Detecting Progression of Treated Choroidal Melanomas: Is Ultrasonography Necessary?

Prompt detection and treatment of local treatment failure after radiotherapy for choroidal melanoma optimises any opportunities for conserving vision and the eye, possibly reducing an increased risk of metastatic disease. Long-term surveillance is therefore required but is hampered by the perceived need to perform ultrasonography, which may not be available at a patient’s local hospital. The aim of this study was to determine whether local treatment failure can reliably be detected with colour fundus photography alone, and, if so, in which patients. Patients were included in the study if diagnosed with local treatment failure between April 2016 and February 2021 after eye-conserving therapy for choroidal melanoma. Wide-field colour and fundal autofluorescence (FAF) images, optical coherence tomography (OCT), and ultrasonography (US) were analysed by two of the authors (GN and UH). The cohort included 87 patients with local treatment failure. In 75 patients with clear media, tumour progression was detected by colour photography alone in 74 (98.7%) patients. Sensitivity was not increased by the addition of either OCT or AF. One patient with clear media developed extraocular extension detected with US without visible change in the intraocular part of the tumour. In the other 12 patients, US was required because of opaque media and a consequently poor fundal view. Local treatment failure after radiotherapy for choroidal melanoma is detected in 98.7% of cases with colour photography when the media are clear. Ultrasonography is useful when photography is prevented by opaque media or tumours having locations in the far periphery

Decreased endothelin receptor B expression in large primary uveal melanomas is associated with early clinical metastasis and short survival

The most devastating aspect of cancer is the metastasis of tumour cells to organs distant from the original tumour site. The major problem facing oncologists treating uveal melanoma, the most common cancer of the eye, is metastatic disease. To lower mortality, it is necessary to increase our understanding of the molecular genetic alterations involved in this process. Using suppression subtractive hybridisation, we have analysed differential gene expression between four primary tumours from patients who have developed clinical metastasis and four primary tumours from patients with no evidence of metastasis to date. We have identified endothelin receptor type B as differentially expressed between these tumours and confirmed this observation using comparative multiplex RT–PCR. In a further 33 tumours, reduced endothelin receptor type B expression correlated with death from metastatic disease. Reduced expression also correlated with other known prognostic indicators, including the presence of epithelioid cells, chromosome 3 allelic imbalance and chromosome 8q allelic imbalance. Endothelin receptor type B expression was also reduced in four out of four primary small cell lung carcinomas compared to normal bronchial epithelium. We also show that the observed down-regulation of endothelin receptor type B in uveal melanoma was not due to gene deletion. Our findings suggest a role for endothelin receptor type B in the metastasis of uveal melanoma and, potentially, in the metastasis of other neural crest tumours

Progress in the management of patients with uveal melanoma. The 2012 Ashton Lecture

Uveal melanomas are diverse in their clinical features and behaviour. More than 90% involve the choroid, the remainder being confined to the ciliary body and iris. Most patients experience visual loss and more than a third require enucleation, in some cases because of pain. Diagnosis is based on slit-lamp biomicroscopy and/or ophthalmoscopy, with ultrasonography, autofluorescence photography, and/or biopsy in selected cases. Conservation of the eye with useful vision has improved with advances in brachytherapy, proton beam radiotherapy, endoresection, exoresection, transpupillary thermotherapy, and photodynamic therapy. Despite ocular treatment, almost 50% of patients develop metastatic disease, which occurs almost exclusively in patients whose tumour shows chromosome 3 loss and/or class 2 gene expression profile. When the tumour shows such lethal genetic changes, the survival time depends on the anatomical stage and the histological grade of malignancy. Prognostication has improved as a result of progress in multivariate analysis including all the major risk factors. Screening for metastases is more sensitive as a consequence of advances in liver scanning with magnetic resonance imaging and other methods. More patients with metastases are living longer, benefiting from therapies such as: partial hepatectomy; radiofrequency ablation; ipilumumab immunotherapy; selective internal radiotherapy; intra-hepatic chemotherapy, possibly with isolated liver perfusion; and systemic chemotherapy. There is scope for improvement in the detection of uveal melanoma so as to maximise any opportunities for conserving the eye and vision, as well as preventing metastatic spread. Patient management has been enhanced by the formation of multidisciplinary teams in specialised ocular oncology centres

Conjunctival melanoma and melanocytic intra-epithelial neoplasia

The rarity of conjunctival melanoma has impeded progress in the management of patients with this cancer; however, much progress has occurred in recent years. Primary acquired melanosis is now differentiated histologically into hypermelanosis and conjunctival melanocytic intra-epithelial neoplasia, for which an objective reproducible scoring system has been developed. Mapping and clinical staging of conjunctival disease has improved. Adjunctive radiotherapy and topical chemotherapy have made tumour control more successful, with reduced morbidity. Genetic analyses have identified BRAF and other mutations, which may predict responsiveness to new chemotherapeutic agents, for example Vemurafenib, should metastatic disease develop. Multicentre studies are under way to enhance survival prediction by integrating clinical stage of disease with histological grade of malignancy and genetic abnormalities. Such improved prognostication would not only be more relevant to individual patients, but would also provide greater opportunities for basic science research

Tebentafusp: T cell redirection for the treatment of metastatic uveal melanoma

Metastatic disease from uveal melanoma occurs in almost 50% of patients suffering from this ocular tumour, with median survival from development of symptoms being around 1 year. In contrast to cutaneous melanoma, kinase inhibitors and immune checkpoint inhibitors are usually ineffective in patients with metastatic uveal melanoma. Tebentafusp is a novel form of immunotherapy based on the immune-mobilising monoclonal T cell receptor against cancer (ImmTAC) platform, which comprises a soluble T cell receptor that is fused to an anti-CD3 single-chain variable fragment. The T cell receptor domain of tebentafusp targets cells present a human leukocyte antigen-A*02:01 complexed with a peptide derived from the melanoma-associated antigen gp100, which is expressed strongly by melanoma cells, weakly by normal melanocytes and minimally by other tissues. The anti-CD3 domain recruits CD3+ T cells (and, indirectly, other immune cells), redirecting these to the melanoma cells. The most common adverse events with tebentafusp are manageable and usually transient. Early survival data in patients with metastatic uveal melanoma are promising when considered alongside historical data. Based on these encouraging results, a randomised study comparing tebentafusp to investigator’s choice of therapy in metastatic uveal melanoma is ongoing

Tebentafusp: T cell redirection for the treatment of metastatic uveal melanoma

Metastatic disease from uveal melanoma occurs in almost 50% of patients suffering from this ocular tumour, with median survival from development of symptoms being around 1 year. In contrast to cutaneous melanoma, kinase inhibitors and immune checkpoint inhibitors are usually ineffective in patients with metastatic uveal melanoma. Tebentafusp is a novel form of immunotherapy based on the immune-mobilising monoclonal T cell receptor against cancer (ImmTAC) platform, which comprises a soluble T cell receptor that is fused to an anti-CD3 single-chain variable fragment. The T cell receptor domain of tebentafusp targets cells present a human leukocyte antigen-A*02:01 complexed with a peptide derived from the melanoma-associated antigen gp100, which is expressed strongly by melanoma cells, weakly by normal melanocytes and minimally by other tissues. The anti-CD3 domain recruits CD3+ T cells (and, indirectly, other immune cells), redirecting these to the melanoma cells. The most common adverse events with tebentafusp are manageable and usually transient. Early survival data in patients with metastatic uveal melanoma are promising when considered alongside historical data. Based on these encouraging results, a randomised study comparing tebentafusp to investigator’s choice of therapy in metastatic uveal melanoma is ongoing

Retinal detachment after trans-scleral local resection of choroidal melanoma

Rhegmatogenous retinal detachment is one of the main complications of trans-scleral local resection of choroidal melanoma. Purpose. To determine the incidence and outcome of rhegmatogenous retinal detachment after trans-scleral local resection for choroidal melanoma. Methods. 67 patients with choroidal melanoma treated consecutively by choroidectomy (50) or cyclochoroidectomy (17) between 1993 and 1995 by a single surgeon (B.D.) were analysed prospectively. Results. Mean patient age was 48.5 yrs, tumour diameter was 13.1mm; tumour thickness was 8.4mm. 36% of tumours extended less than two disc diameters from disc or fovea and 52% extended anterior to ora serrata. Nine patients developed retinal detachment by the close of the study, with Kaplan Meier estimation showing a 14% actuarial rate at 93 days. Although Cox multivariate analysis did not identify any risk factors, the clinical impression is that the resections were technically difficult, because of optic disc involvement (1), extraocular extension (1), longstanding total exudative retinal detachment (1) and pathological tumour diameter more than 16mm (4). Vitreo-retinal surgery achieved anatomical success in 6/9 cases and by the close of the study the eye was retained in 7/9 cases. Conclusion. With appropriate surgical expertise, rhegmatogenous retinal detachment is an uncommon complication after trans-scleral local resection of choroidal melanoma, and can usually be treated successfully.link_to_subscribed_fulltex

Detection of hypermethylation of tumour suppressor genes in ocular adnexal lymphoma using multiplex ligation-dependent probe amplification

Conference Theme: Emerging Therapies for an Aging Populatio

Detection of hypermethylation of tumor suppressor genes in ocular adnexal lymphoma using multiplex ligation-dependent probe amplification

Purpose: Ocular adnexal lymphomas (OAL) occur in the orbit, lacrimal drainage system, conjunctiva and eyelid. They comprise 8% of all extranodal non-Hodgkin lymphomas (NHL) with the extranodal marginal zone B-cell lymphoma (EMZL) being the commonest, accounting for 2/3 of them. Hypermethylation in CpG sites in promoter regions is an epigenetic change that could lead to silencing of a gene. Hypermethylation in tumor suppressor genes (TSGs) occurs in various tumors, including NHL. We examined the methylation status of multiple TSGs in OAL. Methods: Formalin-fixed paraffin-embedded (FFPE) OAL, including both EMZL and non-EMZL OALs, were examined. The majority of OAL were located in the conjunctiva. DNA was extracted and purified from FFPE, and only those with DNA of sufficient quantity and quality were selected for subsequent analysis using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). 33 EMZL and 27 non-EMZL were examined using two MS-MLPA kits, ME001B and ME002, in which methylation status of CpG sites in a total of 35 candidate TSGs were analyzed. Reactive lymphoid hyperplasia cases were used as controls. MLPA PCR products are separated by capillary electrophoresis, and sequencing data were statistically analyzed with specifically designed Excel spreadsheets (NGRL, Manchester, UK). CpG hypermethylation in patient samples was determined when statistical significance of standard error > 0.1 as compared to the reference samples. Results: Specific loci in eight TSGs including CDH13, WT1, MSH6, IGSF4, DAPK1, ESR1, p14-ARF and RAR-beta showed hypermethylation in at least 65% of the 33 EMZL OALs, as well as in majority of the 27 non-EMZL OALs. However, hypermethylation status varied among different subtypes of non-EMZLs, which includes follicular, diffuse-large-B-cell and mantle cell lymphomas. Validation of this data is currently in progress using pyrosequencing. Conclusions: Many OALs demonstrated hypermethylation. Correlation of methylation analysis data with clinical presentation and follow-up may reveal epigenetic markers of prognostic value in these tumors