Metastatic Ocular Melanoma Research Articles

Abstract 776: Functional analysis of BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase) in melanoma.

Abstract In the US alone, 44,250 men and 32,000 women are expected to be diagnosed with melanoma in 2012. Metastatic melanoma is the leading cause of skin cancer-related deaths worldwide. In the metastatic cutaneous melanoma (CM), anti-BRAF and anti-MEK agents have recently been shown to attenuate progression of the disease, though durable responses are still rare (NEJM articles). For metastatic ocular melanoma (OM), there is currently no established treatment strategy. Thus, one major unmet need in the field is the identification of novel “driver” physiologies which underpin the progression of disease and which can be leveraged for therapeutic gain. One new component in the ubiquitination pathway that has been recently implicated in the biology of both CM and OM is BRCA1 associated protein-1 (BAP1). Preliminary data from our laboratory showed that germline inactivating mutations of BAP1 predispose individuals to both CM and metastatic OM along with other neoplasms. In this study we examined the effects of BAP1 knockdown and overexpression on melanoma cell lines and primary melanocytes. BAP1 gene is mutated in melanoma and reported to be tumor suppressor, however suppression of BAP1 led to paradoxical growth inhibition, suggesting that the effects of BAP1 may be context dependent. Currently we are performing global gene expression and allele specific functional studies in an effort to identify novel substrates and other pathways impacted by BAP1. These findings may provide mechanistic insight into the role of BAP1 in melanoma pathogenesis. Citation Format: Raj Kumar, Ching-Ni Njauw, Zhenyu Ji, Benchun Miao, Michael Taylor, Anpuchchelvi Rajadurai, Durga Udayakumar, Hensin Tsao. Functional analysis of BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase) in melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 776. doi:10.1158/1538-7445.AM2013-776

Analysis of toxicity and outcomes in patients undergoing hyperthermic isolated hepatic perfusion with melphalan for metastatic melanoma to the liver.

178 Background: Ocular melanoma (OM) has an annual incidence of 3500 to 4000 patients per year, with liver metastases (LM) accounting for the sole or dominant site of metastases in more than 80% of patients. For patients with LM, median survival is reported to be 2 to 7 months, with an estimated 1-year survival of 10%. We present results utilizing liver directed therapy with high-dose melphalan administered via hypertermic isolated hepatic perfusion (IHP) for patients with unresectable LM from OM. Methods: Between 10/1994 and 6/2012, 105 pts with unresectable LM underwent a 60 min hyperthermic (IHP) with melphalan (1-2 mg/kg IBW). IHP included hepatic isolation at laparotomy with inflow via a cannula in the gastroduodenal artery and outflow via a cannula in the isolated retrohepatic vena cava (IVC). Patients were followed for toxicity, radiographic response (WHO criteria), and hepatic progression-free (HPFS) and overall survival (OS). HPFS and OS probabilities were calculated by Kaplan-Meier. Results: There were 51 males and 54 females (mean age: 50 yr [range: 21-76]) with unresectable OM LM (median # metastases: 26 [range: 3-50]; median percent liver replaced by tumor: 22%). There were 3 operative/treatment mortalities (2.9%). There were 62 responses (CR: n=6, PR: 56) in 102 evaluable patients (61%). For all treated patients, median OS was 12 months (range: 1 to 115 months) with 2 and 3-yr survival of 31% and 21%, respectively. Conclusions: IHP with melphalan results in marked tumor regression and prolonged OS in patients with high hepatic tumor burden from metastatic OM. Although this is a non-randomized trial, response to IHP is associated survival superior to that reported with alternative therapies.

Ocular Melanoma Metastasizing to Intra-Abdominal Lymph Nodes

Background. Visceral metastatic spread of ocular melanoma most commonly occurs via hematogenous route to the liver. Lymphatic spread of ocular melanoma into abdominal lymph nodes has not been reported previously. Case Presentation. A 47-year-old man with a history of ocular melanoma presented with a soft tissue mass on CT scan. The mass encased the portal structures of the hepaticoduodenal ligament. Image-guided biopsy revealed it to be a metastatic melanoma to lymph nodes. The patient underwent surgery with the intent to prolong disease-free survival. On final pathological examination, two lymph nodes were found harboring metastatic melanoma. Conclusion. Extrahepatic lymphatic intra-abdominal spread of ocular melanoma is not impossible. Since this mode of spread is rare, the oncologic significance of surgical resection of isolated intra-abdominal nodal with metastatic ocular melanoma is difficult to determine at the present time.

1130P - Efficacy and Safety of Ipilimumab in Patients with Pretreated, Mucosal Melanoma: Experience from Italian Clinics Participating in the European Expanded Access Programme (EAP)

ABSTRACT Purpose Ocular melanoma is a rare malignancy with an incidence of 5.3–10.9 cases per million per year (Papastefanou and Cohen; J Skin Cancer 2011). Currently, the treatment of metastatic ocular melanoma is limited by the lack of an effective systemic therapy. The EAP provided an opportunity to assess the activity and safety of ipilimumab in patients with ocular melanoma outside of a controlled clinical trial in patients from the EAP in Italy. Methods Ipilimumab was available upon physician request for patients aged ≥16 years with stage III (unresectable) or stage IV skin, ocular or mucosal melanoma, who had failed or did not tolerate previous treatments and for whom no therapeutic option was available. Patients were treated with ipilimumab 3 mg/kg every 3 weeks for 4 doses. Tumour assessments were conducted at baseline and after completion of induction therapy using immune-related response criteria. Patients were monitored for adverse events (AEs), including immune-related AEs, within 3 to 4 days of each scheduled visit using Common Terminology Criteria for Adverse Events v.3.0. Results Of 848 Italian patients participating in the EAP, 83 (9.8%) had ocular melanoma. Of these 83 patients, 55 have data available. With a median follow-up of 3 months, the disease control rate among 46 evaluable patients was 34.8%, including 3 patients with a partial response and 13 with stable disease. As of April 2012, median progression-free survival and overall survival among patients with ocular melanoma were 2.9 months and 5.9 months, respectively. In total, 63.6% patients reported an AE of any grade, most of which were drug-related (47.3%). Grade 3/4 AEs, which were reported by 20.0% patients, were only considered drug-related in 5.4%. AEs were generally manageable and most resolved with treatment as per protocol-specific guidelines. Conclusions Safety and early efficacy results are similar to experience in other melanoma populations, thus suggesting that treatment of ocular melanoma with ipilimumab warrants further investigation in prospective clinical trials. Disclosure M. Maio: Michele Maio has acted as an advisor for Bristol-Myers Squibb and Roche. V. Chairion Sileni: Vanna Chiaron Sileni has acted as an advisor for Bristol-Myers Squibb, Roche, GlaxoSmithKline, Merck Sharp & Dohme and Schering-Plough. P. Queirolo: Paola Queirolo has acted as an advisor for Roche, GlaxoSmithKline, Bristol-Myers Squibb and Schering-Plough and received honoraria from Bristol-Myers Squibb and Roche. P.A. Ascierto: PA has served as a consultant/advisor for Merck Sharp & Dohme, and as an advisor to Bristol-Myers Squibb (BMS), Roche, GlaxoSmithKline, Amgen, Celgene, Medimmune and Novartis. He has received honoraria from BMS, Merck Sharp & Dohme and Roche. All other authors have declared no conflicts of interest.

Combined surgical resection and radiofrequency ablation as treatment for metastatic ocular melanoma

Ocular melanoma is a rare disease with a strong predilection for the liver. Systemic and locoregional treatments for metastatic ocular melanoma have had disappointing results, with an average survival of 5-7 months. Resection and/or radiofrequency ablation (RFA) of liver lesions were attempted to improve the patient outcomes. Eight patients with liver metastasis from ocular melanoma underwent surgery and/or RFA at the University of Southern California, University Hospital from 1 January 2001 to 31 December 2009. Their charts were retrospectively reviewed. All patients had undergone eye enucleation as the primary treatment. Four patients had all metastatic liver lesions addressed: one patient underwent left lateral segmentectomy and three patients had combinations of left lateral segmentectomies, wedge resections and RFA of two to four lesions. Two patients underwent surgical biopsies for diagnosis, one patient was unresectable and one patient underwent RFA of a dominant lesion. The median survival was 36 months. The median survival of patients who underwent surgery alone or in conjunction with RFA to address all liver lesions was 46 months. There are few reports of RFA for metastatic ocular melanoma. RFA of liver lesions in addition to resection can perhaps lead to improved survival and may play a critical role in the future management of this disease.

Nab-paclitaxel salvage chemotherapy for metastatic ocular melanoma.

e19042 Background: Metastatic ocular melanoma is an incurable malignancy characterised by liver predominant involvement. Conventional systemic chemotherapy using drugs such as fotemustine or dacarbizine have low response rates. In liver only disease hepatic arterial infusion of fotemustine has reported a higher response rate. Methods: We report four prospectively followed patients who all received salvage treatment with Nab-paclitaxel after previous intra-arterial fotemustine for metasatic ocular melanoma. Results: One patient who did not respond to to intra-arterial chemotherapy had a radiological response to Nab-paclitaxel with a duration of six months (5 cycles of treatment) with subsequent progression inliver and CNS. Another patient had rapidly progressing liver, peritoneal and nodal metastases with elevated bilirubin. He received dose reduced Nab-paclitaxel sith significant biochemical, radiological and functional improvement. He continues on Nab-paclitaxel in ongoing partial remission and remains clinically improved after six months. Two patients with similarly advanced disease, including one with abnormal bilirubin, did not respond. Subsequent treatments for the three patients progressing after Nab-paclitaxel have been SIR-Spheres followed by Ipilumumab, Ipilumumab and palliation respectively. Typical side effects of Nab-paclitaxel have occurred including alopecia, fatigue, peripheral neuropathy and neutropenia. Conclusions: In summary we have seen clinically useful responses in two of four patients treated. We continue to recruit further patients to better understand the role of Nab-paclitaxel as salvage chemotherapy for metastatic ocular melanoma.

Germline BAP1 Inactivation Is Preferentially Associated with Metastatic Ocular Melanoma and Cutaneous-Ocular Melanoma Families

Background BAP1 has been shown to be a target of both somatic alteration in high-risk ocular melanomas (OM) and germline inactivation in a few individuals from cancer-prone families. These findings suggest that constitutional BAP1 changes may predispose individuals to metastatic OM and that familial permeation of deleterious alleles could delineate a new cancer syndrome.DesignTo characterize BAP1's contribution to melanoma risk, we sequenced BAP1 in a set of 100 patients with OM, including 50 metastatic OM cases and 50 matched non-metastatic OM controls, and 200 individuals with cutaneous melanoma (CM) including 7 CM patients from CM-OM families and 193 CM patients from CM-non-OM kindreds.ResultsGermline BAP1 mutations were detected in 4/50 patients with metastatic OM and 0/50 cases of non-metastatic OM (8% vs. 0%, p = 0.059). Since 2/4 of the BAP1 carriers reported a family history of CM, we analyzed 200 additional hereditary CM patients and found mutations in 2/7 CM probands from CM-OM families and 1/193 probands from CM-non-OM kindreds (29% vs. 0.52%, p = .003). Germline mutations co-segregated with both CM and OM phenotypes and were associated with the presence of unique nevoid melanomas and highly atypical nevoid melanoma-like melanocytic proliferations (NEMMPs). Interestingly, 7/14 germline variants identified to date reside in C-terminus suggesting that the BRCA1 binding domain is important in cancer predisposition.ConclusionGermline BAP1 mutations are associated with a more aggressive OM phenotype and a recurrent phenotypic complex of cutaneous/ocular melanoma, atypical melanocytic proliferations and other internal neoplasms (ie. COMMON syndrome), which could be a useful clinical marker for constitutive BAP1 inactivation.

A phase III random assignment trial comparing percutaneous hepatic perfusion with melphalan (PHP-mel) to standard of care for patients with hepatic metastases from metastatic ocular or cutaneous melanoma.

LBA8512 Background: Patients with hepatic metastases from primary melanoma have a median survival between 6 and 9 months. Few treatment strategies provide a meaningful impact on outcome. This report examines the efficacy of a minimally invasive regional therapy with melphalan (MEL) in patients with hepatic metastases from malignant melanoma. Methods: Between February 2006 and October 2009, 93 patients (M:F; 45:48) were accrued to a phase III, random-assignment trial comparing percutaneous hepatic perfusion (PHP-mel) (n=44) to standard of care (BAC) (n=49). This represents 100% of a planned 92 patient accrual. The primary endpoint was hepatic progression-free survival (H-PFS). Crossover to PHP-mel therapy was permitted at hepatic progression. Secondary endpoints included assessment of response rate (RR), duration of response (RES), and overall survival (OS) after PHP. A planned PHP treatment regimen included 4 to 6 PHP procedures at 28 to 35 day intervals. MEL (3.0 mg/kg) was delivered via the hepatic artery in a 30-minute hepatic artery infusion via a percutaneously placed catheter with hepatic venous hemofiltration using a retrohepatic, double balloon catheter (Delcath Systems, Inc.) and paired hemofiltration cartridges. Patients randomized to BAC were offered treatment considered to be the best alternative regimen by the treating physician. Staging evaluations were performed at baseline and then at 6 to 8 week intervals post baseline. All responses represent investigator-based results and were evaluated via standard RECIST criteria. Intent to treat based survival analysis was via the Kaplan-Meier method, with a 2-sided p< 0.05 defining significance. Results: Median H-PFS was 245 days (CI:136, 267) for PHP-mel vs. 49 days (CI:43, 68) for BAC (p<0.001). Overall response rate was 34.1 % (15/44) (CI: 20.5, 49.9) for PHP (15/44) vs. 2.0 % (1/49) (CI: 0.1, 10.9) for BAC (p<0.001). Upon hepatic progression, crossover to PHP occurred in 27 patients (55%) randomized to BAC. Conclusions: For patients with metastatic melanoma to the liver, H-PFS is significantly improved with PHP-mel versus best available care. [Table: see text]

Phase I dose-escalation study of E6201, a MEK-1 inhibitor, in advanced solid tumors.

2505 Background: E6201 is a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK)-1 and MEK kinase-1, with anticancer activity in preclinical models. Methods: This phase I, open-label study evaluated E6201 MTD in advanced solid tumors. Inclusion criteria were ECOG PS ≤1 and adequate bone marrow, renal, and liver function. Sequential cohorts of 3-6 subjects were given E6201 30-min IV infusion on Days 1, 8, and 15 of a 28-day cycle starting at 20 mg/m2 and increasing in 100% increments up to 320 mg/m2 until 2 Grade 2 toxicities or 1 DLT was observed. Doses were then increased by ≤50% up to 720 mg/m2 or until the MTD was determined. Blood samples were collected on days 1 and 15 for PK analysis. PD assessment included evaluation of CTC, serum IL-6 and IL-8 levels, and effects on proliferation and signal transduction pathway in skin and tumor biopsies. Results: 25 subjects (median age 66.6 [range 44-87] yr) received E6201 doses from 20 to 40, 80, 160, 320, and 480 mg/m2. At 480 mg/m2, 2 subjects had DLTs (QTc prolongation [Grade 3] and confusional state [Grade 4]). E6201 was reduced to 400 mg/m2, at which 1 subject had CNS toxicity (dizziness). Therefore, the 320 mg/m2 cohort was expanded to 3 additional subjects (total 6); 1 subject had 1 DLT (Grade 2 QTc prolongation) and Grade 2 CNS toxicities (dizziness, dysarthria, ataxia), confirming 320 mg/m2 as the MTD. Most-frequent AEs across doses were nausea (16%), constipation, dizziness, peripheral edema, and vomiting (all 12%, all Grade 1/2). E6201 was rapidly eliminated (mean t3/4=2.47- 5.60 hr). Exposure to E6201 was dose related and comparable on days 1 and 15. A trend for decreasing IL-6 and IL-8 levels was observed without clear dose dependency or duration of effect. Surrogate tissue (skin) biopsies were not informative. One subject with metastatic ocular melanoma had stable disease (>10 months) (B-Raf wild-type) and another, with B-Raf mutant papillary thyroid cancer, a partial remission. Conclusions: The E6201 MTD of 320 mg/m2 IV once weekly for 3 out of a 4-week cycle was well tolerated in patients with advanced solid tumors. An expansion phase at MTD will continue to assess efficacy and determine the optimal schedule using biomarker-driven endpoints and tumor response. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eisai Eisai

Combined Resection of the Liver and Pancreas for Malignancy

Combined resection of both the liver and pancreas for malignancy remains a controversial procedure. To many, the need for such an extended procedure implies an extent of disease that is usually not amenable to surgical control, and the extent of the procedure exposes the patients to substantial operative risks. The purpose of this study was to assess our results with combined resection of the liver and pancreas. Forty patients underwent combined liver and pancreas resection from 1996 to 2009. Patient ages ranged from 39 to 69 years (mean 53 years). Underlying diagnoses were neuroendocrine tumor (13), cholangiocarcinoma (13), gallbladder carcinoma (9), gastrointestinal stromal tumor (3), colorectal cancer (1), and metastatic ocular melanoma (1). Pancreatic resections included 26 pancreaticoduodenectomies (PD) and 14 distal pancreatic resections. Liver resections included 18 trisectionectomies (13 right, 5 left), 10 lobectomies (8 right, 2 left), and 12 segmental resections. There was no perioperative mortality. One patient who underwent PD with right trisegmentectomy for gallbladder cancer developed postoperative liver failure that improved with supportive management. Two patients developed bile leaks that resolved with conservative management. One patient developed a pancreatic leak/hemorrhage and required a completion pancreatectomy. Mean hospital stay was 14 days (range 7 to 42 days). Median follow-up was 30 months (range 3 to 76 months). Patients undergoing resection for neuroendocrine tumors had a better 5-year survival than those with hepatobiliary malignancies (100% vs 37% p = 0.01). Combined resection of the liver and pancreas can be performed safely. The need for combined partial hepatectomy and pancreatectomy to remove malignancy should not be considered a contraindication to resection in selected patients.

Isolated Hepatic Perfusion with High-Dose Melphalan Results in Immediate Alterations in Tumor Gene Expression in Patients with Metastatic Ocular Melanoma

Patients with ocular melanoma liver metastases have a poor prognosis, treatment options are limited, and median survival is less than 1 year. In this study, we characterized the early molecular changes that occur in tumors immediately after vascular isolation perfusion with melphalan with hyperthermia in patients with hepatic metastases from ocular melanoma. Patients underwent treatment on a clinical trial using a 60-min hyperthermic isolated hepatic perfusion (IHP) with melphalan. Microarray analysis was performed in 28 tumor samples obtained intraoperatively of which 12 were pre- and 16 were post-IHP. Various statistical analyses were performed to identify differentially expressed genes and gene categories between the groups. Median survival of 17 treated patients was 11.9 months. Unsupervised hierarchical clustering of all tumors resulted in separation of pre and post-IHP samples into two distinct groups. Analysis of genes showed that the Ras GTPase activator, ecotropic viral integration site 5 (EVI5), and several other melanoma-associated genes were overexpressed in pre-IHP tumors. In post-IHP samples the overexpression of a DNA replication associated gene, replication factor C (RFC5), was significantly associated with shortened survival (P < 0.003). Other major gene ontology categories identified in the post-IHP tumor samples were DNA-directed RNA polymerase activity and chromatin remodeling, both important categories involved in DNA replication and repair. These results demonstrate that acute changes in gene expression patterns occur in tumors immediately after treatment with melphalan administered via hyperthermic IHP. Rapid activation of DNA synthesis and repair pathways may be a mechanism of acquired tumor resistance in patients with ocular melanoma.

Review: Therapeutic opportunities in noncutaneous melanoma

Recent evidence suggests that the biology of noncutaneous melanoma differs significantly from cutaneous melanoma and may provide therapeutic opportunity. The most frequent sites of origin of noncutaneous melanoma are the eye and mucosal surfaces. Although noncutaneous melanomas are an uncommon group of cancers (representing less than 10% of all melanomas) a greater understanding of their genetic and molecular abnormalites is being translated into novel treatment strategies. These developments are important because there is currently no effective systemic therapy for noncutaneous melanoma. Significant attention has been focused on the role of c-kit (KIT, CD117), a transmembrane receptor with tyrosine kinase activity. In vitro and ex vivo evidence suggests that c-kit is frequently expressed/over expressed/mutated in noncutaneous melanoma. Anti-tumour effects with c-kit inhibitors are seen in pre-clinical models. A variety of multitargeted kinase inhibitors which have activity against c-kit are currently in early phase clinical trials in metastatic ocular, mucosal and acral melanoma. The few case reports of significant clinical activity with targeted therapies provides hope that greater understanding of the biology of noncutaneous melanoma can be translated into effective treatment.

A randomized phase II trial comparing two doses of lenalidomide for the treatment of stage IV ocular melanoma

e20012 Background: Ocular melanoma is the most common primary intraocular malignancy in adults with an incidence of 4.3 new cases per million. Approximately 50% of patients will develop metastases and the mean survival of those with liver metastases is 8–10 months. There are no effective systemic therapies. Pre-clinical studies of the antiangiogenic and immunomodulatory agent, lenalidomide, have shown promise in animal models of human ocular melanoma. We therefore conducted a phase II trial comparing two doses of oral lenalidomide. Methods: Patients with stage IV ocular melanoma, who met eligibility criteria and demonstrated disease progression, were enrolled on an IRB approved prospective random assignment trial comparing 5 mg and 25 mg of lenalidomide administered once a day orally for 21 days with a 7 day recovery (one cycle). Lesions were measured at baseline and every 3 months and scored for response by RECIST criteria. Patients who completed 3 cycles were eligible for response evaluation. Patients with responding lesions or with stable disease could continue receiving the agent. Toxicity was assessed using the NCI Common Toxicity Criteria. Results: Seventeen patients (13 female, 4 male; mean age 53) met eligibility criteria and were randomized to 5 mg (9 patients) or 25 mg (8 patients) of lenalidomide. The agent was well tolerated at both doses with only three grade 3 toxicities (two decreased ANC and one rash/puritis) requiring dose adjustments. Sixteen patients were eligible for response assessments. Nine patients had progressive disease by RECIST criteria following 3 cycles of therapy. Seven patients (44%) had stable disease for a mean of 7 months (range 6–12 months). There were no RECIST defined responders. There were no differences between the two dose groups with respect to toxicity or disease stabilization. Conclusions: Lenalidomide is well tolerated at doses of 5 mg and 25 mg orally for a 21 day cycle by patients with stage IV ocular melanoma. While no responses were seen, disease stabilization for a mean of 7 months was seen in 44% of patients. This effect was consistent with the pre-clinical animal data. Based on these results, further development of lenalidomide in combination with other agents should be considered for the treatment of metastatic ocular melanoma. [Table: see text]

Combination therapy targeting the tumor microenvironment is effective in a model of human ocular melanoma

BackgroundOcular melanoma is the leading intraocular malignancy. There is no effective treatment for metastatic ocular melanoma. We sought a treatment targeting the tumor microenvironment as well as the tumor cells.MethodsMigration of HUVEC cells, the ability of HUVEC cells to form tubes, and proliferative capacity of a human ocular melanoma cell line were tested in the presence of lenalidomide and sorafenib alone and in combination. The compounds were also tested in a rat aortic ring assay and were tested in a highly aggressive human ocular melanoma xenograft model.ResultsLenalidomide and Sorafenib inhibit HUVEC ability to migrate and form tubes and when used in combination the inhibition is increased. The agents alone and in combination inhibit outgrowth in the rat aortic ring model. The combination of the agents improved the inhibition over either single agent. In a xenograft model, combination therapy inhibited tumor growth over inhibition by single agent alone in a significant fashion (p < 0.004: lenalidomide and p < 0.0035: sorafenib). Furthermore, spontaneous lung metastasis development was completely inhibited in the combination treated animals. Sixty percent of vehicle treated animals developed lung metastases compared to 50% of lenalidomide treated animals, and 33% of sorafenib treated animals.ConclusionLenalidomide and sorafenib are effective at targeting endothelial cells, inhibiting growth of ocular melanoma cells and can inhibit growth of tumors in a xenograft model as well as inhibit development of metastases. Combining these agents works in an additive to synergistic way to inhibit the growth of tumors and development of metastases.

Qualitative assessment of undetectable melanin distribution in lightly pigmented irides

A longstanding issue in biomedical research concerns the biophysical factors affecting the color diversity of the human irides and its connection with ocular diseases. Although the pigmentation and morphological characteristics of heavily and moderately pigmented irides have been extensively discussed in the literature, similar studies are scarce for lightly pigmented irides. We present computer experiments indicating that the spectral signature of these specimens may be directly affected by still undetectable melanin distributions in the outermost iridal layers. Our findings represent in silico evidence of this relationship which, in turn, may have implications in the investigation of the higher risk of death from metastatic ocular melanoma verified in individuals with light-colored irides.

Hepatic Resection for Metastatic Melanoma: Distinct Patterns of Recurrence and Prognosis for Ocular Versus Cutaneous Disease

Resection of melanoma metastatic to the liver remains controversial. We evaluated the efficacy of hepatic resection in patients with metastatic ocular and cutaneous melanoma and assessed factors that could affect survival after resection. Forty patients with hepatic melanoma metastasis underwent resection at four major hepatobiliary centers. Clinicopathologic factors were evaluated with regard to recurrence and survival by using chi(2) and log-rank tests. The primary tumor was ocular in 16 patients and cutaneous in 24. The median disease-free interval from the time of primary tumor treatment to hepatic metastasis was the same for both groups (ocular, 62.9 months; cutaneous, 63.1 months; P = .94). Most patients underwent either an extended hepatic resection (37.5%) or hemihepatectomy (22.5%). Twenty-six patients (65%) received perioperative systemic therapy. Thirty (75.0%) of 40 patients developed tumor recurrence. The median time to recurrence after hepatic resection was 8.3 months (ocular, 8.8 months; cutaneous, 4.7 months; P = .3). Patients with primary ocular melanoma were more likely to experience recurrence within the liver (53.3% vs. 17.4%; P = .015), whereas patients with a cutaneous primary tumor more often developed extrahepatic involvement. The 5-year survival rate for patients with a primary ocular melanoma was 20.5%, whereas there were no 5-year survivors for patients with cutaneous melanoma (P = .03). Patterns of recurrence and prognosis after resection of hepatic melanoma metastasis differ depending on whether the primary melanoma is ocular or cutaneous. Resection should be performed as part of a multidisciplinary approach, because recurrence is common.

Metastatic ocular melanoma to the kidney 20 years after initial diagnosis

Metastatic tumors are the most common malignancies of the kidney. We report a rare case of isolated metastatic ocular melanoma to the kidney occurring 20 years after diagnosis. A 71-year-old man presented with gross hematuria. He had undergone left enucleation 20 years previously for ocular melanoma and had not required adjuvant therapy. A right upper pole mass was identified on computed tomography and was excised laparoscopically. Pathologic examination revealed metastatic melanoma. Metastatic melanoma to the kidney is rare. A high index of suspicion must be maintained in any patient with a renal mass and a history of a nonrenal malignancy.

Lessons to be learned: a case study approach

Malignant melanoma of soft tissue, also called clear cell sarcoma (CCS) of tendons and aponeuroses, presents as a soft tissue mass, usually in the lower extremity of young females. We report two cases of CCS of the upper extremity--in a Korean and a Saudi Arabian girl. Because of the presence of melanin, melanosomes, S-100 protein and the tendency for regional nodal metastases, it has been suggested that this entity be considered a melanoma rather than a soft tissue sarcoma. The evidence for a neuroectodermal origin of these neoplasms is compelling. Despite these features, CCS has been reported as showing a distinct chromosomal translocation pattern t(12;22)(q13;q12) in certain isolated cytogenetic or molecular diagnostic case reports; however, there is no information about the breakpoints at genomic level. Such genetic studies need to be performed on primary and metastatic cutaneous, mucosal or ocular melanomas prior to considering them specific for malignant melanoma of soft tissue/CCS. Microscopically, solid nests and fascicles of pale fusiform or cuboidal cells are divided by fine fibrous tissue septa. Characteristically, the cells possess a round to oval nucleus with a central prominent nucleolus. Pleomorphism may or may not be present; the cytoplasm is clear due to the presence of glycogen but, occasionally, the cytoplasm is more eosinophilic, resembling a melanoma. A tumour size (> or = 5 cm) and the presence of necrosis are statistically significant predictors of poor prognosis. A lesion on the proximal part of an extremity progresses slower than one that is more distal (i.e. acral). An early diagnosis and initial radical surgery are essential for a favourable clinical outcome. Once regional lymph node metastases or haematogenous dissemination has occurred, the prognosis becomes dismal.

Regional treatment options for patients with ocular melanoma metastatic to the liver

Uveal melanoma metastatic to the liver remains an incurable disease. Unlike colorectal carcinoma metastastic to the liver, surgery is not considered a first-line approach because of the diffuse, multifocal nature of the hepatic metastases. Systemic chemotherapy and immunotherapy regimens have had minimal efficacy for patients with metastatic ocular melanoma. Hepatic artery chemoembolization has been explored to a limited degree, but reports of response remain anecdotal. Hepatic arterial infusion with fotemustine had an overall response rate of 38%, but the overall survival is still disappointingly short. Isolated hepatic perfusion is a promising technique for this disease. Although the reported response rate is more than 60%, isolated hepatic perfusion is associated with potential morbidity, and the number of patients treated by this means is still limited. Percutaneous hepatic perfusion has the potential for less morbidity, and its efficacy in this clinical setting warrants further evaluation. The conclusion of this review is that current treatment modalities need further refinement and new ones need to be developed to improve the outlook for patients with uveal melanoma metastatic to the liver. Unlike cutaneous melanoma, which metastasizes to numerous sites, uveal melanoma commonly metastasizes only to the liver. This underscores the importance of developing effective forms of liver-directed therapy.—Hans E. Grossniklaus

Disulfiram inhibits activating transcription factor/cyclic AMP-responsive element binding protein and human melanoma growth in a metal-dependent manner in vitro, in mice and in a patient with metastatic disease

Abstract The thiocarbamate alcoholism drug disulfiram blocks the P-glycoprotein extrusion pump, inhibits the transcription factor nuclear factor-κB, sensitizes tumors to chemotherapy, reduces angiogenesis, and inhibits tumor growth in mice. Thiocarbamates react with critical thiols and also complex metal ions. Using melanoma as the paradigm, we tested whether disulfiram might inhibit growth by forming mixed disulfides with critical thiols in a mechanism facilitated by metal ions. Disulfiram given to melanoma cells in combination with Cu2+ or Zn2+ decreased expression of cyclin A and reduced proliferation in vitro at lower concentrations than disulfiram alone. In electrophoretic mobility shift assays, disulfiram decreased transcription factor binding to the cyclic AMP-responsive element in a manner potentiated by Cu2+ ions and by the presence of glutathione, suggesting that thiocarbamates might disrupt transcription factor binding by inducing S-glutathionylation of the transcription factor DNA binding region. Disulfiram inhibited growth and angiogenesis in melanomas transplanted in severe combined immunodeficient mice, and these effects were potentiated by Zn2+ supplementation. The combination of oral zinc gluconate and disulfiram at currently approved doses for alcoholism also induced &amp;gt;50% reduction in hepatic metastases and produced clinical remission in a patient with stage IV metastatic ocular melanoma, who has continued on oral zinc gluconate and disulfiram therapy for 53 continuous months with negligible side effects. These findings present a novel strategy for treating metastatic melanoma by employing an old drug toward a new therapeutic use.