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Ocular Melanoma

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Eye Cancers

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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Su FF, Chen JL
Expression and clinical significance of p16 and Ki-67 in malignant melanoma of the conjunctiva.
J Biol Regul Homeost Agents. 2019 May-Jun; 33(3):821-825 [PubMed] Related Publications

Rossi E, Pagliara MM, Orteschi D, et al.
Pembrolizumab as first-line treatment for metastatic uveal melanoma.
Cancer Immunol Immunother. 2019; 68(7):1179-1185 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: No standard treatment has been defined for metastatic uveal melanoma (mUM). Although clinical trials testing Nivolumab/Pembrolizumab for cutaneous melanoma did not include mUM, anti PD-1 agents are commonly used for this disease.
PATIENTS AND METHODS: In this prospective observational cohort single arm study, we investigated efficacy and safety of Pembrolizumab as first-line therapy for mUM. The efficacy was evaluated in terms of progression-free survival (PFS), response rate and overall survival (OS). Toxicity was also assessed.
RESULTS: Seventeen patients were enrolled. A median of 8 cycles were administered (range 2-28). Two patients achieved partial response (11.7%), 6 a disease stabilization (35.3%), whereas 9 (53%) had a progression. No complete response was observed. PFS of the overall population was 3.8 months. PFS was 9.7 months for patients with an interval higher than 5 years from diagnosis of primary tumor to metastatic disease and 2.6 months for patients with an interval lower than 5 years [p = 0.039, HR 0.2865 (95% CI 0.0869-0.9443)]. Median OS was not reached. The two responding patients were still on treatment with Pembrolizumab at the time of data analysis. Survival was 12.8 months for patients with clinical benefit, while OS for progressive patients was 3.1 months. PD-L1 expression and genomic abnormalities predictive of relapse after diagnosis of primary tumor were not associated with PFS. Toxicity was mild, without grade 3-4 side effects.
CONCLUSIONS: The efficacy of Pembrolizumab does not seem particularly different when compared to other agents for mUM, but responding patients had a remarkable disease control.

Artzner C, Mossakowski O, Hefferman G, et al.
Chemosaturation with percutaneous hepatic perfusion of melphalan for liver-dominant metastatic uveal melanoma: a single center experience.
Cancer Imaging. 2019; 19(1):31 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: To investigate the outcome and safety data of chemosaturation with percutaneous hepatic perfusion (CS-PHP) of melphalan in patients with liver-dominant metastatic uveal melanoma.
MATERIAL AND METHODS: This is a HIPAA compliant, IRB approved, retrospective study. A total of 28 CS-PHPs were performed in 16 individual patients (six men and ten women, median age 63.1 years [range 49.1 to 78.7 years], one to six CS-PHP procedures per patient) for treatment of liver-dominant metastatic uveal melanoma between June, 2015 and December, 2018. All patients received cross-sectional imaging at baseline and during follow-up. CS-PHP was performed with the Hepatic CHEMOSAT® Delivery System (Delcath Systems, Inc., NY, USA) facilitating extracorporeal filtration of hepatic blood for melphalan removal. Ideal body weight-adjusted melphalan doses were administered into the hepatic arteries. Serious adverse events (SAE), progression-free survival based on response criteria in solid tumors, and overall survival were noted. Survival data were analyzed using Kaplan-Meier estimates.
RESULTS: Partial response after first CS-PHP was observed in nine patients (60%), stable disease in five patients (33%) and progressive disease in one patient (7%). Median overall survival was 27.4 months (95% CI 4.1 to 35.4 month) after first CS-PHP. Median progression-free survival was 11.1 months after first CS-PHP (95% CI 4.9 to 23.6 months). SAEs were observed in the majority of patients with most SAEs limited to grades one and two. Thirteen SAEs of grades three and four were observed in seven individual patients. No grade five SAE was observed.
CONCLUSION: CS-PHP is an efficacious and safe treatment for patients presenting with liver-dominant metastatic uveal melanoma.

Kaliki S, Vasanthapuram VH, Mishra DK
Conjunctival Melanoma in Asian Indians: A Study of 42 Patients.
Semin Ophthalmol. 2019; 34(3):182-187 [PubMed] Related Publications

Brouwer NJ, Marinkovic M, Luyten GPM, et al.
Pigmentation of conjunctival melanoma recurrences and outcome.
Graefes Arch Clin Exp Ophthalmol. 2019; 257(8):1783-1788 [PubMed] Related Publications
PURPOSE: In primary conjunctival melanoma (CoM), one of the characteristics that is associated with an increased risk of metastases and death is a lack of tumour pigmentation. The aim of this study was to investigate whether the degree of pigmentation of CoM recurrences relates similarly to clinical outcome.
METHODS: A data set of 177 patients with a CoM recurrence from the Wills Eye Hospital (USA) and the Leiden University Medical Center (The Netherlands) was analysed. The relation between clinical tumour pigmentation of the recurrences, the characteristics of the primary lesions and clinical outcome was investigated.
RESULTS: In 117 (66%) of 177 patients with a CoM recurrence, tumour pigmentation was known: 71 patients (61%) had recurrences with low pigmentation. Primary lesions had low pigmentation in 39% of cases, which is significantly different (p = 0.001). However, low tumour pigmentation of recurrences correlated with low tumour pigmentation of the primary lesion (p < 0.001). No association was observed between pigmentation of the recurrences and iris colour (p = 0.66). Low pigmentation of the recurrences was not significantly associated with an increased risk for metastases (HR 1.96, p = 0.12) or death (HR 1.79, p = 0.27), whereas primary tumours with low pigmentation did show a greater risk for metastases (HR 2.82, p = 0.016) and death (HR 2.90, p = 0.037).
CONCLUSIONS: CoM recurrences are more often lightly pigmented compared to primary lesions. A correlation exists between the degree of pigmentation of primary and recurrent lesions, but recurrences can appear with any degree of pigmentation. Unlike primary CoM, the level of pigmentation of CoM recurrences is not related to metastasis or death.

Fallico M, Reibaldi M, Avitabile T, et al.
Intravitreal aflibercept for the treatment of radiation-induced macular edema after ruthenium 106 plaque radiotherapy for choroidal melanoma.
Graefes Arch Clin Exp Ophthalmol. 2019; 257(7):1547-1554 [PubMed] Related Publications
PURPOSE: To assess the efficacy of intravitreal aflibercept in patients suffering from post-radiation macular edema following plaque radiotherapy for choroidal melanoma.
METHODS: This prospective, interventional case series included patients affected by radiation maculopathy (RM) with macular edema secondary to ruthenium-106 plaque brachytherapy for choroidal melanoma. The effect of intravitreal aflibercept on best-corrected visual acuity (BCVA), central foveal thickness (CFT) detected by spectral domain optical coherence tomography (sd-OCT), and Horgan's grading scale of RM was evaluated throughout the 24-month follow-up. Intraocular pressure (IOP) and possible complications were also recorded.
RESULTS: Nine eyes of 9 patients were included. A mean of 4.4 ± 1.2 injections were given over the 24 months. At the end of follow-up, mean BCVA was significantly improved, from 0.9 ± 0.19 logMAR at baseline to 0.56 ± 0.3 logMAR (P = 0.028), and mean CFT was significantly decreased, from 546 ± 123 μm at baseline to 223 ± 34 μm (P < 0.001). Intravitreal aflibercept lowered baseline maculopathy stage as well. No significant change in IOP values and no complications, such as endophthalmitis, was recorded.
CONCLUSION: Intravitreal aflibercept is an effective treatment for patients with radiation-induced macular edema, allowing functional and anatomical improvements to be achieved with a relatively low number of injections.

Schefler AC, Koca E, Bernicker EH, Correa ZM
Relationship between clinical features, GEP class, and PRAME expression in uveal melanoma.
Graefes Arch Clin Exp Ophthalmol. 2019; 257(7):1541-1545 [PubMed] Related Publications
BACKGROUND: Metastatic risk for uveal melanoma (UM) patients can be characterized by gene expression profiling (GEP) (Castle Biosciences, Friendswood, TX). Class 1A tumors carry low metastatic risk; class 1B tumors have intermediate risk; and class 2 tumors have high risk. Preferentially expressed antigen in melanoma (PRAME) is a tumor-associated antigen which is expressed in various neoplasms including UM. Recently, PRAME expression in uveal melanoma was first recognized to confer an additional metastatic risk beyond GEP status.
METHODS: This was a retrospective, consecutive, multicenter chart review study. All patients diagnosed with UM at two major ocular oncology centers from August 2016 to February 2018 who underwent both GEP and PRAME mRNA expression testing were included. Patient age at diagnosis, gender, and tumor variables such as thickness, largest basal diameter (LBD), tumor volume, TNM stage, and GEP class and PRAME status were extracted from the medical records. Statistical analysis was performed to analyze the association of PRAME +/- status with all clinical and molecular variables.
RESULTS: One hundred forty-eight UM patients were identified. TNM was stage I in 51 (34.5%), stage IIA in 33 (22.3%), stage IIB in 34 (23%), stage IIIA in 20 (13.5%), and stage IIIB in 10 (6.8%) patients. Fifty-five patients (37%) were PRAME-positive, a significant fraction. There was no association between higher TNM stage and positive PRAME status (p = 0.129). PRAME expression was found to be independent of gender, patient age, and tumor thickness. PRAME expression was statistically associated with LBD and tumor volume. Higher GEP class was associated with higher TNM staging (p < 0.001). Worsening GEP class was associated with PRAME+ status with 28% of GEP class 1A tumors having PRAME+ status, 29% of GEP class 1B tumors having PRAME+ status, and 56% of GEP class 2 tumors having PRAME+ status.
CONCLUSIONS: In this study cohort, PRAME+ status was significantly associated with LBD and tumor volume as well as worsening GEP class. Nearly a third of GEP class 1A tumors expressed PRAME. Given the recent published data on increased metastatic risk among patients with tumors expressing PRAME, this study suggests that a significant fraction of 1A patients may harbor an increased metastatic risk. Future large, multicenter studies with long-term follow-up will clarify this finding.

Jespersen H, Bagge RO, Ullenhag G, et al.
Concomitant use of pembrolizumab and entinostat in adult patients with metastatic uveal melanoma (PEMDAC study): protocol for a multicenter phase II open label study.
BMC Cancer. 2019; 19(1):415 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: While recent years have seen a revolution in the treatment of metastatic cutaneous melanoma, no treatment has yet been able to demonstrate any prolonged survival in metastatic uveal melanoma. Thus, metastatic uveal melanoma remains a disease with an urgent unmet medical need. Reports of treatment with immune checkpoint inhibitors have thus far been disappointing. Based on animal experiments, it is reasonable to hypothesize that the effect of immunotherapy may be augmented by epigenetic therapy. Proposed mechanisms include enhanced expression of HLA class I and cancer antigens on cancer cells, as well as suppression of myeloid suppressor cells.
METHODS: The PEMDAC study is a multicenter, open label phase II study assessing the efficacy of concomitant use of the PD1 inhibitor pembrolizumab and the class I HDAC inhibitor entinostat in adult patients with metastatic uveal melanoma. Primary endpoint is objective response rate. Eligible patients have histologically confirmed metastatic uveal melanoma, ECOG performance status 0-1, measurable disease as per RECIST 1.1 and may have received any number of prior therapies, with the exception of anticancer immunotherapy. Twenty nine patients will be enrolled. Patients receive pembrolizumab 200 mg intravenously every third week in combination with entinostat 5 mg orally once weekly. Treatment will continue until progression of disease or intolerable toxicity or for a maximum of 24 months.
DISCUSSION: The PEMDAC study is the first trial to assess whether the addition of an HDAC inhibitor to anti-PD1 therapy can yield objective anti-tumoral responses in metastatic UM.
TRIAL REGISTRATION: ClinicalTrials.gov registration number: NCT02697630 . (Registered 3 March 2016). EudraCT registration number: 2016-002114-50.

He M, Chaurushiya MS, Webster JD, et al.
Intrinsic apoptosis shapes the tumor spectrum linked to inactivation of the deubiquitinase BAP1.
Science. 2019; 364(6437):283-285 [PubMed] Related Publications
Malignancies arising from mutation of tumor suppressors have unexplained tissue proclivity. For example,

Oxenreiter MM, Lane AM, Jain P, et al.
Conservative management of suspicious melanocytic lesions of the iris.
Graefes Arch Clin Exp Ophthalmol. 2019; 257(6):1319-1324 [PubMed] Related Publications
PURPOSE: The diagnosis of iris melanoma can be difficult, with no established diagnostic criteria currently available. Careful monitoring of patients with suspicious iris lesions is one approach to managing these tumors. We determined the risk of malignant transformation and melanoma-related mortality in patients under observation to evaluate the validity of this management approach.
METHODS: This was a retrospective chart review of patients with suspicious iris lesions diagnosed at Massachusetts Eye and Ear Infirmary (MEE) between 1975 and 2014. All patients with an initial diagnosis of suspicious iris lesion followed and/or treated after malignant transformation at the MEE in this 39-year period were included in the cohort. Rates of malignant transformation and melanoma-related mortality were calculated. Treatment outcomes after proton beam irradiation were evaluated in patients who developed iris melanomas during observation.
RESULTS: Two hundred thirty-four patients had a diagnosis of suspicious iris lesion (median follow-up, 5.8 years). Malignant transformation occurred in 16 (6.8%) patients with suspicious lesions during the observation period (median follow-up, 9.9 years). All patients diagnosed with iris melanomas were treated with proton beam irradiation (PBI). Complications after treatment included cataract (18.8%), secondary glaucoma (6.3%), and neovascular glaucoma (12.5%). Two of 16 patients (12.5%) who developed iris melanomas died of metastatic melanoma 32.6 months and 10 years after treatment with PBI. Both cases had been followed regularly to monitor for malignant transformation of their suspicious lesions (8.2 years and 3.2 years before melanoma diagnosis, respectively).
CONCLUSIONS: These data suggest that suspicious iris lesions have low malignant potential, and a conservative approach to the management of these lesions is appropriate. Survival does not appear to be compromised with an observational approach, and there is potential for preservation of good visual function because vision-threatening treatments can be avoided.

Scholz SL, Hérault J, Stang A, et al.
Proton radiotherapy in advanced malignant melanoma of the conjunctiva.
Graefes Arch Clin Exp Ophthalmol. 2019; 257(6):1309-1318 [PubMed] Related Publications
BACKGROUND: The management of conjunctival melanoma is challenging and frequently ends in exenteration. The aim of this retrospective study was to evaluate the long-term results of proton beam radiation with regard to various clinical parameters.
METHODS: Eighty-nine patients with extended conjunctival melanoma (≥T2) and multifocal bulbar located tumors (T1c/d) were treated consecutively with proton radiotherapy (dose 45 Gy). The following parameters were assessed: TNM stage, tumor origin, local recurrence, performance of exenteration, occurrence of metastases, overall survival, and potential complications. A time-to-event analysis was preformed to the primary endpoints: relapse, metastasis, exenteration, and death by use of Kaplan-Meier cumulative survival estimates and Cox proportional hazards regression that provides hazard ratios and 95% confidence intervals.
RESULTS: The median follow-up time was 4.2 years (max. 21.7 years). Local recurrence and metastatic disease occurred in 33% and 16% of patients, respectively. Exenteration-free survival and overall survival tended to be worse in T3 melanoma. No association between tumor origin and local recurrence, metastatic disease, or overall survival was observed. Main complications after proton radiotherapy were sicca-syndrome (30%), secondary glaucoma (11%), and limbal stem cell deficiency (8%).
CONCLUSIONS: In summary, proton radiotherapy in conjunctival melanoma is an effective alternative to exenteration, with a 5-year cumulative probability of eye preservation of 69%.

Reichstein D, Karan K
Endoresection utilizing pars plana vitrectomy for benign and malignant intraocular tumors.
Curr Opin Ophthalmol. 2019; 30(3):151-158 [PubMed] Related Publications
PURPOSE OF REVIEW: Endoresection of intraocular tumors is a complicated procedure utilizing pars plana vitrectomy techniques. Though it has potential downsides and complications, there is potential for this technique in the treatment of malignant and benign intraocular tumors.
RECENT FINDINGS: Endoresection has been utilized in some form for the last three decades, but recent advances in vitreoretinal surgery have improved the technique. Endoresection is used most commonly to treat posterior uveal melanoma, but success in treating benign tumors, such as astrocytoma or retinal capillary hemangioblastoma has emboldened surgeons to expand its indications. It appears that removal of a malignant tumor, such as uveal melanoma may spare the eye some damaging effects of radiation retinopathy and radiation optic neuropathy. These benefits may occur even when the tumor is treated concurrently with plaque brachytherapy, proton beam irradiation, or stereotactic radiotherapy. The benefits of the technique are tempered, however, by the inherent difficulties associated with performing the surgery. These include potentially severe intraoperative bleeding, recurrent rhegmatogenous retinal detachment with proliferative vitreoretinopathy, air embolism, and recurrence of the tumor at the edge of the resection. Nonetheless, endoresection has recently been used for retinoblastoma in refractory cases in order to spare the globe.
SUMMARY: Endoresection is an advanced vitreoretinal surgical technique that has potential advantages in the treatment of malignant and benign intraocular tumors.

Shields CL, Lim LS, Dalvin LA, Shields JA
Small choroidal melanoma: detection with multimodal imaging and management with plaque radiotherapy or AU-011 nanoparticle therapy.
Curr Opin Ophthalmol. 2019; 30(3):206-214 [PubMed] Related Publications
PURPOSE OF REVIEW: To explore risk factors for choroidal nevus transformation into melanoma using multimodal imaging and review current treatment options.
RECENT FINDINGS: A recently published longitudinal study of 3806 choroidal nevi, imaged with optical coherence tomography (OCT), ultrasonography, and standard wavelength autofluorescence, revealed transformation into melanoma in 5.8% at 5 years and 13.9% at 10 years, using Kaplan-Meier analysis. Multivariate factors predictive of transformation included thickness more than 2 mm (by ultrasonography), fluid subretinal (by OCT), symptoms vision loss (by Snellen acuity), orange pigment (by autofluorescence), melanoma hollow (by ultrasonography), and DIaMeter more than 5 mm (by photography). These important factors can be recalled by the mnemonic 'To Find Small Ocular Melanoma Doing IMaging' (TFSOM-DIM). The mean 5-year estimate of nevus growth into melanoma was 1.1% for those with 0 risk factor, 11% with one factor, 22% with two factors, 34% with three factors, 51% with four factors, and 55% with five risk factors. Management of small choroidal melanoma typically involves plaque radiotherapy with 5 and 10-year rates of tumor recurrence at 7 and 11%, visual acuity loss (≥3 Snellen lines) at 39 and 49%, and melanoma-related metastasis at 4 and 9%. A novel infrared dye-conjugated virus-like nanoparticle (AU-011) is currently under investigation for treatment of small choroidal melanoma, with a goal to induce tumor regression and minimize vision loss.
SUMMARY: The mnemonic, TFSOM-DIM, can assist the clinician in detection of small choroidal melanoma. Treatment of small melanoma with plaque radiotherapy offers tumor control but with potential vision loss. A novel nanoparticle therapy using AU-011 is currently under trial.

Falzone L, Romano GL, Salemi R, et al.
Prognostic significance of deregulated microRNAs in uveal melanomas.
Mol Med Rep. 2019; 19(4):2599-2610 [PubMed] Free Access to Full Article Related Publications
Uveal melanoma (UM) represents the most frequent primary tumor of the eye. Despite the development of new drugs and screening programs, the prognosis of patients with UM remains poor and no effective prognostic biomarkers are yet able to identify high‑risk patients. Therefore, in the present study, microRNA (miRNA or miR) expression data, contained in the TCGA UM (UVM) database, were analyzed in order to identify a set of miRNAs with prognostic significance to be used as biomarkers in clinical practice. Patients were stratified into 2 groups, including tumor stage (high‑grade vs. low‑grade) and status (deceased vs. alive); differential analyses of miRNA expression among these groups were performed. A total of 20 deregulated miRNAs for each group were identified. In total 7 miRNAs were common between the groups. The majority of common miRNAs belonged to the miR‑506‑514 cluster, known to be involved in UM development. The prognostic value of the 20 selected miRNAs related to tumor stage was assessed. The deregulation of 12 miRNAs (6 upregulated and 6 downregulated) was associated with a worse prognosis of patients with UM. Subsequently, miRCancerdb and microRNA Data Integration Portal bioinformatics tools were used to identify a set of genes associated with the 20 miRNAs and to establish their interaction levels. By this approach, 53 different negatively and positively associated genes were identified. Finally, DIANA‑mirPath prediction pathway and Gene Ontology enrichment analyses were performed on the lists of genes previously generated to establish their functional involvement in biological processes and molecular pathways. All the miRNAs and genes were involved in molecular pathways usually altered in cancer, including the mitogen‑activated protein kinase (MAPK) pathway. Overall, the findings of the presents study demonstrated that the miRNAs of the miR‑506‑514 cluster, hsa‑miR‑592 and hsa‑miR‑199a‑5p were the most deregulated miRNAs in patients with high‑grade disease compared to those with low‑grade disease and were strictly related to the overall survival (OS) of the patients. However, further in vitro and translational approaches are required to validate these preliminary findings.

Gandini S, Doré JF, Autier P, et al.
Epidemiological evidence of carcinogenicity of sunbed use and of efficacy of preventive measures.
J Eur Acad Dermatol Venereol. 2019; 33 Suppl 2:57-62 [PubMed] Related Publications
The International Agency for Research on Cancer classified, in July 2009, exposure to artificial tanning devices (sunbeds) as carcinogenic to humans. This classification was based on evidence from epidemiological and experimental animal studies. The present chapter will review these epidemiological evidences. The summary risk estimates from 27 epidemiological studies obtained through a meta-analysis showed an increased risk of melanoma: summary relative risk (SRR) = 1.20 [95% confidence interval (CI) 1.08-1.34]. The risk was higher when exposure took place at younger age (SRR = 1.59; 95% CI 1.36-1.85). The risk was independent of skin sensitivity or population and a dose response was evident. A meta-analysis of 12 studies was conducted for non-melanoma skin cancers and showed a significantly increased risk for basal cell carcinoma (SRR = 1.29; 95% CI 1.08-1.53) and for squamous cell carcinoma (SRR = 1.67; 95% CI 1.29-2.17). As for melanoma, the risk for other skin cancers increased for first exposures at young age. Epidemiological studies have gradually strengthened the evidence for a causal relationship between indoor tanning and skin cancer and they fit with prior knowledge on relationship between UV exposure and skin cancer. Additionally, several case-control studies provided consistent evidence of a positive association between use of sunbed and ocular melanoma, also with greater risk for first exposures at younger age. Preventive measures based on information on risk or by requiring parental authorization for young users proved to be inefficient in several studies. The significant impact of strong actions or total ban, such as performed in Iceland, or a total ban of sunbed use, as in Brazil or Australian states, needs to be further assessed.

Lorenzo D, Piulats JM, Ochoa M, et al.
Clinical predictors of survival in metastatic uveal melanoma.
Jpn J Ophthalmol. 2019; 63(2):197-209 [PubMed] Related Publications
PURPOSE: To determine the clinical factors that influence survival in patients with metastatic uveal melanoma.
STUDY DESIGN: Single-center, retrospective review of patients' medical records.
METHODS: The following data of ninety-nine consecutive patients (49 men, 50 women) with metastatic uveal melanoma were registered: patient demographics; primary tumor characteristics; features of first melanoma-related metastasis; symptoms and patient status at distant disease debut and metastasis treatment. Overall survival was analyzed by Kaplan-Meier estimates. A Cox proportional hazards regression model was applied to identify independent predictors associated with survival.
RESULTS: Mean patient age at metastatic diagnosis was 60.7 years (standard deviation, 12.8). The liver was the first metastatic site in most (92.9%) cases. The median disease-free interval was 26 months (interquartile range, 34). Median overall survival after detection of the first metastasis was 8 months (interquartile range, 14). The baseline characteristics of the primary uveal melanoma were not associated with survival in patients with stage IV disease. In the multivariate analysis, the following factors at first metastatic diagnosis were associated with improved overall survival: disease-free interval > 36 months; better performance status; and normal serum lactate dehydrogenase and gamma glutamyl transpeptidase levels. Overall survival was not influenced by specific metastatic treatment.
CONCLUSION: Although metastatic uveal melanoma has a poor prognosis, this study reveals the existence of several independent prognostic factors for prolonged overall survival. These findings may help improve survival estimates in patients with advanced disease.

Meijer TS, Burgmans MC, Fiocco M, et al.
Safety of Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Liver Metastases from Ocular Melanoma Using the Delcath Systems' Second-Generation Hemofiltration System: A Prospective Non-randomized Phase II Trial.
Cardiovasc Intervent Radiol. 2019; 42(6):841-852 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To investigate the safety and toxicity of percutaneous hepatic perfusion with melphalan (M-PHP) with the Delcath Systems' second-generation (GEN 2) filter and compare the outcomes with historical data from studies using the first-generation filter.
MATERIALS AND METHODS: A prospective, single-arm, single-center phase II study was carried out including 35 patients with unresectable, histologically confirmed liver metastases from ocular melanoma between February 2014 and June 2017. Main exclusion criteria were extrahepatic disease and age > 75 years. M-PHP was performed with melphalan 3 mg/kg (maximum dose 220 mg). Safety and toxicity were assessed according to the Common Terminology Criteria for Adverse Events version 4.03.
RESULTS: A total of 67 M-PHPs were performed in 35 patients (median 2 procedures). Although hematologic grade 3/4 events were seen in the majority of patients (thrombocytopenia 54.5%, leukopenia 75.6%, neutropenia 66.7%, anemia (only grade 3) 18.1%), these were all well manageable or self-limiting. Of the non-hematologic grade 3 events (n = 14), febrile neutropenia (n = 3), pulmonary emboli (n = 2) and post-procedural hemorrhage (n = 2) were most common. A case of sepsis with bacterial pharyngitis was the only non-hematologic grade 4 event. Prior therapy for liver metastases was found to be a predictor of late grade 3/4 neutropenia with an odds ratio of 5.5 (95% CI 1.4-21.7).
CONCLUSIONS: M-PHP using the GEN 2 filter has an acceptable safety and toxicity profile, and seems to reduce hematologic toxicity when compared to M-PHP with a first-generation filter. Prior therapy of liver metastases is a possible predictive factor in developing grade 3/4 hematologic toxicity.

Cheng Y, Feng J, Zhu X, Liang J
Cytokines concentrations in aqueous humor of eyes with uveal melanoma.
Medicine (Baltimore). 2019; 98(5):e14030 [PubMed] Free Access to Full Article Related Publications
Uveal melanoma (UM) is the major intraocular malignancy in adults, of which the molecular biology is still unknown. Therefore, this study was designed to determine the aqueous concentrations of angiogenic, inflammatory, and chemotactic cytokines in eyes with UM.Aqueous humor samples were collected from 38 patients with UM and 22 patients undergoing cataract surgery. Interleukin 6, 8 (IL-6, IL-8, respectively), interferon-inducible protein-10 (IP-10), placental growth factor1 (PIGF1), regulated on activation, normal T Cell expressed and secreted (RANTES), monocyte chemoattractant protein-1 (MCP-1), nerve growth factor-beta (NGF-β), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and vascular endothelia growth factor A (VEGF-A) were assessed by multiplex bead assay.In the study group, significantly higher concentrations of IL-6 (P = .006), IL-8 (P = .018), IP-10 (P = .004), RANTES (P = .008), MCP-1 (P = .02), NGF-β (P = .013), EGF (P < .001), PIGF1 (P = .01), bFGF (P = .016), and VEGF (P = .017) were measured, when compared with the control group.Several angiogenic, inflammatory, and chemotactic cytokines are highly expressed in the aqueous humor of the UM eyes, which provides new insights into the pathophysiology of UM and could be potential targets for treatment.

Delgado-Ramos GM, Thomas F, VanderWalde A, et al.
Risk factors, clinical outcomes, and natural history of uveal melanoma: a single-institution analysis.
Med Oncol. 2019; 36(2):17 [PubMed] Related Publications
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. We describe the characteristics of UM patients at a tertiary referral center in the Mid-Southern United States, and explore associations and predictors of outcomes. This is a retrospective cohort study of patients with UM seen at West Cancer Center, from 07/2006 to 08/2017. Clinical characteristics and their relationship to outcomes (time-to-death and metastasis) were explored using Cox regression analysis. We identified 208 patients, 51% males, 97% Caucasians, 80% were symptomatic, with a median follow-up of 2.34 years, IQR (1.01-3.03), of which 19.2% died during follow-up. Metastases were diagnosed in 19% (4 older patients had metastases at diagnosis), 53% of those by surveillance. Without considering metastases as a time-varying covariate, age (HR = 1.06/year, CI 1.0-1.1; p < 0.001), headaches (HR = 5.7, CI 1.6-20.5; p = 0.03), and tumor stage (T) were significant covariates for time-to-death. Tumor stages T3 versus T1 (HR = 6.4; CI 1.5-27.7; p = 0.01) and T4 versus T1 (HR = 5.98; CI 1.3-27.8; p = 0.02) were associated with worse outcomes. When considering metastases as a time-varying covariate (HR = 35.8, CI 17-75.2; p < 0.001), only age remains in the model (HR = 1.04/year; p < 0.001). However, tumor stage (p < 0.001), headaches (p = 0.008), and age (p < 0.001) are associated with time-to-metastasis. One in five patients developed metastasis which was the most influential factor on mortality. Predictors of mortality were metastasis, age, tumor stage, and headache as a reported symptom. Surveillance successfully diagnosed metastatic disease in most patients. Most patients had symptoms preceding their UM diagnosis highlighting an opportunity for earlier recognition of UM.

Zimpfer A, Schneider B, Blanck O, et al.
Pathologic Features of Tumor Activity and Stability in Uveal Melanoma Specimens after Fractionated CyberKnife Radiosurgery.
Pathol Oncol Res. 2019; 25(2):731-740 [PubMed] Related Publications
To evaluate uveal melanoma cell activity and pathologic features after stereotactic CyberKnife radiosurgery in specimens from five patients. Specimens from five patients treated by CyberKnife radiosurgery in three fractions were included in this study. Because of persistent retinal detachment in 3 patients, tumour endoresection was performed at four, seven and ten month after CyberKnife radiosurgery. At nine and twelve months after treatment, enucleation of the eye globe was performed in 2 patients because of secondary tumour bleeding and missing regression. After histomorphological analysis and determination of Ki67-proliferation index, DNA cytophotometry, fluorescence in-situ hybridization evaluation for chromosome 3 loss, GNA11and GNAQ mutation analysis were performed. Four of the five tumours included in this study showed variable radiation-induced morphologic changes in the form of enlargement of cells and nuclei, cytoplasmic vacuolisation and nuclear fragmentation. The DNA content of a large fraction of tumour cells was hypoploid. On the other hand, single strikingly hyperchromatic melanoma cells showed marked aneuploidy. The proliferation fraction in the three endoresected tumours was very low (<1%), but it was elevated in the enucleation cases. Monosomy 3 was detected in two of the endoresection cases, but none of the enucleation cases. None of the patients experienced a local tumour recurrence, but two of the patients developed liver metastasis. Many melanoma cells seemed to be vital within the first 6 months after CyberKnife radiosurgery, but obvious radiation-induced morphologic changes, including tumour necrosis, hypoploid DNA content plus low Ki-67 index could indicate sublethal cell damage.

Xin X, Zhang Y, Ling F, et al.
Identification of a nine-miRNA signature for the prognosis of Uveal Melanoma.
Exp Eye Res. 2019; 180:242-249 [PubMed] Related Publications
The present study aims to construct a miRNA-based predictive signature of Uveal melanoma (UM) based on the database of the cancer genome atlas (TCGA). We obtained miRNA expression profiles and clinical information of 80 UM patients from TCGA, and randomly divided them into a training and a testing set. After data processing and forward screening, a total of 204 miRNAs with prognostic value were then examined by the Cox proportional hazard regression model in the training set. Receiver operating curve (ROC) analysis was applied to validate the accuracy of the signature. The biological relevance of putative miRNA target genes was also analyzed using the bioinformatics method. As a result, a linear prognostic model consisting of 9 miRNAs (miR-195, miR-224, miR-365a, miR-365b, miR-452, miR-4709, miR-7702, miR-513c, miR-873) was developed to divide UM patients into a high- and a low-risk group. Patients assigned to the high-risk group had significantly shorter overall survival than those in the low-risk group, which was further confirmed by the Area under curve (AUC) value of 0.858 at 5 year obtained from ROC. Gene Ontology (GO) analysis indicated that predicted target genes of these miRNAs are primarily associated with the modulation of protein expression and function, such as the activity of ubiquitin protein ligase and protein kinase. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that these genes were involved in multiple signaling pathways linked to carcinogenesis. The tumor specific 9-miRNA signature was also verified in the testing and entire set. In summary, based on UM data of TCGA, we identified and validated a 9-miRNA-based prognostic signature.

Chua V, Orloff M, Teh JL, et al.
Stromal fibroblast growth factor 2 reduces the efficacy of bromodomain inhibitors in uveal melanoma.
EMBO Mol Med. 2019; 11(2) [PubMed] Free Access to Full Article Related Publications
Alterations in transcriptional programs promote tumor development and progression and are targetable by bromodomain and extraterminal (BET) protein inhibitors. However, in a multi-site clinical trial testing the novel BET inhibitor, PLX51107, in solid cancer patients, liver metastases of uveal melanoma (UM) patients progressed rapidly following treatment. Mechanisms of resistance to BET inhibitors in UM are unknown. We show that fibroblast growth factor 2 (FGF2) rescued UM cells from growth inhibition by BET inhibitors, and FGF2 effects were reversible by FGF receptor (FGFR) inhibitors. BET inhibitors also increased FGFR protein expression in UM cell lines and in patient tumor samples. Hepatic stellate cells (HSCs) secrete FGF2, and HSC-conditioned medium provided resistance of UM cells to BET inhibitors. PLX51107 was ineffective

Kase S, Suimon Y, Ishijima K, Ishida S
Rhegmatogenous retinal detachment in a patient with choroidal melanoma simulating choroidal detachment: a case report.
J Med Case Rep. 2018; 12(1):389 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Ophthalmologists and retina specialists may consider choroidal detachment if patients with rhegmatogenous retinal detachment present with choroidal elevation. That misdiagnosis may lead to inappropriate treatments, development of tumor cell dissemination, and eventual promotion of patient death. We report a case of a patient with rhegmatogenous retinal detachment associated with choroidal melanoma simulating choroidal detachment according to fundus findings.
CASE PRESENTATION: A 78-year-old Japanese woman with blurred vision in her right eye was referred to our hospital because of rhegmatogenous retinal detachment with complicated atypical choroidal detachment. Her intraocular pressure was normal with clear anterior chamber. Retinal detachment involving the inferior and nasal retina was observed, and a retinal hole was noted in the same quadrant. A small yellowish choroidal elevation was located in the inferonasal site. Gadolinium-enhanced magnetic resonance imaging revealed enhancement corresponding to the elevation, leading to the identification of a choroidal tumor. Enucleation of the patient's right eye was eventually performed. The enucleated eye histologically demonstrated malignant melanoma.
CONCLUSIONS: If hypotony or an inflammatory sign is absent, ophthalmologists should pay attention to the differential diagnosis of choroidal elevations observed in such patients.

Melzer C, Sharma A, Peters S, et al.
Basal cell carcinomas developing independently from BAP1-tumor predisposition syndrome in a patient with bilateral uveal melanoma: Diagnostic challenges to identify patients with BAP1-TPDS.
Genes Chromosomes Cancer. 2019; 58(6):357-364 [PubMed] Related Publications
Basal cell carcinomas (BCC) have been recently included into the spectrum of BAP1-tumor predisposition syndrome (TPDS). Uveal melanoma (UM) is also a tumor often observed in patients with this hereditary tumor syndrome, in particular bilateral UM is highly suspicious for BAP1-TPDS although no patient has been reported yet. Based on our index patient with BAP1-TPDS with bilateral UM (choroid OD, oculus dexter; iris OS, oculus sinister), several BCCs and thyroid cancer as well as a family history for cancer, this paper analyzes hints and pitfalls to diagnose this syndrome clinically and histologically. A previously undescribed germline variant, namely a heterozygous deletion of a single nucleotide on position 2001 (c.2001delG;p.[Thr668Profs*24] in exon 16 of the BAP1 gene), was identified. Structural changes in the C-terminal of the BAP1 protein were observed by in silico analysis. While the excised iris melanoma showed loss of BAP1 nuclear staining by immunohistochemical staining, the BCCs of our patient (and in the control group, n = 13) were BAP1 positive. Genetic analysis of the BCC of the ocular adnexae confirmed a remaining intact BAP1 copy. The constellation of (bilateral) UM in combination with BCC should raise suspicion for a BAP1-TPDS. As our BCCs probably developed independently from the BAP1-TPDS and UMs frequently show loss of nuclear BAP1 staining, genetic analysis is mandatory to diagnose this syndrome.

Yi Q, Zou WJ
A novel four‑snoRNA signature for predicting the survival of patients with uveal melanoma.
Mol Med Rep. 2019; 19(2):1294-1301 [PubMed] Related Publications
Uveal melanoma (UM), the predominant histological subtype of intraocular malignant tumors in adults, often results in high rates of mortality; effective prognostic signatures used to predict the survival of patients with UM are limited. Small nucleolar RNAs (snoRNAs) are emerging as important regulators in the processes of carcinogenesis and tumor progression, but knowledge of their application as prognostic markers in UM is limited. In the present study, the expression profiles of snoRNAs in UM were determined; a total of 60 snoRNAs were notably associated with the overall survival of patients with UM via univariate Cox survival analysis. Subsequently, a prognostic signature based on four snoRNAs was proposed, which retained their prognostic significance determined by a multivariate Cox survival analysis. The formula is as follows: ACA17 * (‑1.602) + ACA45 * 0.803 + HBII‑276 * 0.603 + SNORD12 * 1.348. Furthermore, the results of in silico analysis indicated that perturbation of the phototransduction, GABAergic synapse and amphetamine addiction pathways may be the potential molecular mechanisms underlying the poor prognosis of patients with UM. Collectively, the present study proposed a potential prognostic signature for patients with UM and the prospective mechanisms at the genome‑wide level were determined.

Singh P, Sen S, Banerjee M, Meel R
Choroidal melanoma masquerading as orbital cellulitis.
BMJ Case Rep. 2018; 11(1) [PubMed] Related Publications
Orbital cellulitis is the most common subset of orbital inflammatory disease. We describe a patient with necrotic choroidal melanoma who presented with orbital cellulitis. MRI revealed a mass lesion suggesting intraocular melanoma with no extrascleral extension. There was no metastasis on positron emission tomography-CT scan. Enucleation with orbital implant was performed. Histopathological analysis of the specimen revealed intraocular necrotic melanoma with very few recognisable melanoma cells. The necrotic subtype is more commonly associated with extrascleral extension, distant metastasis and poorer prognosis than other melanoma types. Sterile orbital cellulitis may rarely be a manifestation of ocular tumours in adults, and a high index of suspicion should be maintained to rule out the same.

Rose AM, Luo R, Radia UK, et al.
Detection of mutations in SF3B1, EIF1AX and GNAQ in primary orbital melanoma by candidate gene analysis.
BMC Cancer. 2018; 18(1):1262 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Ocular melanoma is a rare but often deadly malignancy that arises in the uvea (commonest primary site), conjunctiva or the orbit. Primary orbital melanoma (POM) is exceedingly rare, with approximately 60 cases reported to date. Despite recent advances in our understanding of the genetics of primary uveal and conjunctival melanomas, this information is lacking for POM.
METHODS: DNA was extracted from 12 POM tissues, with matched germline DNA (where available). MLPA was conducted to detect chromosomal alterations and Sanger sequencing used to identify point mutations in candidate melanoma driver genes (BRAF, NRAS, KRAS, GNA11, GNAQ), and other genes implicated in melanoma prognosis (EIF1AX, SF3B1). Immunohistochemistry was performed to analyse BAP1 nuclear expression.
RESULTS: MLPA detected copy number alterations in chromosomes 1p, 3, 6 and 8. Sequencing of melanoma driver genes revealed GNAQ (p.Q209L) mutations in two samples; although it is possible that these samples represent extraocular spread of an occult uveal melanoma. A recurrent mutation in SF3B1 (p.R625H) was observed in indolent, but not aggressive, tumours; a mutation in EIF1AX (p.N4S) was detected in one patient with non-aggressive disease.
CONCLUSIONS: EIF1AX and SF3B1 mutations appear have a role in determining the clinical course of POM and detection of these changes could have clinical significance. Further in depth analysis of this rare group using differing 'omic technologies will provide novel insights into tumour pathogenesis.

Fiorentzis M, Katopodis P, Kalirai H, et al.
Conjunctival melanoma and electrochemotherapy: preliminary results using 2D and 3D cell culture models in vitro.
Acta Ophthalmol. 2019; 97(4):e632-e640 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To investigate the cytotoxic effect of bleomycin, mitomycin C (MMC) and Fluorouracil (5-FU) in combination with electroporation (EP) on human conjunctival melanoma (CM) and normal conjunctival cell lines using 2D and 3D cell culture systems in vitro.
METHODS: Two CM (CRMM1, CRMM2) and one normal conjunctival epithelial cell line (HCjE-Gi) were treated with various EP conditions and increasing concentrations of 5-FU, MMC and bleomycin. Cell survival was assessed by MTT viability assay. All cell lines were seeded to create spheroids and were treated with bleomycin on day 3 and day 8 combined with EP. Spheroids were collected, fixed in buffered formalin and subsequently paraffin embedded for histological assessment of the effects of the treatment on cell viability.
RESULTS: CM cell lines were resistant to electroporation alone and showed a reduction in cell number only when treated with 1000 Volts/cm and 8 pulses. HCjE-Gi cells showed higher sensitivity to electric pulses over 750 Volts/cm. MMC and 5-FU demonstrated a higher cytotoxicity for the HCjE-Gi cell line. The CM cell lines were resistant to MMC and 5-FU. Bleomycin (1 μg/ml) alone had no significant effect on the HCjE-Gi even when combined with EP conditions ≥750 Volts/cm. In contrast, it significantly (p -, paired t-test) reduced cell viability in the CM cell lines. Spheroids treated with bleomycin and EP showed a reduction in tumour mass and proliferation rates after treatment.
CONCLUSION: Our in vitro study using 2D and 3D models indicates that the application of EP may effectively enhance chemotherapy with bleomycin in CM. This may offer new viable perspectives for CM treatment.

Jacobsen BH, Ricks C, Harrie RP
Ocular ultrasound versus MRI in the detection of extrascleral extension in a patient with choroidal melanoma.
BMC Ophthalmol. 2018; 18(1):320 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: To describe the superiority of ocular ultrasound in the diagnostic management of extrascleral extension in choroidal melanoma.
CASE PRESENTATION: We present a case of a 94-year-old male with choroidal melanoma of the right eye imaged with MRI and ocular ultrasound to aid in the detection of extrascleral extension.
CONCLUSIONS: With advancement in technology and new imaging modalities emerging, it can become difficult to determine the best diagnostic approach for patients. We believe that ocular ultrasound remains the superior imaging modality in detection of extrascleral extension in choroidal melanoma.

Furdová A, Juhas J, Šramka M, Králik G
Ciliary body melanoma treatment by stereotactic radiosurgery.
Cesk Slov Oftalmol. Spring 2018; 73(5-6):204-210 [PubMed] Related Publications
INTRODUCTION: Malignant melanoma of the ciliary body (corpus ciliare) represents 10 to 15 percent of tumors of the uveal tract. The aim of the work is to evaluate the effectiveness of stereotactic radiosurgery performed on LINAC linear accelerator and the occurrence of postoperative complications.
MATERIAL AND METHODS: Retrospective analysis of patients with ciliary body melanoma treated with stereotactic radiosurgery on linear accelerator in the period 1/2011 to 12/2016 in Slovakia.
RESULTS: From 1/2011 to 12/2016 a group of 27 patients with melanoma of the ciliary body underwent one day session stereotactic radiosurgery irradiation on linear accelerator (SRCH). Primary enucleation was indicated in 10 (37 %) patients. A group of 17 (63 %) patients were treated with stereotactic radiosurgery. In a group of 17 patients indicated for SRCH, 7 (41 %) were diagnosed in T1 stage, 8 (47 %) in T2 stage. In 2 (12 %) patients who refused primary enucleation, palliative irradiation was indicated in T3 stage, and later metastases appeared in liver and systemic chemotherapy was indicated. The therapeutic dose in all patients was TD 35 Gy, TD max 42 Gy. The mean age of patients at the time of irradiation was 60.8, the youngest patient was 40 and the oldest was 80 years old. The follow-up period was 12 months to 5 years.
CONCLUSION: Currently, in Slovakia, the only irradiation possibility to treat ciliary body melanoma is stereotactic radiosurgery. In our group of 17 patients, this method appears to be effective in the treatment of T1 to T2 stage. The results are comparable to brachytherapy and proton beam irradiation therapy. Key words: corpus ciliare, uveal melanoma, linear accelerator, stereotactic radiosurgery.

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