Metastatic Ocular Melanoma Research Articles

Clinical features and prognosis of patients with metastatic ocular and orbital melanoma: A bi-institutional study.

Metastatic ocular and orbital melanomas are extremely rare. The clinical characteristics and standard treatments for these patients are not fully established. We retrospectively analyzed patients with metastatic ocular and orbital melanoma from Fudan University Shanghai Cancer Center and Eye & ENT Hospital of Fudan University between January 2012 and May 2022. Overall, 51 patients with metastatic ocular and orbital melanoma were included. The most common primary sites were uvea (73%), followed by conjunctiva (22%), lacrimal sac (4%), and orbit (2%). Patients with uveal melanoma (UM) had a significantly younger age (48 vs. 68 years, p < 0.001), higher incidence of liver metastases (89% vs. 9%, p<0.001), a lower incidence of lymph nodes metastases (16% vs. 46%, p = 0.043) and a lower incidence of BRAF mutation (0% vs. 55%, p<0.001) compared with patients with conjunctival melanoma (CM). The overall response rate of the first-line treatment was 18%. Three of the four patients with BRAF-mutated CM responded to dabrafenib and trametinib treatment. The median progression-free survival (PFS) and overall survival (OS) of first-line treatment were 5.1 and 11.9 months, respectively. Among patients with liver metastases, liver-directed treatment was correlated with better patient PFS (p < 0.001) and OS (p < 0.001) after adjusting for number of metastatic sites and primary sites. CM and UM have different characteristics. Patient with CM had a high incidence of BRAF mutation, and the treatment of BRAF and MEK inhibitors conferred clinical benefit. Liver directed therapies had a potential benefit in disease control in patients with liver metastases.

Abstract CT207: Phase I trial of vesicular stomatitis virus expressing human interferon beta and tyrosinase related protein 1 (VSV-IFNb-TYRP1) in metastatic ocular melanoma

Abstract Oncologic viruses (OV) can induce tumor death through both direct oncolysis and immune-mediated destruction. Our study investigates the use of a novel OV with a Vesicular Stomatitis Virus (VSV) vector modified to express interferon-beta (IFN-b) and Tyrosinase Related Protein 1 (TYRP1) (VSV-IFNb-TYRP1). VSV is an attractive vector since humans are not naturally infected with VSV; thus, pre-existing immunity is minimal. IFN-b leads to increased T-cell responses and tumor cell apoptosis, while TYRP1, a melanocyte differentiation antigen, increases immunogenicity of the therapy. We conducted a Phase 1 clinical trial with a 3+3 design in patients with metastatic uveal melanoma. VSV-IFNb-TYRP1 was injected into a liver metastasis under image guidance, then administered on the same day as a single intravenous (IV) infusion. IV doses started at dose level (DL) 1 1 × 1010 TCID50, then escalated to DL2 3 × 10 10, DL3 1 × 1011, and DL4 3 × 1011. The dose delivered intratumorally (IT) varied based on the IV dose. The primary endpoints were safety and maximum tolerated dose (MTD). Efficacy was a secondary endpoint. Correlative studies focused on understanding viral pharmacokinetics (PK) and immunological responses induced by VSV-IFNb-TYRP1 therapy. Twelve patients with previously treated metastatic uveal melanoma were enrolled. Median follow up was 19.1 months. Four DLs were evaluated with one patient at DL4 experiencing dose limiting toxicities (DLTs), including decreased platelet count (grade 3), increased aspartate aminotransferase (AST), and cytokine release syndrome (CRS). Non-DLTs at DL4 were fatigue, fever, CRS, hematological toxicities (decreased platelets and lymphocytes), and AST elevation. Four patients had stable disease (SD) and 8 had progressive disease (PD) as their best response. ELIspot data show that three of the four patients with response to TYRP1 also had a response to gp100, suggesting possible epitope spreading. These four patients received immune checkpoint inhibitor treatment as the next line of therapy, which led to clinical benefit for two patients. Our study evaluated VSV-IFNb-TYRP1 administered via IT and IV routes in a previously treated population of metastatic uveal melanoma patients and found no major safety events. Although there were no clear objective responses to VSV-IFNb-TYRP1, dose-dependent immunogenicity to melanoma antigens was seen. While OV response alone is not sufficient for clinical benefit, the evidence of epitope spreading is encouraging. Future studies of VSV-IFNb-TYRP1 will evaluate combinations with other therapies. Citation Format: Katherine E. Smith, Adam Weisbrod, Carrie Strand, Jacob Allerd, Jose S. Pulido, Alysha Newsom, Lianwen Zhang, Nandakumar Packiriswamy, Heather Montane, Lisa Kottschade, Anastasios Dimou, Yiyi Yan, Markovic Svetomir, Kah Whye Peng, Richard G. Vile, Matthew S. Block, Roxana S. Dronca. Phase I trial of vesicular stomatitis virus expressing human interferon beta and tyrosinase related protein 1 (VSV-IFNb-TYRP1) in metastatic ocular melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT207.

Chemosaturation of the Liver - an Update.

Percutaneous hepatic perfusion (CS-PHP) is a treatment option for primary and secondary liver neoplasms and subject of intensive research. This present article provides an overview of CS-PHP regarding patient safety, feasibility and effectiveness based on recent studies. We performed a PubMed search including the search terms chemosaturation, hepatic chemosaturation, percutaneous perfusion and melphalan. CS-PHP is a promising procedure for the treatment of uveal melanoma and cholangiocellular carcinoma. There are insufficient data regarding the effectiveness of CS-PHP with respect to other tumor entities. Since CS-PHP can be accompanied by multiple transient side effects and complications, close interdisciplinary cooperation is necessary. · Chemosaturation of the liver is a safe procedure.. · CS-PHP is a potent therapy for hepatic metastatic ocular melanoma and cholangiocellular carcinoma.. · The procedure requires close interdisciplinary coordination.. · CS-PHP is a repeatable and thus long-term therapeutic option for some patients.. · Ebel S, Struck MF, van Boemmel F et al. Chemosaturation of the Liver - an Update. Fortschr Röntgenstr 2023; 195: 30 - 37.

Efficacy of immunotherapy and sequencing of checkpoint inhibition for metastatic ocular melanoma.

e21526 Background: Ocular melanoma (OM) is the most common intraocular tumor in adults. However, it is still rare as compared to other subtypes of melanoma. Treatment of primary OM is certainly successful, but most therapies assessed in treatment of metastatic OM have not shown promise. Immunotherapy (IO), which has otherwise held prospect for durable remissions in other metastatic melanoma has shown no evidence in metastatic OM. Our study aims at narrowing the gap in knowledge in the treatment of OM with IO. Methods: We conducted a retrospective cohort study of patients with metastatic OM treated during the period 2017-2021 at the University of Louisville. Patients aged 18 years or more with treatment-naïve metastatic (Stage IV) OM were included. Data was censored according to date of last recorded clinical follow up or death. The primary outcome of interest was overall survival (OS). Subgroup analysis was done to examine survival based on initial treatment with dual versus single checkpoint inhibition. After progression on initial therapy, patients previously on dual inhibition went on to receive single inhibition, and vice versa. Kaplan-Meier survival analyses were generated using all-cause mortality as the competing outcome event and log-rank testing to evaluate differences between groups with alpha set at 0.05 for significance. Results: A total of 21 patients with Stage IV OM were identified with 4 excluded due to lack of data. The majority were male (10/17) and median age was 66 years, ranging from 30 to 89 years. More than half (10/17) received dual checkpoint inhibition as initial IO, with ipilimumab and nivolumab. The remainder received pembrolizumab or Nivolumab monotherapy (7/17). IO was well tolerated with no treatment related mortality and incidence of immune-related adverse effects similar to cutaneous melanoma. The median follow-up time overall was 56 months using the reverse Kaplan-Meier method with a median OS of 15 months. Estimated 2-year OS was 41%. No significant difference was found between single and dual checkpoint inhibition as the initial treatment regimen. Conclusions: While IO has markedly improved survival in advanced melanomas, OM continues to have inferior survival. Consistent with the literature by Zimmer et al, survival in this cohort is better than that reported with ipilimumab monotherapy. The median survival of 15 months is consistent with that reported by Heppt et al in the German multicenter study. IO for Stage IV OM was well tolerated, resulting in median survival of 15 months and 2-year OS of 41%. There was no survival advantage to initial treatment with single versus dual checkpoint inhibition, allowing for crossover at progression. Further research with novel agents and enrollment in clinical trials are needed in ocular melanoma.

Laparoscopic distal pancreatectomy for metastatic melanoma originating from the choroidal membrane: a case report

BackgroundMetastatic melanoma originating from the choroidal membrane is extremely rare. Here, we report a case of laparoscopic distal pancreatectomy for malignant melanoma that developed after heavy-particle therapy for malignant choroidal melanoma.Case presentationA 43-year-old Japanese woman underwent 70 Gy heavy-particle radiotherapy for a right choroidal malignant melanoma. Positron emission tomography-computed tomography examination was performed 4 years after treatment, when contrast accumulation was observed on the posterior wall of the stomach. Endoscopic ultrasonography and computed tomography showed a mass with contrast enhancement in contact with the stomach wall. Based on the imaging findings, a gastrointestinal stromal tumor of the posterior wall of the lower gastric corpus with extramural growth was suspected. Laparoscopic surgery was performed under general anesthesia. A black-pigmented tumor originating from the pancreas was discovered. Following an intraoperative diagnosis of metastasis of malignant melanoma, a laparoscopic distal pancreatectomy was performed. The pathological diagnosis was pancreatic metastasis of malignant melanoma. The patient was treated with adjuvant immune checkpoint inhibitors and chemotherapy after surgery, which led to long-term survival.ConclusionsIncluding this case, only eight case reports on pancreatic resection for metastatic ocular malignant melanoma have been reported. The ocular malignant melanoma with distant metastasis has a poor prognosis. Therefore, in our case, careful follow-up is required. A single pancreatic metastasis from a malignant melanoma of the choroid can be successfully managed by laparoscopic radical resection of the pancreas, and molecularly targeted adjuvant chemotherapy.

Ortho- and Ectopic Zebrafish Xeno-Engraftment of Ocular Melanoma to Recapitulate Primary Tumor and Experimental Metastasis Development.

There are currently no animal models for metastatic ocular melanoma. The lack of metastatic disease models has greatly hampered the research and development of novel strategies for the treatment of metastatic ocular melanoma. In this protocol we delineate a quick and efficient way to generate embryonic zebrafish models for both the primary and disseminated stage of ocular melanoma, using retro-orbital orthotopic and intravascular ectopic cell engraftment, respectively. Combining these two different engraftment strategies we can recapitulate the etiology of cancer in its totality, progressing from primary, localized tumor growth under the eye to a peri-vascular metastasis formation in the tail. These models allow us to quickly and easily modify the cancer cells prior to implantation with specific labeling, genetic or chemical interference; and to treat the engrafted hosts with (small molecular) inhibitors to attenuate tumor development. Here, we describe the generation and quantification of both orthotopic and ectopic engraftment of ocular melanomas (conjunctival and uveal melanoma) using fluorescently labelled stable cell lines. This protocol is also applicable for engraftment of primary cells derived from patient biopsy and patient/PDX derived material (manuscript in preparation). Within hours post engraftment cell migration and proliferation can be visualized and quantified. Both tumor foci are readily available for imaging with both epifluorescence microscopy and confocal microscopy. Using these models, we can confirm or refute the activity of either chemical or genetic inhibition strategies within as little as 8 days after the onset of the experiment, allowing not only highly efficient screening on stable cell lines, but also enables patient directed screening for precision medicine approaches.

Ortho- and Ectopic Zebrafish Xeno-Engraftment of Ocular Melanoma to Recapitulate Primary Tumor and Experimental Metastasis Development

There are currently no animal models for metastatic ocular melanoma. The lack of metastatic disease models has greatly hampered the research and development of novel strategies for the treatment of metastatic ocular melanoma. In this protocol we delineate a quick and efficient way to generate embryonic zebrafish models for both the primary and disseminated stage of ocular melanoma, using retro-orbital orthotopic and intravascular ectopic cell engraftment, respectively. Combining these two different engraftment strategies we can recapitulate the etiology of cancer in its totality, progressing from primary, localized tumor growth under the eye to a peri-vascular metastasis formation in the tail. These models allow us to quickly and easily modify the cancer cells prior to implantation with specific labeling, genetic or chemical interference; and to treat the engrafted hosts with (small molecular) inhibitors to attenuate tumor development. Here, we describe the generation and quantification of both orthotopic and ectopic engraftment of ocular melanomas (conjunctival and uveal melanoma) using fluorescently labelled stable cell lines. This protocol is also applicable for engraftment of primary cells derived from patient biopsy and patient/PDX derived material (manuscript in preparation). Within hours post engraftment cell migration and proliferation can be visualized and quantified. Both tumor foci are readily available for imaging with both epifluorescence microscopy and confocal microscopy. Using these models, we can confirm or refute the activity of either chemical or genetic inhibition strategies within as little as 8 days after the onset of the experiment, allowing not only highly efficient screening on stable cell lines, but also enables patient directed screening for precision medicine approaches.

NCDB Analysis of Melanoma 2004-2015: Epidemiology and Outcomes by Subtype, Sociodemographic Factors Impacting Clinical Presentation, and Real-World Survival Benefit of Immunotherapy Approval.

Simple SummaryMelanoma is clinicopathologically a heterogeneous disease with rising incidence. Metastatic disease is associated with poor outcomes, and immunotherapy was first approved in 2011 for its treatment. In our analysis of a large national database, we describe the epidemiology, clinical presentation, and survival outcomes of cutaneous, ocular, and mucosal melanoma in recent years. Metastatic cutaneous melanoma had better survival than both metastatic ocular and mucosal melanoma. We found higher odds of metastatic disease at diagnosis amongst African Americans compared to Caucasians. Additionally, for metastatic cases, we noted 25% lower mortality in those treated at an academic facility compared to community cancer programs and a 20% real-world survival benefit following approval of immunotherapy. This real-world survival benefit was definitely seen in Caucasians and those with cutaneous or mucosal melanoma. Further investigation is needed to confirm this benefit in African Americans and ocular melanoma.Background: The incidence of invasive melanoma is rising, and approval for the first immune checkpoint inhibitor (ICI) to treat metastatic melanoma occurred in 2011. We aim to describe the epidemiology and outcomes in recent years, sociodemographic factors associated with the presence of metastasis at diagnosis, and the real-world impact of ICI approval on survival based on melanoma subtype and race. Methods: This is a retrospective analysis of the National Cancer Database (NCDB) from the years 2004–2015. The primary outcome was the overall survival of metastatic melanoma by subtype. Secondary outcomes included sociodemographic factors associated with the presence of metastasis at diagnosis and the impact of treatment facility type and ICI approval on the survival of metastatic melanoma. Results: Of the 419,773 invasive melanoma cases, 93.80% were cutaneous, and 4.92% were metastatic at presentation. The odds of presenting with metastatic disease were higher in African Americans (AA) compared to Caucasians (OR 2.37; 95% CI 2.11–2.66, p < 0.001). Treatment of metastatic melanoma at an academic/research facility was associated with lower mortality versus community cancer programs (OR 0.75, 95 % CI 0.69–0.81, p-value < 0.001). Improvement in survival of metastatic melanoma was noted for Caucasians after the introduction of ICI (adjusted HR 0.80, 95% CI 0.78–0.83, p < 0.001); however, this was not statistically significant for AA (adjusted HR 0.80, 95% CI 0.62–1.02, p-value = 0.073) or ocular cases (HR 1.03, 95% CI 0.81–1.31, p-value = 0.797). Conclusion: Real-world data suggest a 20% improvement in survival of metastatic melanoma since the introduction of ICI. The disproportionately high odds of metastatic disease at presentation in AA patients with melanoma suggest the need for a better understanding of the disease and improvement in care delivery.

Ocular Melanoma Presenting as Masquerade Syndrome.

A masquerade syndrome is an ophthalmological entity where a neoplasm mimics an inflammatory condition. Ocular melanoma (chiefly uveal) may present with symptoms suggestive of intraocular inflammation such as endogenous endophthalmitis. Ocular melanoma is most commonly found in middle-aged and older caucasian patients. One-third of all uveal melanoma cases present asymptomatically. Early diagnosis facilitates treatment before ocular melanoma reaches metastatic stage IV. Current therapy options for stage IV patients are palliative care and clinical trial participation.LEARNING POINTSMasquerade syndrome and intraocular haemorrhage can hide a neoplastic aetiology.A biopsy should be carried out for correct diagnosis if intraocular haemorrhage is present and a neoplastic pathology is suspected.A multidisciplinary approach should be adopted to enhance the quality of life of patients with metastatic ocular melanoma.

Hepatic artery infusion of melphalan in patients with liver metastases from ocular melanoma.

Ocular melanoma has a predilection for liver metastases. Systemic treatment is ineffective and the optimal regional therapy approach is poorly defined. Isolated hepatic perfusion (IHP) with melphalan has emerged as a viable treatment option, however a subset of patients are not candidates for this treatment. We therefore sought to determine if melphalan could be safely administered via the hepatic artery for these patients. A retrospective review of patients treated with hepatic artery infusion (HAI) of melphalan was undertaken. All patients had contraindications to IHP and were without other therapy options. Melphalan infusion was repeated every four weeks with consideration for dose escalation in the absence of toxicity or significant disease progression. Fourteen patients were treated with HAI of melphalan from 2010 to 2015. All patients had hepatic dysfunction or prohibitive tumor volume precluding IHP. There were no procedure-related complications. Three patients (21%) died within 30 days and the median survival was 2.9 months. Elevated baseline bilirubin > 2.5 mg/dL was associated with worse overall survival (0.93 vs 6.3 months, P < 0.05). HAI of melphalan is safe and feasible for patients with metastatic ocular melanoma. Further study to determine the optimal utilization of this treatment approach is warranted.

268 Metastatic Ocular Melanoma to the Ovary Mimicking a Primary Ovarian Tumor, an Interesting and Rare Case Report

268 Metastatic Ocular Melanoma to the Ovary Mimicking a Primary Ovarian Tumor, an Interesting and Rare Case Report

Treatment of metastatic uveal melanoma with adoptive transfer of tumour-infiltrating lymphocytes: a single-centre, two-stage, single-arm, phase 2 study

Uveal melanoma is a rare tumour with no established treatments once metastases develop. Although a variety of immune-based therapies have shown efficacy in metastatic cutaneous melanoma, their use in ocular variants has been disappointing. Recently, adoptive T-cell therapy has shown salvage responses in multiple refractory solid tumours. Thus, we sought to determine if adoptive transfer of autologous tumour-infiltrating lymphocytes (TILs) could mediate regression of metastatic uveal melanoma. In this ongoing single-centre, two-stage, phase 2, single-arm trial, patients (aged ≥16 years) with histologically confirmed metastatic ocular melanoma were enrolled. Key eligibility criteria were an Eastern Cooperative Oncology Group performance status of 0 or 1, progressive metastatic disease, and adequate haematological, renal, and hepatic function. Metastasectomies were done to procure tumour tissue to generate autologous TIL cultures, which then underwent large scale ex-vivo expansion. Patients were treated with lymphodepleting conditioning chemotherapy (intravenous cyclophosphamide [60 mg/kg] daily for 2 days followed by fludarabine [25 mg/m2] daily for 5 days, followed by a single intravenous infusion of autologous TILs and high-dose interleukin-2 [720 000 IU/kg] every 8 h). The primary endpoint was objective tumour response in evaluable patients per protocol using Response to Evaluation Criteria in Solid Tumors, version 1.0. An interim analysis of this trial is reported here. The trial is registered at ClinicalTrials.gov, number NCT01814046. From the completed first stage and ongoing expansion stage of this trial, a total of 21 consecutive patients with metastatic uveal melanoma were enrolled between June 7, 2013, and Sept 9, 2016, and received TIL therapy. Seven (35%, 95% CI 16-59) of 20 evaluable patients had objective tumour regression. Among the responders, six patients achieved a partial response, two of which are ongoing and have not reached maximum response. One patient achieved complete response of numerous hepatic metastases, currently ongoing at 21 months post therapy. Three of the responders were refractory to previous immune checkpoint blockade. Common grade 3 or worse toxic effects were related to the lymphodepleting chemotherapy regimen and included lymphopenia, neutropenia, and thrombocytopenia (21 [100%] patients for each toxicity); anaemia (14 [67%] patients); and infection (six [29%] patients). There was one treatment-related death secondary to sepsis-induced multiorgan failure. To our knowledge, this is the first report describing adoptive transfer of autologous TILs to mediate objective tumour regression in patients with metastatic uveal melanoma. These initial results challenge the belief that metastatic uveal melanoma is immunotherapy resistant and support the further investigation of immune-based therapies for this cancer. Refinement of this T-cell therapy is crucial to improve the frequency of clinical responses and the general applicability of this treatment modality. Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.

Metastatic ocular melanoma to the liver exhibits infiltrative and nodular growth patterns

We examined liver specimens from 15 patients with uveal melanoma (UM) who had died of their disseminated disease. We found 2 distinct growth patterns of UM metastasis: infiltrative (n = 12) and nodular (n = 3). In the infiltrative pattern, individual UM cells with a CD133+ cancer stem cell-like phenotype were present and formed aggregates of stage I <50-μm-diameter micrometastases in the sinusoidal spaces. These micrometastases appeared to expand, destroy adjacent hepatocytes, and form stage II 51- to 500-μm-diameter and then stage III >500μm-diameter metastases, which were encapsulated by collagenized fibrous septae. In the nodular growth pattern, CD133+ melanoma cells aggregated adjacent to portal venules and subsequently appeared to grow and efface the adjacent hepatocytes to form stage II 51- to 500-μm-diameter nodules that surrounded the portal venule. These avascular nodules appeared to further expand to form stage III >500-μm-diameter nodules that exhibited vascularization with minimal fibrosis. The tumor stem cell-like phenotype seen in individual UM cells was lost as the tumors progressed. There were CD56+ natural killer cells in sinusoidal spaces and CD3+ lymphocytes in periportal areas. The nodular growth pattern showed UM cells expressing MMP9 and VEGF. UM cells in both above-described growth patterns exhibited variable BAP1 expression. We propose that changes in the liver microenvironment are related to metastatic UM growth. We hypothesize that these changes include immune regulation within the sinusoidal space for the infiltrative pattern and changes in the VEGF/PEDF ratio for the nodular pattern.

Oliver Wolf Sacks, BMBCh, FRCP, CBE (1933–2015)

Oliver Wolf Sacks, BMBCh, FRCP, CBE. Figure credit: James Estin/The New York Times/Redux Oliver Sacks died on August 30, 2015, at the age of 82 years, from metastatic ocular melanoma. He was a physician and a Professor of Neurology, but is of course best known as an author who used case histories to illustrate the personal aspects of neurologic conditions for the layman and professional alike. Dr. Sacks had great empathy and deep respect for individuals with chronic neurologic diseases and their capacity to adapt, but did not gloss over the harsh realities of their conditions and the suffering they had to endure. He wrote about dementia and visual agnosia ( The Man Who Mistook His Wife For a Hat , 1985),1 deafness ( Seeing Voices , 1989),2 autism and Tourette syndrome ( An Anthropologist on Mars , 1995),3 achromatopsia and Guam neurodegeneration ( The Island of The Color Blind , 1997),4 migraine headaches ( Migraine , 1970),5 hallucinations ( Hallucinations , 2012),6 and the relationship between music and a variety of brain disorders ( Musicophilia: Tales of Music and the Brain , 2007).7 He even used himself as a subject, writing about losing awareness of one of his legs after an accident ( A Leg To Stand On , 1984),8 in which he explored the “Arctics and Tropics of neurologic disorders.” He is best known for writing Awakenings (1973),9 in which he described patients with encephalitis lethargica who had been in a longstanding catatonic state until they were treated with the newly discovered levodopa. The story was immortalized in a movie starring Robin Williams and Robert De Niro ( Awakenings , 1990), which brought the horrors of a …

Low thyroid hormone levels improve survival in murine model for ocular melanoma.

Uveal melanoma is highly metastatic, prognosis is poor and there are no effective treatments to extend survival. Accumulating evidence suggests that thyroid hormones have a mitogenic effect via binding to αvβ3 integrin. We aimed to examine the impact of thyroid status on survival in a murine B16F10 model for ocular melanoma, highly expressing the integrin. In two independent experiments oral propylthiouracil (PTU) was used to induce hypothyroidism (n=9), thyroxine to induce hyperthyroidism (n=11) and mice given plain water served as control (n=8). At day 21, the subretinal space was inoculated with 10(2) B16F10 cells. In non-inoculated mice (n=6 of each group) serum free T4 (FT4) levels were measured and additional non-inoculated mice (3 given PTU and 4 given thyroxine or water) served as internal control to demonstrate the impact of the dissolved substance. The PTU-inoculated mice showed clinical evidence of intraocular tumor growth significantly later than the thyroxine mice (P=0.003) and survival time was significantly longer (P<0.001). FT4 levels differed significantly between groups (P<0.001) and with no signs of illness in the internal control group. Our findings suggest that hyperthyroidism shortens survival, whereas relative hypothyroidism may have a protective role in metastatic ocular melanoma.

100. A single institution experience with percutaneous hepatic perfusion for unresectable melanoma or sarcoma to the liver

Background: Patients (pts) with unresectable melanoma or sarcoma metastases to the liver have a poor prognosis and few therapeutic options. Percutaneous hepatic perfusion (PHP) is a minimally invasive, catheter directed method of isolating the liver, perfusing with high dose chemotherapy with extracorporeal hemofiltration and systemic return via venovenous bypass. A recently completed, randomized, phase III clinical trial has shown promise with a significantly improved hepatic progression free survival (hPFS) in pts with metastatic ocular or cutaneous melanoma to the liver undergoing PHP, [hPFS 8 months] over best alternative care [hPFS 1.6 months], p<0.0001.

Preclinical scheduling for metastatic ocular melanoma treatment by using a xenograft model approach

AbstractPurpose The prognosis for patients with disseminated ocular melanoma is poor. Responses to standard chemotherapy are low and serious toxicities are common. Here, we determine the feasibility of treating melanoma xenograft models in mice in order to guide the selection of treatments in metastatic patients.Methods A patient‐derived xenograft model was established in SCID mice for metastatic choroidal and conjunctival melanoma. Mice bearing growing tumors were randomly assigned to the control or treatment groups. Mice were treated with dacarbazine and everolimus in the choroidal melanoma model. Dacarbazine and dabrafenib were used in the conjunctival melanoma model.Results Everolimus resulted in tumor stasis in the choroidal melanoma model while dacarbazine had no antitumor effect. In the conjunctival melanoma model the relative tumor volumes in mice treated with dacarbazine and dabrafenib were similar to the control group. Since this is a feasibility study we included only a limited number of cancer drugs. More drugs will have to be screened in future studies. The oncologists in our institution were aware of the results but it had no influence on the choice of treatments for the patients. To our knowledge this is the first report of a conjunctival melanoma xenograft model in SCID mice.Conclusion Our results suggest that ocular melanoma xenograft models can be used to determine which drugs achieve antitumor activity. These data could help oncologists in the choice of treatments for metastatic patients.

The Mayo Clinic experience with the use of kinase inhibitors (KIs), ipilimumab, and bevacizumab in the treatment of metastatic ocular melanoma.

e20011 Background: We sought to evaluate our experience treating metastatic ocular melanoma (metOM), for which no standard treatment exists. Methods: We retrospectively reviewed all cases of metOM ...

Metastatic melanoma to the liver: A contemporary and comprehensive review of surgical, systemic, and regional therapeutic options

Effective management of hepatic metastases from ocular and cutaneous melanoma remains a major therapeutic challenge. Treatment options include hepatic resection, hepatic intra-arterial (HIA) chemotherapy, chemoembolization, and hepatic perfusions. Evaluating the efficacy of these interventions is limited by the retrospective nature of most of the data, although controlled phase 3 studies are starting to emerge. Studies of hepatic resection are strongly suggestive of a survival benefit following surgery in selected patients. Effective systemic agents for metastatic cutaneous melanoma are available and supported by randomized controlled phase 3 trials. In contrast, no active systemic treatment has yet been identified for metastatic ocular melanoma. HIA and intravenous delivery of fotemustine have been compared in a randomized phase 3 trial in patients with unresectable metastases from melanoma, but no differences between the 2 approaches were observed. Hepatic arterial chemoembolization appears only to be moderately effective according to uncontrolled studies; targeting patients with less liver involvement may improve outcomes. A recent phase 3 study showed a significant improvement in hepatic progression-free survival with percutaneous hepatic perfusion compared with best alternative care in patients with metastatic melanoma; however, the overall survival analysis was confounded by crossover of control patients to active treatment. In conclusion, hepatic resection offers the possibility of long-term survival in carefully selected patients with liver-limited metastases from melanoma. In patients with unresectable cutaneous melanoma, effective systemic therapy is the best treatment option. For patients with unresectable ocular melanoma, regional treatments are likely to assume a greater role until effective systemic treatments are identified.

Isolated hepatic perfusion for metastatic melanoma

Unresectable hepatic metastases from melanoma present a challenge to the physician. Although there have been advances in systemic therapies for patients with metastatic cutaneous melanoma to the liver, the overall prognosis is poor and is worse in patients with metastatic ocular melanoma. Isolated hepatic perfusion, open or percutaneous, allows high doses of cytotoxic chemotherapy to be delivered directly to the liver while minimizing systemic exposure, and has emerged as a viable treatment options for these complex patients.