Combination of Molecule-Targeted Therapy and Photodynamic Therapy Using Nanoformulated Verteporfin for Effective Uveal Melanoma Treatment.

Uveal melanoma (UM) is the most common primary ocular malignancy in adults and has high mortality. Recurrence, metastasis, and therapeutic resistance are frequently observed in UM, but no beneficial systemic therapy is available, presenting an urgent need for developing effective therapeutic drugs. Verteporfin (VP) is a photosensitizer and a Yes-Associated Protein (YAP) inhibitor that has been used in clinical practice. However, VP's lack of tumor targetability, poor biocompatibility, and relatively low treatment efficacy hamper its application in UM management. Herein, we developed a biocompatible CD44-targeting hyaluronic acid nanoparticle (HANP) carrying VP (HANP/VP) to improve UM treatment efficacy. We found that HANP/VP showed a stronger inhibitory effect on cell proliferation than that of free VP in UM cells. Systemic delivery of HANP/VP led to targeted accumulation in the UM-tumor-bearing mouse model. Notably, HANP/VP mediated photodynamic therapy (PDT) significantly inhibited UM tumor growth after laser irradiation compared with no treatment or free VP treatment. Consistently, in HANP/VP treated tumors after laser irradiation, the tumor proliferation and YAP expression level were decreased, while the apoptotic tumor cell and CD8+ immune cell levels were elevated, contributing to effective tumor growth inhibition. Overall, the results of this preclinical study showed that HANP/VP is an effective nanomedicine for tumor treatment through PDT and inhibition of YAP in the UM tumor mouse model. Combining phototherapy and molecular-targeted therapy offers a promising approach for aggressive UM management.

The rationale for treating uveal melanoma with adjuvant melatonin: a review of the literature.

BACKGROUND: Uveal melanoma is a rare form of cancer with high mortality. The incidence of metastases is attributed to early seeding of micrometastases from the eye to distant organs, primarily the liver. Once these seeded clusters of dormant tumor cells grow into larger radiologically detectable macrometastases, median patient survival is about 1 year. Melatonin is an important hormone for synchronizing circadian rhythms. It is also involved in other aspects of human physiology and may offer therapeutic benefits for a variety of diseases including cancer. METHODS: Articles involving the physiological effects of melatonin, pharmacokinetics, and previous use in cancer studies were acquired using a comprehensive literature search in the Medline (PubMed) and Web of Science databases. In total, 147 publications were selected and included in the review. RESULTS: Melatonin has been observed to suppress the growth of cancer cells, inhibit metastatic spread, enhance immune system functions, and act as an anti-inflammatory in both in vitro and in vivo models. Melatonin may also enhance the efficacy of cancer treatments such as immuno- and chemotherapy. Numerous studies have shown promising results for oral melatonin supplementation in patients with other forms of cancer including cutaneous malignant melanoma. Cell line and animal studies support a hypothesis in which similar benefits may exist for uveal melanoma. CONCLUSIONS: Given its low cost, good safety profile, and limited side effects, there may be potential for the use of melatonin as an adjuvant oncostatic treatment. Future avenues of research could include clinical trials to evaluate the effect of melatonin in prevention of macrometastases of uveal melanoma.

Uveal Melanoma Metastasis to the Contralateral Eye Structures: A Retrospective Comparative Analysis of 13 Consecutive Patients.

PURPOSE: To report uveal melanoma (UM) metastasis to the contralateral ocular and periocular structures. DESIGN: Retrospective study. PARTICIPANTS: Thirteen patients with UM metastasis to the contralateral ocular and periocular structures were included. METHODS: Clinical records were reviewed retrospectively. MAIN OUTCOME MEASURES: The development and time to onset of contralateral ocular and periocular metastasis, systemic metastasis, and death. RESULTS: Of the 13 000 treated UM patients, 13 patients were diagnosed with UM metastasis to the contralateral ocular and periocular structures. Mean patient age at primary UM diagnosis was 60 years (median, 60 years; range, 37-87 years). The primary uveal melanoma was in the choroid (n = 11) or ciliary body (n = 2) and was treated with brachytherapy (n = 11), proton beam radiotherapy (n = 1), or enucleation (n = 1). Systemic metastasis developed in 11 patients (85%) at a mean of 66 months (median, 34 months; range, 12-216 months) after diagnosis of the primary UM. All 11 patients (100%) showed liver metastasis and 8 patients (62%) also showed extrahepatic metastasis. The sites of metastasis to the contralateral ocular or periocular structures included the choroid in 4 patients (31%), the orbit in 7 patients (54%), and the eyelid in 2 patients (15%). One patient with eyelid metastasis demonstrated concurrent conjunctival nodule. Mean time to diagnosis of contralateral ocular or periocular metastasis was 94 months (median, 48 months; range, 9-375 months). Contralateral choroidal metastasis was multifocal in 3 of 4 patients (75%). Of 7 patients with orbital metastasis, 5 showed extraocular muscle involvement with restricted ocular motility. Treatment for contralateral choroidal metastasis included brachytherapy (n = 2), transpupillary thermotherapy (n = 1), and observation (n = 1). Treatment for contralateral periocular (orbit or eyelid) metastasis was excision (n = 5), external beam radiotherapy (n = 2), and observation (n = 2). Of 13 patients, death was documented in 11 patients at a mean of 17 months (median, 9 months; range, 3-54 months) as a result of systemic UM metastasis (n = 10) or unrelated cause (n = 1). CONCLUSIONS: Metastasis resulting from UM to the contralateral ocular and periocular structures is rare and generally occurs in patients with disseminated metastasis. Orbital tissue is the most common site of involvement, and these patients have short life expectancy.

[Screening of drugs that selectively inhibit uveal melanoma cells with SF3B1 mutations].

OBJECTIVE: To screen compounds that can selectively inhibit uveal melanoma cells with splicing factor 3B subunit 1 (SF3B1) mutations in comparison with isogenic SF3B1 wild-type counterparts in a cell model of SF3B1 mutant allele knockout. METHODS: Principal component analysis was used to analyze transcriptome alternative splicing in TCGA cohorts of uveal melanoma with wild-type SF3B1 and SF3B1 mutations, and abnormal alternative splicing events derived from SF3B1 mutations were identified. The SF3B1 mutant allele in Mel202 cells was knocked out using CRISPR-Cas9 technology, and Sanger sequencing was used to verify the edited sequence. MTT and colony formation assays were used to assess the proliferation of Mel202 and Mut-KO cells. RT-PCR agarose electrophoresis combined with Sanger sequencing was used to determine alternative splicing events in Mel202 and Mut-KO cells. MTT assay was performed to screen the compounds that showed selective inhibitory effect against Mel202 cells with SF3B1 mutation. RESULTS: Specific knockout of SF3B1 mutant allele in Mel202 cells obviously promoted the cell proliferation and caused changes in alternative splicing of ZDHHC16 and DYNLL1 transcripts. The screening data showed that 13 compounds had selective inhibitory activity against Mel202 cells with SF3B1 mutation (Fold change≥2), and among them, tetrandrine and lapatinib showed good dose-effect curves. CONCLUSION: This study provides a cell screening model for identification of potential individualized treatment drugs for patients with uveal melanoma with SF3B1 mutation.

Preclinical evaluation of drug combinations identifies co-inhibition of Bcl-2/XL/W and MDM2 as a potential therapy in uveal melanoma.

INTRODUCTION: Uveal melanoma (UM) is a rare and malignant intraocular tumour with a dismal prognosis. Despite a good control of the primary tumour by radiation or surgery, up to 50% of patients subsequently develop metastasis for which no efficient treatment is yet available. METHODOLOGY: To identify therapeutic opportunities, we performed an in vitro screen of 30 combinations of different inhibitors of pathways that are dysregulated in UM. Effects of drug combinations on viability, cell cycle and apoptosis were assessed in eight UM cell lines. The best synergistic combinations were further evaluated in six UM patient-derived xenografts (PDXs). RESULTS: We demonstrated that the Bcl-2/XL/W inhibitor (ABT263) sensitised the UM cell lines to other inhibitors, mainly to mammalian target of rapamycin (mTOR), mitogen-activated protein kinase kinase (MEK) and murine double minute 2 (MDM2) inhibitors. mTOR (RAD001) and MEK1/2 (trametinib) inhibitors were efficient as single agents, but their combinations with ABT263 displayed no synergism in UM PDXs. In contrast, the combination of ABT263 with MDM2 inhibitor (HDM201) showed a trend for a synergistic effect. CONCLUSION: We showed that inhibition of Bcl-2/XL/W sensitised the UM cell lines to other treatments encouraging investigation of the underlying mechanisms. Furthermore, our findings highlighted Bcl-2/XL/W and MDM2 co-inhibition as a promising strategy in UM.

Uveal melanoma: physiopathology and new in situ-specific therapies.

Uveal melanoma is the most common primary intraocular tumor in adults. It can arise from melanocytes in the anterior (iris) or posterior uveal tract (choroid and ciliary body). Uveal melanoma has a particular molecular pathogenesis, being characterized by specific chromosome alterations and gene mutations (e.g., GNAQ/GNA11; BAP1), which are considered promising targets for molecular therapy. Primary treatment of uveal melanoma includes radiotherapy (brachytherapy and charged-particle therapy), phototherapy (photocoagulation, transpupillary thermal therapy, and photodynamic therapy) and surgery (local resection, enucleation and exenteration). Approximately half of patients with uveal melanoma will, however, develop metastasis, especially in the liver. The treatment of metastatic uveal melanoma includes systemic chemotherapy, immunotherapy and molecular targeted therapy. Liver-directed therapies, such as resection, chemoembolization, immunoembolization, radioembolization, isolated hepatic perfusion and percutaneous hepatic perfusion, are also available to treat metastatic uveal melanoma. Several clinical trials are being developed to study new therapeutic options to treat uveal melanoma, mainly for those with identified liver metastases. The present work discusses the physiopathology and new in situ-specific therapies for the treatment of uveal melanoma.

The Anti-malarial Drug Artesunate Blocks Wnt/ß-catenin Pathway and Inhibits Growth, Migration and Invasion of Uveal Melanoma Cells.

BACKGROUND: Uveal melanoma is the most common primary intraocular malignancy in adults. So far, there have been no effective targeted therapeutic agents in patients with uveal melanoma. Artesunate is a semi-synthetic derivative of artemisinin extracted from traditional Chinese medicine Artemisia annua L for treatment of severe and multidrug-resistant malaria. Besides its antimalarial activity, artesunate is identified as an anti-cancer drug due to the inhibition of Wnt/ß- catenin pathway in multiple types of cancer. However, the effect of artesunate on uveal melanoma remains unknown. OBJECTIVE: We evaluated the anti-tumor effects of artesunate on uveal melanoma cells, and analyzed in terms of Wnt/ß-catenin pathway, cell growth, cell death, cell migration, invasion and cancer stemlike cells (CSCs) properties. METHODS: Primary (92.1, Mel270) and metastatic (Omm1 and Omm2.3) uveal melanoma cells were used. Immunofluorescence staining, dual luciferase reporter assay, Western blotting, MTS, soft agar cloning technique, Annexin V/PI analyses, wound healing scratch assay, in vitro transwell migration and invasion assays, aldehyde dehydrogenase (ALDH) analyses and melanosphere formation assay et al. were carried out. RESULTS: Artesunate suppressed the phosphorylation of GSK3ß at S9, and lowered the protein level of ß-catenin and its downstream targets (c-Myc, cyclin D1). Artesunate potently inhibited cell viability and colony formation ability. Treatment with artesunate significantly induced apoptosis. In addition, artesunate significantly reduced the migration and invasion of uveal melanoma cells, impaired the traits of CSCs in vitro. CONCLUSION: Artesunate may be a potential interest for the therapy of uveal melanoma.

Melanogenesis in uveal melanoma cells: Effect of argan oil.

The mechanisms underlying cutaneous melanogenesis have been widely studied; however, very little is known about uveal melanogenesis. Melanin is normally produced by uveal melanocytes and gives the color to the iris. A derangement from this normal production may occur, for instance, by iatrogenic events, such as glaucoma therapy with prostaglandins that may enhance cutaneous and iris pigmentation. In this study, we investigated the mechanisms that regulate uveal melanogenesis in human uveal melanoma cells (92.1) and murine cutaneous melanoma cells (B16-F1). In the first part of the study, we compared the effects of known cutaneous pigmenting agents on the B16-F1 and 92.1 cells, showing an opposite response of the two cell lines. Subsequently, using argan oil, a known depigmenting agent for murine cutaneous melanoma cells, on 92.1 cells, we found that in these cells, it also functioned as an inhibitor of melanogenesis and tyrosinase expression. From a molecular perspective, treatment of the 92.1 cells with argan oil decreased melanogenesis-associated transcription factor (MITF) gene expression by inducing MITF phosphorylation at Ser73, thus leading to MITF ubiquitination and disposal. It also led to the downregulation of the extracellular signal-regulated kinase (ERK)1/2 and Akt pathways, also known to be involved in cutaneous melanogenesis, although with an opposing function. Taken together, our data indicate that: ⅰ) some differences exist in the regulation of melanogenesis between cutaneous and uveal melanoma cells; and ⅱ) argan oil exerts a depigmenting effect on 92.1 cells through its action on the ERK1/2 and Akt pathways.

Pattern of Local Recurrence After I-125 Episcleral Brachytherapy for Uveal Melanoma in a Spanish Referral Ocular Oncology Unit.

PURPOSE: To describe the time, frequency, and clinical characteristics of treatment failure after I-125 brachytherapy in patients with uveal melanoma treated and followed in a Spanish referral ocular oncology unit. DESIGN: Prospective, consecutive, interventional case series. METHODS: Patients diagnosed with uveal melanoma from 1995 to 2016 and treated with episcleral brachytherapy were included. Demographic data collection, ophthalmic evaluation, ultrasound scan, and systemic studies were performed at baseline, every 6 months thereafter for 5 years, and subsequently at annual intervals. Recurrence was defined as presence of tumor growth after treatment. Baseline analysis was performed by descriptive methods and survival by Kaplan-Meier curves. RESULTS: From 732 patients diagnosed with uveal melanoma, 311 were treated with brachytherapy. In the follow-up (mean 79 months, standard deviation = 55), 16 local tumor recurrences (5.1%) were detected. All relapsing patients had choroidal tumors and 15 presented with visual symptoms. All patients were treated with I-125 brachytherapy, and 2 received associated transpupillary thermotherapy. All the eyes were enucleated after recurrence. Kaplan-Meier analysis showed a mean time of recurrence of 3.7 years (standard deviation = 2.94 years, ranging from 1 to 12 years). Three patients had metastasis in the follow-up. Kaplan-Meier analysis showed worse survival for patients with recurrence. CONCLUSION: Local treatment failure was a relatively infrequent event after I-125 brachytherapy in our series. Recurrences appear not only early but also late in the follow-up. They do not have a distinctive clinical pattern and are associated with poorer survival.

OPTIC NERVE MENINGOCELE SIMULATING EXTRAOCULAR EXTENSION OF CHOROIDAL MELANOMA.

PURPOSE: To report a case of optic nerve meningocele simulating massive, recurrent extraocular extension of choroidal melanoma. METHOD: Case report. RESULTS: A 53-year-old white man with choroidal melanoma in his left eye of 7.3-mm thickness was treated with plaque radiotherapy and transpupillary thermotherapy. On 1-year follow-up examination, visual acuity was 20/20 in the right eye and 20/30 in the left eye. The regressed choroidal melanoma scar in the left eye measured 1.5 mm in thickness with stable margins. The optic disk was normal. Ultrasonography demonstrated regressed echogenic choroidal scar, with an echolucent multilobulated retrobulbar mass, suspicious for extraocular extension. On magnetic resonance imaging, the retrobulbar mass corresponded to a distended and kinked optic nerve sheath, filled with extensive subarachnoid fluid and normal-size optic nerve with apposition against the posterior globe. There was no extraocular extension of tumor. Similar but less distended right optic nerve sheath was documented, consistent with optic nerve sheath meningocele in both eyes. Observation was advised and the findings remained stable. CONCLUSION: Optic nerve sheath meningocele is a benign dilatation of the optic nerve sheath that can simulate orbital tumor or extraocular extension of intraocular tumor. Magnetic resonance imaging can reliably differentiate these conditions.

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.

[Regional chemotherapy in treatment of patients with unresectable liver metastases of uveal melanoma].

PURPOSE: Retrospective efficacy analysis of transcatheter arterial treatment for unresectable liver metastases of uveal melanoma. MATERIALS AND METHODS: There were performed 38 courses: hepatic arterial chemoembolization with Lipiodol (HACE, n 9) and combination of HACE with hepatic artery infusion (HAI, n = 29). In 9 patients we used the following chemotherapeutic agents: doxorubicin (10-50mg), carboplatin (150 to 450 mg), dacarbazine (200-400mg), mustophoran (360-624mg) and mitomycinum C (5-10mg). RESULTS: There were no mortality or serious complication. According to mRECIST, partial response, stabilization and progression of liver metastases was seen in 1, 3 and 5 patients, retrospectively. The mean survival after arterial treatment was 9,4 (2-34) mo. The 6-, 12- and 18- mo survival rates were 56%, 22% and 11% respectively. CONCLUSION: Transcatheter therapy in unresectable liver metastases of uveal melanoma is safe and can prolong survival of selected patients up to 34 mo.

EXTRAOCULAR EXTENSION OF CILIOCHOROIDAL MELANOMA AFTER TRANSSCLERAL FINE-NEEDLE ASPIRATION BIOPSY.

PURPOSE: To describe development of extraocular extension of ciliochoroidal melanoma after transscleral fine-needle aspiration biopsy (FNAB) for cytogenetic studies. METHODS: Transscleral FNAB was performed for cytogenetic analysis of melanoma using a long 27-gauge needle attached to a 10-mL syringe by connector tubing entering obliquely through the sclera overlying the tumor base. An iodine 125 radioactive plaque was immediately applied to the sclera over the tumor and biopsy site after FNAB. PATIENTS: One patient with large ciliochoroidal melanoma of the right eye. RESULTS: Cytogenetic analysis of the melanoma revealed monosomy of chromosome 3. On examination, 18 months after plaque radiotherapy, there was regression of the tumor; however, a few small subepithelial pigmented lesions were noted in the conjunctiva close to the FNAB site. Excisional biopsy of the conjunctival pigmented lesions with 3 mm margins and with supplemental cryotherapy to the surrounding conjunctival margins and to the underlying sclera was performed. Histopathologic evaluation showed an oval nodule composed of a mixture of spindle and epithelioid cells deep within the substantia propria consistent with extraocular extension of uveal melanoma. Magnetic resonance imaging of the orbits showed no evidence of orbital involvement. This is the only case of extraocular extension developing among 408 consecutive transscleral biopsies (0.2%) performed at our center for cytogenetic or cytopathologic analysis. CONCLUSION: Although rare, transscleral FNAB of ciliochoroidal melanoma can lead to extraocular extension of the tumor through the biopsy site. Possible techniques to reduce the risk of this problem are discussed.

Oridonin induces apoptosis in uveal melanoma cells by upregulation of Bim and downregulation of Fatty Acid Synthase.

Oridonin is an orally available drug isolated from Traditional Chinese Medicine. Previous studies with oridonin have demonstrated broad-spectrum anticancer activity in a variety of cancer types. However, the effect of oridonin in uveal melanoma has not been addressed. In this study, we aimed to investigate whether oridonin elicited anticancer activity and its underlying mechanism in human uveal melanoma cells. We demonstrated that oridonin potently reduced cell viability, induced apoptosis and inhibited clonogenic survival and growth with single digit micromolar concentrations in uveal melanoma OCM-1 and MUM2B cell lines. We found that oridonin markedly increased the expression of proapoptotic Bcl-2 family protein Bim in uveal melanoma cells, and knockdown Bim by small interfering RNA significantly attenuated oridonin-induced cell death, indicating an essential role of Bim in oridonin-mediated anticancer activity. Additionally, we observed that oridonin suppressed Fatty Acid Synthase (FAS) expression in uveal melanoma cells, and enforced FAS expression by insulin partially rescued the cells from oridonin-induced apoptosis, showing that inhibition of FAS also contributed to oridonin-mediated apoptosis. Taken together, we reported that oridonin displays potent anticancer effect against uveal melanoma cells through upregulation of Bim and inhibition of FAS. Since oridonin is a popular anticancer agent, our study therefore may have translational implication on the management of patients with uveal melanoma.

Clinical Course of a Presumed Metastatic Uveal Melanoma to the Contralateral Choroid.

We present the ultrasound and optic coherence tomography follow-up of a presumed choroidal metastasis from a contralateral melanoma. A 53-year-old male was diagnosed with uveal melanoma with extraescleral extension in his left eye. A year later, the fundus examination revealed a flat, gray-green, pigmented choroidal lesion in the right eye. The ultrasonography showed a mass, almost flat, and all these findings were compatible with a choroidal melanocytic lesion with risk factors for growth. One month later, melanocytic skin lesions appeared on the scalp, as well as small tumors. Three months later, an ultrasonography on B scan showed a growth of the tumor size. The patient developed a progressive deterioration and died. Three possibilities can explain the occurrence of a choroidal pigmented tumor in the contralateral eye: first, bilateral primary choroidal melanomas; second, both choroidal tumors are metastatic in origin from an unknown primary melanoma; and third, the contralateral tumor is a metastatic tumor from the primary choroidal melanoma.

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.

MR-guided laser-induced thermotherapy (LITT) in patients with liver metastases of uveal melanoma.

PURPOSE: Evaluation of the local tumour control rate and survival data for magnetic resonance (MR) imaging-guided laser ablation of uveal malignant melanoma liver metastases by using laser-induced interstitial thermotherapy (LITT). MATERIALS AND METHODS: The LITT was performed in 18 patients with liver metastases (n = 44) from uveal malignant melanoma. All patients tolerated this intervention well. With the Kaplan-Meier method, the survival rates were calculated. Indications for the procedure were defined for patients with no more than five metastases, none of which were larger than 5 cm in diameter: The Indication for LITT treatment were recurrent liver metastases after partial liver resection (22%), locally non-resectable tumours (17%) or metastases in both liver lobes (61%). RESULTS: The mean survival rate for all treated patients was 3.6 years (95% CI: 2.19, 5.06). We started the calculation on the date of diagnosis of the metastases treated with LITT. The median survival was 1.83 years; 1-year survival, 88%; 3-year survival 47%, 5-year survival 17%. Calculated after the first LITT treatment the median survival was 2.8 years (95% CI: 1.0, 5.0). 10 patients were treated by transarterial chemoembolization before LITT. CONCLUSION: MR-guided LITT treatment shows a high local tumour control and survival rates in patients with liver metastases of uveal malignant melanoma.

Outcomes of iodine-125 plaque brachytherapy for uveal melanoma with intraoperative ultrasonography and supplemental transpupillary thermotherapy.

PURPOSE: To assess the impact on local tumor control of intraoperative ultrasonographic plaque visualization and selective application of transpupillary thermotherapy (TTT) in the treatment of posterior uveal melanoma with iodine-125 (I-125) episcleral plaque brachytherapy (EPB). METHODS AND MATERIALS: Retrospective analysis of 526 patients treated with I-125 EPB for posterior uveal melanoma. Clinical features, dosimetric parameters, TTT treatments, and local tumor control outcomes were recorded. Statistical analysis was performed using Cox proportional hazards and Kaplan-Meier life table method. RESULTS: The study included 270 men (51%) and 256 women (49%), with a median age of 63 years (mean, 62 years; range, 16-91 years). Median dose to the tumor apex was 94.4 Gy (mean, 97.8; range, 43.9-183.9) and to the tumor base was 257.9 Gy (mean, 275.6; range, 124.2-729.8). Plaque tilt >1 mm away from the sclera at plaque removal was detected in 142 cases (27%). Supplemental TTT was performed in 72 patients (13.7%). One or 2 TTT sessions were required in 71 TTT cases (98.6%). After a median follow-up of 45.9 months (mean, 53.4 months; range, 6-175 months), local tumor recurrence was detected in 19 patients (3.6%). Local tumor recurrence was associated with lower dose to the tumor base (P=.02). CONCLUSIONS: Ultrasound-guided plaque localization of I-125 EPB is associated with excellent local tumor control. Detection of plaque tilt by ultrasonography at plaque removal allows supplemental TTT to be used in patients at potentially higher risk for local recurrence while sparing the majority of patients who are at low risk. Most patients require only 1 or 2 TTT sessions.

Fotemustine chemoembolization of hepatic metastases from uveal melanoma: a retrospective single-center analysis.

OBJECTIVE: The purpose of the current study was to retrospectively evaluate response and survival in patients with hepatic metastasis from uveal melanoma treated by palliative transarterial chemoembolization (TACE) with fotemustine. MATERIALS AND METHODS: During the study period, 21 patients with hepatic metastases from uveal melanoma were treated by TACE. A series of TACE interventions (mean number per patient, 3.29 interventions; range, 1-6 interventions) was performed on each patient with an emulsion of fotemustine dissolved in 10 mL of saline mixed with 10 mL of an oily contrast agent. Tumor response based on the Response Evaluation Criteria in Solid Tumors was evaluated using contrast-enhanced CT scans obtained 6-10 weeks after embolization. RESULTS: CT showed partial regression after TACE in three patients (14%). Six patients (29%) presented with stable disease but no significant change in tumor size after TACE, and 12 patients (57%) presented with progressive disease after TACE treatment. The overall response rate was 43%. The mean survival after diagnosis of hepatic metastasis was 28.7 months. CONCLUSION: TACE of hepatic metastasis from uveal melanoma with fotemustine is well tolerated, and the survival rates in this study (mean, 28.7 months) are among the longest reported.