Recent approaches for the treatment of uveal melanoma: Opportunities and challenges.

Uveal melanoma (UM) is the most prevalent primary intraocular cancer in adult population. Primary methods for treatment of UM involves surgery Proton Beam Therapy (PBT), Plaque Brachytherapy, phototherapy, and Charged Particle Radiation Therapy (CPT). It has been found that approximately 50 % of patients diagnosed with UM ultimately experience development of metastatic disease. Furthermore, it has been identified that majority of the patient experience metastasis in liver with a prevalence of 95 %. Management of metastatic UM (MUM) involves various therapeutic modalities, including systemic chemotherapy, molecular targeted therapy, immunotherapy and liver directed interventions. We outline gene mutation in UM and addresses various treatment modalities, including molecular targeted therapy, miRNA-based therapy, and immunotherapy. Additionally, inclusion of ongoing clinical trials aimed at developing novel therapeutic options for management of UM are also mentioned.

Surgical Approach in Intraocular Tumors

Surgery in intraocular tumors is done for excision/biopsy and the management of complications secondary to the treatment of these tumors. Excision/biopsy of intraocular tumors can be done via fine-needle aspiration biopsy (FNAB), transretinal biopsy (TRB), partial lamellar sclerouvectomy (PLSU), and endoresection. FNAB, TRB, and PLSU can be used in tumors that cannot be diagnosed by clinical examination and other ancillary testing methods. PLSU is employed in tumors involving the iridociliary region and choroid anterior to the equator. Excisional PLSU is performed for iridociliary and ciliary body tumors with less than 3 clock hours of iris and ciliary body involvement and choroidal tumors with a base diameter less than 15 mm. However, for biopsy, PLSU can be employed with any size tumor. Endoresection is a procedure whereby the intraocular tumor is excised using vitrectomy techniques. The rationale for performing endoresection is based on the fact that irradiated uveal melanomas may cause complications such as exudation, neovascular glaucoma, and intraocular pigment and tumor dissemination (toxic tumor syndrome), and removing the dead tumor tissue may contribute to better visual outcome. Endoresection is recommended 1-2 weeks after external radiotherapy. Pars plana vitrectomy is also used in the management of complications including vitreous hemorrhage, retinal detachment, and epiretinal membrane that can occur after treatment of posterior segment tumors using radiotherapy and transpupillary thermotherapy. It is important to make sure the intraocular tumor has been eradicated before embarking on such treatment.

Clinical Characteristics of UM and Association of Metastasis of Uveal Melanoma with Congenital Oculocutaneous Melanosis in Asian Patients: Analysis of 1151 Consecutive Eyes.

PURPOSE: To analyze the clinical characteristics of uveal melanoma (UM) and evaluate the relationship of congenital oculocutaneous melanosis (OCM) to the prognosis of Asian patients with UM. DESIGN: Retrospective cohort study. PARTICIPANTS: We included a total of 1151 Asian patients with UM who were managed at the Beijing Tongren Hospital from June 26, 2005, to July 27, 2020. METHODS: I-125 plaque brachytherapy, local resection, thermotherapy, or enucleation. MAIN OUTCOME MEASURES: Melanoma-related metastasis and death. RESULTS: Of 1151 Asian patients with UM, congenital OCM was present in 23 (0.20%). The melanocytosis involved the conjunctiva (78%), sclera (74%), eyelid (70%), face (26%), forehead (2.2%), iris (0.87%), choroid (0.87%), and auricle (0.4%). Univariate analysis of Cox proportional hazards regression model showed that age, tumor thickness, largest tumor basal diameter, and ciliary body involvement were the risk factors for the poor prognosis of Asian patients with UM. By multivariable analysis, the only factor predictive of melanoma-related metastasis and death was the largest tumor basal diameter (hazard ratio [HR], 1.21 [1.11-1.33], P < .001; 1.17 [1.01-1.35], P = 0.033). Probability-of-censoring weighted (IPW) estimation was used to mitigate selection bias due to loss to follow-up. Probability-of-censoring weighted estimation revealed the largest tumor basal diameter and ciliary body involvement were associated with metastasis (HR, 1.29 [1.15-1.45], P < 0.001; HR, 2.64 [1.01-6.90], P < 0.048). During the median follow-up period of 53 (33-67) months, 2 patients with OCM (8.7%) developed melanoma-related metastasis. By using nested case-control design and matched with the factors of age, largest tumor basal diameter, tumor thickness, and ciliary body involvement, Kaplan-Meier survival analysis showed that UM combined with OCM did not increase the risk of melanoma-related metastasis and death (P = 0.68, log-rank test). CONCLUSIONS: The prominent risk for metastasis from UM was the largest tumor basal diameter in Asian patients. Estimation of IPW revealed that the largest tumor basal diameter and ciliary body involvement were the risk factors for UM metastasis. Patients with UM combined with OCM had a similar risk for metastasis compared with those with no OCM.

Uveal melanoma.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. UMs are usually initiated by a mutation in GNAQ or GNA11, unlike cutaneous melanomas, which usually harbour a BRAF or NRAS mutation. The annual incidence in Europe and the USA is ~6 per million population per year. Risk factors include fair skin, light-coloured eyes, congenital ocular melanocytosis, ocular melanocytoma and the BAP1-tumour predisposition syndrome. Ocular treatment aims at preserving the eye and useful vision and, if possible, preventing metastases. Enucleation has largely been superseded by various forms of radiotherapy, phototherapy and local tumour resection, often administered in combination. Ocular outcomes are best with small tumours not extending close to the optic disc and/or fovea. Almost 50% of patients develop metastatic disease, which usually involves the liver, and is usually fatal within 1 year. Although UM metastases are less responsive than cutaneous melanoma to chemotherapy or immune checkpoint inhibitors, encouraging results have been reported with partial hepatectomy for solitary metastases, with percutaneous hepatic perfusion with melphalan or with tebentafusp. Better insight into tumour immunology and metabolism may lead to new treatments.

Nomogram for visual acuity outcome after iodine-125 plaque radiotherapy and prophylactic intravitreal bevacizumab for uveal melanoma in 1131 patients.

AIMS: To develop a nomogram for prediction of visual acuity outcome following plaque radiotherapy for uveal melanoma. METHODS: Retrospective review of uveal melanoma treated with plaque radiotherapy and prophylactic intravitreal bevacizumab injections at 4-month intervals for 2 years duration. Two nomograms for poor visual acuity outcome (Snellen <20/200) were developed based on (1) Clinical risk factors. (2) Or clinical and treatment risk factors. RESULTS: There were 1131 included cases. The most important clinical risk factors (points for nomogram) for poor visual acuity outcome included subretinal fluid involving four quadrants (100), tumour thickness >4 mm (69), presenting visual acuity ≤20/30 (65), non-Caucasian race (58), tumour shape mushroom, bilobed, or multilobulated (57), and insulin-dependent diabetes (54). Risk of poor visual acuity at 2 years and 4 years increased from 11% and 24% with 40 points to 97% and >99% with 304 points. A second analysis was performed using both clinical and treatment risk factors. The most important factors included presenting visual acuity ≤20/30 (100), tumour largest basal diameter >11 mm (80), radiation dose rate to tumour base ≥164 cGy/hour (78), tumour thickness >4 mm (76), insulin-dependent diabetes (75) and abnormal foveolar status by optical coherence tomography at presentation (72). Risk of poor visual acuity at 2 years and 4 years increased from 6% and 14% with 56 points to 88% and 99% with 496 points. CONCLUSIONS: A nomogram using clinical or treatment risk factors can predict visual acuity outcome following plaque radiotherapy and prophylactic intravitreal bevacizumab for uveal melanoma and is available online at https://fighteyecancer.com/nomograms/.

Clinical spectrum, treatment and outcomes of uveal melanoma in a tertiary centre.

INTRODUCTION: We aimed to describe the clinical characteristics, diagnostic challenges, treatment patterns and outcomes of uveal melanoma (UM) in a tertiary care centre. METHODS: This is a retrospective case series of 11 consecutive patients with UM who were managed in a tertiary referral centre between 2002 and 2017. Epidemiological, clinical, pathological and radiological characteristics were reviewed. Classification of choroidal melanoma as small, medium or large was based on the criteria established by the Collaborative Ocular Melanoma Study. RESULTS: Mean age at presentation was 42.9 (range 27‒67) years. In 7 (64%) patients, a definitive diagnosis of UM was made after a mean follow-up period of 6.4 (range 1‒17) months. There were one, six and four patients with small-, medium- and large-sized choroidal melanomas, respectively. Treatment was enucleation in 5 (45.5%) patients, plaque brachytherapy in 4 (36.4%) patients, transpupillary thermotherapy in 1 (9.1%) patient, and observation in 1 (9.1%) patient. Median follow-up was 29 months. Metastatic disease developed in 5 (45.5%) patients at the mean age of 46.6 (range 38‒56) years, with median overall survival of 20 months. Genetic mutations in three patients were monosomy 3 (n = 2), and gain of 3q and 8q (n = 1). CONCLUSION: Our study supports the finding that UM in Chinese and Asian Indian patients presents at a younger age than in Caucasians. Although it is rare, ophthalmologists should remain mindful of this life-threatening disease. We propose establishing a national and regional registry for ocular tumours with genetic information to characterise the disease spectrum in Southeast Asia.

Local Failure After Episcleral Brachytherapy for Posterior Uveal Melanoma: Patterns, Risk Factors, and Management.

PURPOSE: To evaluate the patterns, the risk factors, and the management of recurrence following brachytherapy in patients with posterior uveal melanoma, given that an understanding of the recurrence patterns can improve early recognition and management of local treatment failure in such patients. DESIGN: Retrospective cohort study. METHODS: Setting: Multispecialty tertiary care center. PARTICIPANTS: A total of 375 eyes treated with episcleral brachytherapy for posterior uveal melanoma from January 2004 to December 2014. Exclusion criteria included inadequate follow-up (<1 year) and previous radiation therapy. Main Outcomes and Measures: Local control rate and time to recurrence were the primary endpoints. Kaplan-Meier estimation and Cox proportional hazards models were conducted to identify risk factors for recurrence. RESULTS: Twenty-one patients (5.6%) experienced recurrence (follow-up range 12-156 months; median 47 months). The median time to recurrence was 18 months (range 4-156 months). Five-year estimated local recurrence rate was 6.6%. The majority (90.5%) of the recurrences occurred within the first 5 years. The predominant site of recurrence was at the tumor margin (12 patients, 57.1%). Univariate analysis identified 3 statistically significant recurrence risk factors: advanced age, largest basal diameter, and the use of adjuvant transpupillary thermotherapy (TTT). Recurrent tumors were managed by repeat brachytherapy, TTT, or enucleation. CONCLUSIONS: Local recurrences following brachytherapy are uncommon 5 years after episcleral brachytherapy. Follow-up intervals can be adjusted to reflect time to recurrence. Most of the eyes with recurrent tumor can be salvaged by conservative methods.

Episcleral brachytherapy of uveal melanoma: role of intraoperative echographic confirmation.

PURPOSE: To compare the rates of tumour recurrence following episcleral brachytherapy for uveal melanoma before and after implementation of intraoperative echographic confirmation of plaque placement. MATERIALS AND METHODS: All patients with primary single ciliary body or choroidal melanoma treated with iodine-125 or ruthenium-106 plaque brachytherapy between 1 January 2004 and 30 December 2013 were included. Exclusion criteria were patients with previous radiation treatment and patients who received adjuvant transpupillary thermotherapy. Since February 2007, intraoperative echographic confirmation was initiated to ensure that the plaque was centred on the tumour base and/or all tumour margins were covered by the plaque. RESULTS: 252 patients were included in the study. Local tumour control after primary brachytherapy was achieved in 242/252 (96.0%). Of the 10 patients with treatment failure, 8 patients had local recurrence and 2 patients had failure to response. With the incorporation of the intraoperative echographic confirmation for plaque positioning the treatment failure rate decreased from 9.3% (5/54 patients) to 1.5% (3/198 patients). Continuous and categorical univariable predictors of recurrence were analysed for statistical significance. The only statistically significant variable was the intraoperative echographic confirmation (HR: 0.16; p=0.032) for recurrence within the first 24 months. CONCLUSIONS: Intraoperative echographic confirmation of plaque placement during episcleral brachytherapy for choroidal melanoma reduces the risk of early local recurrence.

Management of uveal tract melanoma: A comprehensive review.

Uveal tract melanoma is the most common primary intraocular malignancy in adults, accounting for about 5-10% of all the melanomas. Since there are no lymphatic vessels in the eye, uveal melanoma can only spread hematogenously leading to liver metastasis. A wide variety of treatment modalities are available for its management, leading to dilemma in selecting the appropriate therapy. This article reviews the diagnostic and therapeutic modalities available and thus, can help to individualize the treatment plan for each patient.

Secondary Enucleations for Uveal Melanoma: A 7-Year Retrospective Analysis.

PURPOSE: To describe the indications for secondary enucleations in uveal melanoma and analyze associations and outcomes. DESIGN: Retrospective interventional case series. METHODS: Data of patients who underwent secondary enucleation for uveal melanoma in the London Ocular Oncology Service, between 2008 and 2014, were retrieved from medical records analyzed. Cox regression model was performed to analyze associations with secondary enucleation and metastases and Kaplan-Meier estimates to assess the probability of metastatic spread and death. RESULTS: During the study period 515 enucleations were performed for uveal melanoma, 99 (19%) of which were secondary enucleations. Tumors were located at the ciliary body in 21 eyes (21%), juxtapapillary in 31 (31%), and choroid elsewhere in 47 (48%). Primary treatment included Ru(106) plaque radiotherapy, proton beam radiotherapy, and transpupillary thermotherapy in 85, 11, and 3 eyes, respectively. Indications for secondary enucleation were tumor recurrence in 60 (61%), neovascular glaucoma in 21 (21%), and tumor nonresponse in 18 eyes (18%). Twenty patients (20%) were diagnosed with metastasis and 12 out of 20 died of metastatic spread. On multivariate analysis, juxtapapillary tumor location was found to associate with tumor nonresponse (P = .004) and nonresponding patients with metastatic spread (P = .04). CONCLUSIONS: Indications for secondary enucleations for uveal melanoma were tumor recurrence, neovascular glaucoma, and tumor nonresponse. This review identified a possible high-risk group (nonresponse), which proved radioresistant to treatment. These tumors were more frequently found in the juxtapapillary location and were associated with metastatic spread.

Local Recurrence After Primary Proton Beam Therapy in Uveal Melanoma: Risk Factors, Retreatment Approaches, and Outcome.

PURPOSE: To evaluate the risk factors, recurrence rates, retreatments, and long-term patient outcomes following proton beam therapy for uveal melanoma. DESIGN: Retrospective interventional case series. METHODS: All patients treated with primary proton beam therapy for uveal melanoma at the oncology service at Charité-Berlin and Helmholtz-Zentrum-Berlin between May 1998 and December 2008 were reviewed for local recurrence. Of 982 patients, 982 eyes matched the inclusion criteria. The data were obtained from electronic health records, operative reports, discharge letters, and radiation planning. Comparisons of fundus photographs and ultrasound measurements were performed to assess the growth pattern of the tumor and to determine the success of retreatment, in the case that a globe-retaining therapy was undertaken. RESULTS: Of 982 patients, 35 patients (3.6%) developed local recurrence. The median follow-up was 60.7 months (6.0-170.4 months). Local control rate was 96.4% and the overall eye retention rate was 95.0% in this cohort. Local recurrence was correlated with a higher risk for metastasis and reduced survival. Largest tumor diameter was identified as the sole statistically significant risk factor for local recurrence (P = .00001). All globe-retaining retreatment approaches for local recurrence, including proton beam therapy, brachytherapy, and transpupillary thermotherapy used for recurrences at the tumor margins, showed good local tumor control and similar metastasis-free survivals. CONCLUSIONS: This study showed that each globe-retaining retreatment approach can result in satisfying local tumor control. In case of early detection of local recurrence, preservation of the globe can be warranted. Therefore, regularly performed follow-ups should be ensured.

Ruthenium-106 plaque brachytherapy for uveal melanoma.

BACKGROUND: To report on local tumour control, eye preservation and visual outcome after ruthenium-106 brachytherapy for uveal melanoma. METHODS: Medical records of 143 eyes with uveal melanoma, treated by ruthenium-106 brachytherapy between 1997 and 2012 at one single centre, were included. Primary outcome measures were local tumour control, eye preservation and visual outcome. The influence of patient, tumour and treatment parameters on outcome was analysed by time to event analysis and competing risk regression. RESULTS: The median overall follow-up was 37.9 months. Tumour control: recurrent tumour growth was observed in 17 patients. The estimated local tumour recurrence rate at 12, 24 and 48 months after irradiation was 3%, 8.4% and 14.7%, respectively. The only significant risk factors for tumour recurrence were age (p=0.046) and reduced initial visual acuity (VA, p=0.045). No significant difference could be shown for tumour size or tumour category (T1-T2 vs T3-T4), and for any other tumour or treatment parameters (including combined transpupillary thermo-therapy (TTT)).Eye preservation: The likelihood of keeping the eye 12, 24 and 48 months after irradiation was 97.7%, 94.7% and 91.8%, respectively. Most significant risk factors for secondary enucleation were initial VA (p<0.001), tumour height (p=0.002) and tumour category (p=0.015). VISION: The chances of keeping VA of 20/200 or better at 1, 2 and 5 years after treatment were 86.4%, 80.8% and 61.7%, respectively. Patients receiving sandwich-TTT showed significantly worse visual outcomes. CONCLUSIONS: Ruthenium-106 brachytherapy appears to be a useful treatment regarding tumour control, eye preservation and visual function. Adjunct sandwich therapy resulted in worse visual outcome.

Using risk factors for detection and prognostication of uveal melanoma.

The early detection of malignancy, particularly uveal melanoma, is crucial in protecting visual acuity, salvaging the eye, and preventing metastasis. Risk factors for early detection of uveal melanoma have been clearly delineated in the literature and allow identification of melanoma when it is tiny and simulates a nevus. These factors include thickness >2 mm, presence of subretinal fluid (SRF), symptoms, the orange pigment, margin near optic disc, acoustic hollowness, surrounding halo, and absence of drusen. The importance of early detection is realized when one considers melanoma thickness, as each millimeter increase in melanoma thickness imparts 5% increased risk for metastatic disease. Newer imaging modalities like enhanced depth imaging optical coherence tomography and fundus autoflouroscence facilitate in detection of SRF and orange pigment. Additional molecular biomarkers and cytological features have been identified which can predict the clinical behavior of a small melanocytic lesion. Features that suggest a poor prognosis include higher blood levels of tyrosinase m-RNA, vascular endothelial growth factor, insulin-like growth factor; monosomy 3 and gains in chromosome 8. Management of uveal melanoma includes enucleation (for large), local eye wall resection, brachytherapy, charged particle irradiation, and thermotherapy (for small to medium tumors). Although the role of a good clinical evaluation cannot be underestimated, it is advisable to evaluate the various radiological, molecular, and cytological features, to enhance the accuracy of early diagnosis and improved prognosis.

Management of posterior uveal melanoma: past, present, and future: the 2014 Charles L. Schepens lecture.

PURPOSE: To review the management of ciliary body and choroidal melanoma (posterior uveal melanoma [PUM]) over the last century with an emphasis on changing concepts. DESIGN: Retrospective review. PARTICIPANTS: Review of personal experience over 40 years and pertinent literature on management of PUM. METHODS: Diagnosis and therapy for PUM. MAIN OUTCOME MEASURES: Patient survival. RESULTS: In the early 1900s, most patients presented with a large symptomatic melanoma that necessitated enucleation, and the systemic prognosis was poor. In the 1970s, controversy erupted regarding the role of enucleation for PUM. Some authorities advocated prompt enucleation, and others proposed that enucleation promoted metastasis, known as the "Zimmerman hypothesis." Others recommended observation, withholding treatment until tumor growth was documented. During the 1970s, there was a trend toward eye-saving procedures, including laser photocoagulation, surgical removal of tumor, and techniques of radiotherapy. Despite local treatment success, systemic prognosis remained guarded with approximately 40% mortality overall. However, there was convincing evidence that smaller tumors offered a significantly better prognosis. Currently, there is a movement toward earlier identification and treatment of small melanomas using clinical factors predictive of malignant potential, in keeping with similar philosophy regarding other cancers. Further understanding of melanoma cytogenetics and molecular pathways have helped to recognize patients at risk for metastasis. At-risk patients are offered systemic therapeutic trials to prevent metastasis. We anticipate that the future management of PUM will focus on detection of clinical and imaging clues for earliest diagnosis, prompt local tumor treatment, and systemic targeted therapies for microscopic metastasis or prevention of metastasis. Personalized evaluation of patient-specific melanoma molecular pathway signature could allow for therapeutic intervention at a site specific to the pathway abnormality that leads to the development of melanoma. CONCLUSIONS: Management of PUM has made major strides over the past century from the days of enucleation for massive, fatal tumor to early detection of smallest tumors with a more favorable prognosis. Current and future targeted specific tumor pathway interruption using systemic agents could improve survival.

Immunohistochemical characteristics of uveal melanoma assording to the age at diagnosis, histological type and extension of the tumor.

The purpose of this study was to investigate the relationship between MMP9 expression and tumour invasion in different structures of the eye. We also examined whether there was any correlation between the growth factors (TGFb and EGF), onco-suppressor proteins (p16 and p53) and Ki-67, and the tumour histological subtypes, atypia level and age at diagnosis. Tumour specimens were obtained from 42 primary uveal melanomas immediately after enucleation at The Helmholtz Moscow Research Institute of Eye Diseases. The patients were not treated with radio- or thermotherapy. During our systematic study, we exclusively employed 10%-formalin fixed, paraffin-wax-embedded tissue sections of UM for histological diagnosis and immunohistochemistry. According to our data the hyperexpression of MMP9 and EGFR correlates with a high proportion of spindle cells in a tumour (Kruskal-Wallis test p=0,1 for each). Moreover, we have demonstrated the association between the level of EGFR, TGFb and MMP9 expression and the initial invasion stage (Spearman's test p=0,1). In addition, we have revealed the significant correlation between TGFb hyperexpression and atypia level (Spearman's test p=0,059). Our data reflect that the diagnoses at an advanced age correlate with hyperexpression of p16 (Kruskal-Wallis test p=0,068). An interesting result is that p16 level reduced in inverse proportion to that of TGFb. On the basis of our data and previous studies, we reached the conclusion that after the lapse of time the level of p16 rises significantly in order to inhibit proliferating activity of melanocytes in the normally functioning pigmented layer. However, although the probability of UM diagnoses in elderly is increasing, we have no reliable data for the relationship with high atypia levels.

Salvage proton beam therapy in local recurrent uveal melanoma.

PURPOSE: To evaluate survival and ocular outcome in recurrent uveal melanoma treated with proton beam therapy as salvage therapy. DESIGN: Retrospective, interventional case series. METHODS: We evaluated 48 patients with local recurrence of uveal melanoma after primary treatment with brachytherapy, transpupillary thermotherapy, proton beam therapy, laser photocoagulation, CyberKnife radiation, or photodynamic therapy. All patients received proton beam therapy as a salvage therapy at the Helmholtz Zentrum Berlin between July 2000 and December 2010. Kaplan-Meier analysis was used to obtain survival rates. RESULTS: The Kaplan-Meier estimator for local tumor control was 92.1% at 10 years after secondary treatment with proton beam therapy. Local recurrence developed in 3 patients; 1 of them underwent enucleation. During follow-up, 20.8% of the patients died (16.7% of metastasis, 4.1% of other causes or not specified). The most frequent surgical interventions were phacoemulsification (20.8%) and pars plana vitrectomy (10.4%). The Kaplan-Meier estimators were 77.4% for survival and 70.1% for the absence of metastasis 10 years after the primary treatment. CONCLUSIONS: Proton beam therapy as a salvage treatment resulted in high local tumor control rates in recurrent uveal melanoma, especially if the primary therapy was transpupillary thermotherapy or plaque brachytherapy. Preservation of the globe was possible in most patients. Enucleations were indicated only in case of re-recurrences of uveal melanoma, but not because of secondary complications like intractable pain or secondary glaucoma. Retreatment was associated with vision deterioration, but loss of vision remained exceptional. Further larger prospective studies are needed to confirm the presented results of our retrospective analysis.

Clinical characteristics of 95 patients with ocular adnexal and uveal lymphoma: treatment outcomes in extranodal marginal zone subtype.

BACKGROUND: Lymphoma rarely presents in the ocular adnexa but is usually extranodal marginal zone (ENMZ) lymphoma when it does. Involved-field radiotherapy (IFRT) is the standard of care for unilateral disease, but the optimal management of more extensive disease is unclear. PATIENTS AND METHODS: We retrospectively evaluated the clinical characteristics and outcomes of 95 patients with ocular adnexal lymphoma (OAL) or uveal lymphoma treated or diagnosed at our institution. All patients identified were included in the risk factor analysis for progression-free survival (PFS). The initial treatment-related outcomes were assessed for ENMZ OAL only (n = 62). RESULTS: With a median follow-up of 32 months, significant risk factors for PFS after initial treatment were age (hazard ratio, 1.33; 95% confidence interval, 1.02-1.74), female gender (hazard ratio, 2.04; 95% confidence interval, 1.04-4.00), and a history of lymphoma (hazard ratio, 2.31; 95% confidence interval, 1.12-4.78). In ENMZ, IFRT was associated with improved PFS (median, 5.4 years; P < .001). Progression occurred in 7 of 39 (23%), with 6 of the 7 (86%) at systemic sites. Single-agent rituximab was typically used for bilateral ocular or systemic presentations of ENMZ OAL. Progression occurred in 7 of 11 (64%), with no progression at systemic sites. All progression events in those initially treated with rituximab occurred in the ocular adnexa. CONCLUSION: The results of the present study have confirmed IFRT as the standard for unilateral ENMZ OAL. Single-agent rituximab was an effective agent for bilateral ocular or systemic ENMZ OAL, particularly for systemic control, but ocular progression should be closely monitored. Combined modality therapy should be studied further in bilateral and systemic ENMZ OAL.

[Spectral domain optical coherence tomography for evaluation of transpupillary thermotherapy efficacy in early uveal melanoma].

Prognostic significant signs of early uveal melanoma were revealed in 51 patients before and 3 months after a single transpupillary thermotherapy session using spectral domain optical coherence tomography with enhanced depth imaging, that allows planning of appropriate eye-preserving treatment.

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.

Detection and time to treatment of uveal melanoma in the United Kingdom: an evaluation of 2,384 patients.

PURPOSE: To determine the mode of detection of uveal melanoma and time to treatment in the United Kingdom. DESIGN: Prospective cohort study. PARTICIPANTS: A total of 2384 patients diagnosed with uveal melanoma at the Liverpool Ocular Oncology Center between 1996 and early 2011. METHODS: A questionnaire was completed with every new patient, and the results were correlated with clinical features and treatment. MAIN OUTCOME MEASURES: Tumor detection, practitioner initiating referral, referral pathway, time to treatment, baseline clinical features, and primary ocular treatment. RESULTS: The referral process was initiated by an optometrist, family doctor, or ophthalmologist in 68.0%, 18.2%, and 13.8% of patients, respectively. On referral, 30.2% of patients were asymptomatic. Twenty-three percent of patients reported that their tumor was initially missed; these tended to have a more advanced tumor when they reached our center. The time from referral to treatment had a median of 49 days, exceeding 6 months in 19.8% of patients. This delay was longer in patients who reported that their tumor was missed (median, 92 vs. 40 days; Mann-Whitney, P<0.001). Ophthalmologists delayed the referral process by more than 6 months in 10.9% of patients. Primary enucleation was performed in 33.3% of patients and was more likely in those who reported that their tumor was missed (44.8% vs. 29.8%; chi-square, P<0.001). CONCLUSIONS: Many patients with uveal melanoma experience long delays in treatment because their tumor was missed or misdiagnosed. Such patients tend to have a more advanced tumor by the time they reach an oncology center and are more likely to require enucleation.