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PurposeLocal treatment of uveal melanoma by radiotherapy involves the use of brachytherapy with radioactive plaques attached to the sclera, or proton irradiation. Both treatments induce growth arrest within the tumour and its slow involution over several years. Although ocular retention rates are excellent, regrowth of tumours due to resistance and neovascular glaucoma leads to enucleation of up to 10% of affected eyes. Proton irradiation involves part of the iris in most cases and we noticed that neovascularisation only occurred in the part of the iris that was not irradiated. We therefore conducted this study to determine the relationship between the development of iris neovascularisation and iris irradiation.MethodsA total of 21 enucleation specimens from patients who had previously had proton irradiation were collected from the files of the Department of Pathology, Moorfields Eye Hospital during the 5-year period from 1994 to 1999. Sections of these eyes were assessed for VEGF-A, bFGF, and von Willebrand Factor (vWF) by immunohistochemistry. Ophthalmic notes and radiotherapy records were reviewed to assess the extent of iris irradiation.ResultsIn all, 11 cases showed clinical evidence of iris neovascularisation and were selected for further study. Three of these eyes also showed clinical evidence of regrowth of the tumour. Histological evidence of iris neovascularization was noted in all 11 of the eyes examined, and was only present in the nonirradiated side of the iris in 8/11 eyes. NVI was present on both sides of the iris in three cases, but was less severe in the irradiated part. Expression of VEGF-A was at most weak within the tumour, but was present in the detached retina and in the epithelium of both ciliary body and iris. Some bFGF staining was noted around vessels in the iris stroma.ConclusionsOur results suggest that irradiation leads to iris atrophy, and that atrophic, irradiated iris is resistant to the development of neovascularisation.Eye (2006) 20, 832–836. doi:10.1038/sj.eye.6702072; published online 16 September 2005 [ABSTRACT FROM AUTHOR]

We report three patients with the atypical mole syndrome (AMS) [also known as dysplastic naevus or FAMMM syndrome] who presented with primary acquired melanosis (PAM). PAM is a melanocytic lesion of the conjunctiva which may progress to conjunctival melanoma. The association of this rare condition with the AMS phenotype in three individuals suggests that PAM may be a conjunctival manifestation of the AMS. [ABSTRACT FROM AUTHOR]

Four patients with malignant melanoma of the eyelid skin and 74 patients with conjunctival malignant melanoma are presented Surgery was recommended for eyelid lesions and local excision followed by cryotherapy for conjunctival lesions One patient with an eyelid skin malignant melanoma died and two patients with extensive malignant melanoma of the conjunctiva died Nodular lesions involving the lid margin have the worst prognosis of eyelid skin malignant melanomas, and the greater the extent of conjunctival involvement the worse the prognosis for conjunctival malignant melanomas The complications of cryotherapy are minor, but the follow-up period in this series is too short to comment on survival times. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

123I metaiodobenzylguanidine (MIBG) is a radiopharmaceutical used for imaging neural crest tumours. The possibility of using 123I MIBG for imaging retinoblastomas has been assessed in this pilot study. Ten patients were studied, nine with clinically and histologically proved retinoblastomas and one with Coats's disease. 123I MIBG scintigraphy correctly identified the neoplasm in eight patients but gave a negative result in two, one of whom had Coats's disease and the other a retinoblastoma which proved to be extensively necrotic on histological examination. These preliminary results suggest that 123I MIBG scintigraphy may have a role in differentiating retinoblastomas from lesions that simulate them. [ABSTRACT FROM PUBLISHER]

The possibility of using radiolabelled monoclonal antibody fragments to image uveal melanomas has been assessed in a pilot study. 99mTc labelled F(ab')2 fragments of MoAb 225.28S raised against cutaneous melanomas were used. Initially 10 patients were imaged. In five patients the clinical findings were typical of uveal melanoma. Immunoscintigraphy was positive in all five cases. In a further five patients there was doubt about the diagnosis. One was though to have a choroidal haemangioma but failed to respond to treatment and immunoscintigraphy was positive, suggesting a diagnosis of melanoma. Two patients were assigned a diagnosis of choroidal haemangioma, one of melanocytoma or possible retinal pigment epithelium carcinoma, and one of metastasis. Immunoscintigraphy was negative in all these four cases. In combination with established diagnostic tests immunoscintigraphy may have a part to play in differentiating uveal melanoma from other similar tumours. [ABSTRACT FROM PUBLISHER]

It can be difficult to distinguish between various forms of pale intraocular tumour, and in particular between an amelanotic malignant melanoma, a choroidal haemangioma, and a solitary metastasis. If a monoclonal antibody specific for melanoma could be identified, it might be radiolabelled to provide a scanning technique which could distinguish between an ocular melanoma and a similar lesion. This pilot, in vitro study was undertaken to determine if monoclonal antibody against cutaneous melanoma recognises any antigenic similarity in ocular melanomas. Three cutaneous melanoma MoAbs 225.28S, 376.96S, and 763-24T and a non-specific MoAb HMFG2 were studied. Cell impressions were obtained from fresh ocular malignant melanomas. Standard staining techniques with immunofluorescence were used. MoAb 225.28S, 376.96S, and 763.24T were positive in melanomas with a dominant epithelioid cell type and in those with a dominant spindle cell type. It is concluded that MoAb 225.28S, 376.96S, and 763.24T may be suitable for imaging ocular melanomas after labelling with 123I, 111In, or 99mTc. [ABSTRACT FROM PUBLISHER]

This study documents for the first time light and electron microscopical changes in the retinal pigment epithelium (RPE) following treatment with high dose desferrioxamine for systemic iron overload. The changes include loss of microvilli from the apical surface, patchy depigmentation, vacuolation of the cytoplasm, swelling and calcification of mitochondria, and disorganisation of the plasma membrane. In addition, Bruch's membrane overlying degenerate RPE cells appeared abnormally thickened owing to the accumulation of large amounts of mature elastic fibres, pre-elastic oxytalan, and long spacing collagen. The specificity of these changes and the mechanism of toxicity are discussed. [ABSTRACT FROM PUBLISHER]

Twelve out of a series of 630 children with retinoblastoma, treated in the ocular oncology units at St Bartholomew's and Moorfields Eye Hospitals during the past 30 years, have developed ectopic intracranial retinoblastoma. The ectopic tumour occurred in the pineal region in eight children and in the suprasellar region in four. Ten patients had bilateral retinoblastoma, one unilateral disease, and one child presented with an isolated suprasellar tumour but no evidence of retinal disease. The interval from the initial diagnosis of retinoblastoma to the development of ectopic intracranial disease ranged from 4 to 70 months, median 34 months. Methods of treatment for the ectopic tumour varied, but all 12 children died with a median survival of only 8 months following the diagnosis of ectopic retinoblastoma. Subsequent spread of tumour to other sites within the central nervous system proved to be the most frequent cause of death. Ectopic intracranial retinoblastoma is a potentially curable neoplasm, but it requires adequate therapy to the whole neuraxis as well as high dose equivalent radiotherapy to the primary tumour. [ABSTRACT FROM PUBLISHER]

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.

The majority of ocular melanomas occur in the uveal tract. Chemotherapy is generally ineffective and large tumours requiring enucleation have a greater than 50% mortality at 5 years. Monosomy for chromosome 3 is common in uveal melanoma and it is known that there is loss of responsiveness to transforming growth factor beta (TGFbeta) in melanoma cell lines. Since the gene for TGFbeta receptor II (TGFbetaR2) is located on chromosome 3p22, this study investigates the possibility that the TGFbeta pathway, and TGFbetaR2 in particular, might be involved in the pathogenesis of this rare eye tumour. To this end, the expression of molecules in the pathway has been examined by immunocytochemistry (TGFbeta, TGFbetaR2, SMAD2, SMAD3, SMAD4, and p27), backed up by a cell culture assay of TGFbeta-mediated growth suppression, RT-PCR for SMAD4, and loss of heterozygosity (LOH) on 3p22. There was LOH at 3p22 in 6/19 tumours and loss of TGFbetaR2 expression in 10/27 tumours. Immunohistochemistry for SMADs 2, 3, and 4 showed potential loss of signal transduction in 14/27 tumours. The results indicate abnormality of the TGFbeta pathway in 61% of tumours for which unequivocal results were obtained and suggest that abrogation of control of melanocyte growth by the TGFbeta pathway may be important in the formation of uveal melanoma., (Copyright 2000 John Wiley & Sons, Ltd.)

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 analyze the results of vitreous surgery for late retinal detachment (RD) after successful treatment of retinoblastoma., Methods: The records of all patients with retinoblastoma seen at a single ocular oncology service between 1982 and 1998 were reviewed to identify patients treated for late RD. Previous treatments, characteristics of the RD, surgical techniques used, and visual and anatomic results of the surgery were recorded., Results: Of more than 500 charts reviewed, four patients treated for late RD were identified. All four had received previous, whole-eye, external beam radiotherapy and subsequently required cataract surgery. Other previous treatments included radioactive plaque, cryotherapy, xenon photocoagulation, and chemotherapy. At presentation, some patients had shifting subretinal fluid. None had a tear identifiable preoperatively, but two patients had a definite small slit tear at a tumor edge identified at surgery. One patient had a primary scleral buckle that failed. All patients had vitreous surgery with silicone oil. Average postsurgical follow-up was 30 months. Preoperative visual acuity ranged from 20/80 to light perception and improved postoperatively in two patients. The retina remained completely attached in three patients., Conclusions: Despite shifting subretinal fluid and no identifiable tear, a rhegmatogenous RD should be considered if it occurs late in patients with otherwise stable, treated retinoblastoma. Tumor reactivation must be excluded carefully. Vitreous surgery can be used to repair the RD successfully and improve vision.

Purpose: Uveal melanoma undergoes haematogenous dissemination, particularly to the liver. It is routine practice to screen for metastatic disease. The purpose of this study was to evaluate such screening tests and to determine their value in detecting metastatic disease at presentation., Methods: In this study of a series of 245 patients with uveal melanoma of whom 55 (22%) died, the sensitivity, specificity, positive and negative predictive powers and likelihood ratio of the blood tests, chest radiographs and liver ultrasound investigations performed at diagnosis were determined., Results: All the screening investigations were found to have a low yield, but the most sensitive were those for gamma-glutamyl transpeptidase (gamma GT; sensitivity 21%) and alkaline phosphatase (sensitivity 25%), with gamma GT being more specific (specificity 92%). No blood test had a positive predictive power greater than 50%. The chest radiograph and liver ultrasonography were both 100% specific but had sensitivities of 2% and 14% respectively., Conclusions: Only the chest radiograph and liver ultrasonography had positive predictive powers greater than 50% and these tests had very poor sensitivity. We conclude that there is no good test available for screening for metastatic uveal melanoma.

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.

Purpose: To evaluate the efficacy of topical mitomycin C in treating conjunctival and corneal epithelial dysplasia and neoplasia., Methods: Seven eyes of seven patients with conjunctival and corneal epithelial dysplasia and neoplasia were treated with one drop of topical mitomycin C 0.04% four times a day for 7 days in alternate weeks. The patients' charts were reviewed retrospectively. Patients with either multiple recurrences or extensive ocular surface involvement were treated. In all eyes, the diagnosis of epithelial dysplasia or neoplasia was confirmed by histopathology before the onset of therapy. Patients were examined at least every 14 days during treatment and examined at intervals after completion of treatment., Results: With topical mitomycin C, six eyes of seven patients had complete clinical regression of their conjunctival and corneal epithelial dysplasia and neoplasia. One eye of one patient had partial clinical regression of conjunctival and corneal epithelial dysplasia. Follow-up after completion of topical mitomycin C therapy and excision of residual disease ranged from 2 to 16 months (mean, 9 months; SD, 4.3 months) and was without clinical sign of recurrence. Topical mitomycin C therapy was associated with transitory ocular discomfort, conjunctival injection, tearing, photophobia, and punctate epithelial keratopathy., Conclusion: In this small series of eyes, topical mitomycin C was effective as a treatment for conjunctival and corneal epithelial dysplasia and neoplasia.

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.

Objective: To determine the visual anatomical results and survival after combined chemotherapy and whole eye radiotherapy for patients with bilateral Reese-Ellsworth group V retinoblastoma., Setting: A national referral center for retinoblastoma., Patients: Fourteen patients with bilateral Reese-Ellsworth group V retinoblastoma seen between March 1, 1989, and April 30, 1995, were treated., Interventions: Patients were treated with chemotherapy (using carboplatin, etoposide, and vincristine) and whole eye radiotherapy (40-44 Gy in 20-22 equivalent fractions). A medical record review was performed to determine outcomes., Main Outcome Measures: Survival, eye preservation rate, and visual acuity., Results: Two patients died, 1 from a primitive neuroectodermal tumor and the other from the meningeal spread of retinoblastoma. Four eyes were enucleated primarily because of severe disease at presentation. Of the remaining 20 eyes, 6 required enucleation. The disease recurred in 4 of those patients, and neovascular glaucoma developed in 2 patients. Of the 12 surviving children, 5 have a visual acuity better than l/60 in at least 1 eye., Conclusion: Although most of the treated group V eyes could be salvaged with chemotherapy plus radiotherapy, the resultant visual acuity was often poor.