Our experience with proton therapy of these tumours has been disappointing in preventing radiation optic neuropathy and maculopathy and offers little advantage over external irradiation. The majority of our patients with this condition are now treated with low-dose lens-sparing external beam radiotherapy or brachytherapy, which has encouraging visual results and is a far more cost-effective option.

Purpose: Choroidal hemangioma is a benign hamartoma that causes accumulation of subretinal fluid and resultant visual loss. Although photocoagulation can result in resolution of subretinal fluid, some have found that recurrence is common and final visual acuity often is poor. The purpose of this study is to evaluate the visual and anatomic results of radiation therapy and photocoagulation in treating patients with visual loss from choroidal hemangiomas., Methods: A retrospective review was performed of patients with circumscribed choroidal hemangiomas (CCH) or diffuse choroidal hemangiomas (DCH) treated for visual loss caused by accumulation of subretinal fluid. Of 23 patients with CCH, 13 were treated by photocoagulation, 8 by plaque brachytherapy, and 2 by lens-sparing external beam radiation therapy (LSRT). All five patients with DCH were treated by LSRT., Results: Of patients with CCH treated by brachytherapy, six (75%) of eight had visual acuity of 6/12 or better at 1 year and 8 (100%) of 8 had no subretinal fluid. Of patients with CCH treated by photocoagulation, 5 (38%) of 13 had visual acuity of 6/12 or better at 1 year and 6 (46%) of 13 had no subretinal fluid. Of patients with CCH treated by LSRT, none of two had visual acuity of 6/12 or better at 1 year and one of two had no subretinal fluid. Of the five patients with DCH treated by LSRT, all had complete resolution of subretinal fluid. Two had marked visual improvement and in the other three, vision was stabilized., Conclusions: Plaque brachytherapy is an effective alternative to photocoagulation for treatment of subretinal fluid caused by CCH. Lens-sparing external beam radiation therapy is effective treatment in patients with DCH.

Uveal melanoma has a high mortality rate and responds poorly to existing chemotherapy. We have therefore examined the sensitivity of uveal melanoma to cytotoxic agents using an ex vivo chemosensitivity assay to determine whether some agents which have not been used for this tumor might have activity. An ATP-based tumor chemosensitivity assay (ATP-TCA) was used to determine the effect of nine cytotoxic drugs at multiple dilutions in 28 primary uveal melanoma specimens. Evaluable assay results from up to 16 tumors with each drug showed variable sensitivity to alkylating agents (three of nine with mitomycin C, one of 15 with cisplatin and seven of 15 with treosulfan), cytosine arabinoside (seven of 16), paclitaxel (one of five) and doxorubicin (two of 16). No tumors were sensitive to temozolomide, or 5-fluorouracil, and only one of 14 to vincristine. The combination of treosulfan with cytosine arabinoside resulted in enhanced tumor cell inhibition in three of five tumors tested. Combinations containing paclitaxel combined with doxorubicin or cisplatin showed some activity, but none achieved 100% inhibition and the results were similar to those obtained with paclitaxel alone. Uveal melanoma shows considerable heterogeneity of sensitivity to cytotoxic drugs, with considerable resistance to most agents, matching clinical experience. The results suggest that cytosine arabinoside or gemcitabine plus treosulfan may be an active combination. Clinical trials will commence shortly. The use of the ATP-TCA provides a method of testing multiple agents and combinations in a way which would be otherwise impossible in rare tumors such as uveal melanoma.

Background: It has been suggested that pregnancy may promote metastases in melanoma and that the contraceptive pill may be an etiologic factor. The purpose of this study is to determine if uveal or conjunctival melanomas express estrogen or progesterone receptors., Methods: Twenty-seven choroidal and five conjunctival melanomas were investigated. Immunohistochemistry was performed using the antibodies ER-D5, which recognizes heat-shock protein 27 (formerly called the estrogen receptor-associated cytoplasmic antigen); ER-1D5, which recognizes the estrogen receptor; and PgR, which recognizes the progesterone receptor., Results: Most of the conjunctival and uveal melanomas stained strongly for heat-shock protein 27 but none of the tumors showed positive nuclear staining for either the estrogen or the progesterone receptor., Conclusions: No evidence was found for either estrogen receptor or progesterone receptor expression in choroidal or conjunctival melanomas. Based on the literature, there is little evidence for these hormones having a role in the development or progression of these tumors.

Background: Patients with the atypical mole syndrome are prone to cutaneous melanoma, but their risk of ocular melanoma has not been established. We studied the skin of 207 consecutive patients with eye melanoma referred to Moorfields Hospital in London, England, in an attempt to determine what percentage of these patients had the atypical mole syndrome phenotype., Observations: Five patients were seen who had primary melanomas of both the eye and the skin. In three of these patients, the cutaneous melanomas were discovered only as a result of this study. The number of cutaneous melanomas expected in this cohort of patients with eye melanomas was no more than 0.4 on the basis of the United Kingdom incidence of both tumors. This difference was highly significant., Conclusions: The occurrence of primary cutaneous melanoma in five patients from a cohort of 207 patients with eye melanoma (or the premalignant melanocytic lesion of the conjunctiva called "primary acquired melanosis") provides strong evidence of an association between cutaneous and ocular melanoma. Three of the five patients also had the atypical mole syndrome phenotype, suggesting that the atypical mole syndrome predisposes to both types of melanoma.

Symptoms and signs of orbital inflammation may be prominent features in the presentation of choroidal malignant melanoma, even when the tumour is solely intraocular. Three cases with this clinical presentation are described.

The outcome is reported in 17 patients in whom an eye was enucleated for malignant melanoma of the choroid with extrascleral extension and who subsequently underwent adjuvant external beam radiotherapy to the orbit as the primary treatment of the extraocular spread of their tumour. Extrascleral extension was encapsulated in five, non-encapsulated in two, and had been surgically transected at enucleation in 10 cases. All the patients have been followed up from enucleation to the present day. Orbital recurrence occurred in only one patient. The overall actuarial survival rate was 51% at 5 years, 44% at 10, and 33% at 15 years. A low orbital recurrence rate of 6% compares very favourably with published figures for this event after enucleation for melanoma with extrascleral extension but without radiotherapy. Adjuvant orbital radiotherapy may have a place in the treatment of selected cases of extracleral extension of intraocular malignant melanoma.

Malignant melanoma is one of the most common primary intraocular neoplasms. Recently, 99mTc radiolabelled (Fab')2 fragments of monoclonal antibody 225.28S raised against cutaneous melanomas have been used for imaging uveal melanomas. We report here a case where uptake of radiolabelled antibody was observed in a choroidal melanoma of the right eye and a benign choroidal naevus of the left.

This is the first report of an amelanotic melanoma arising in the unpigmented choroid of a tyrosinase-positive oculocutaneous albino (TPOCA). Melanosomes within the tumour showed a maturation arrest in the unpigmented type II (premelanosome) phase. Other neural crest derived melanocytes in iris and choroid showed similar limited melanogenesis. The neuroectodermally derived melanocytes of the iris, ciliary body, and retinal pigment epithelium (RPE) contained mature melanosomes, though clinically the RPE was pale. The significance of this tumour arising in an albinotic eye is discussed.