Survival of Patents with Metastases from Uveal Melanoma

Gragoudas, Evangelos S.; Egan, Kathleen M.; Seddon, Johanna M.; Glynn, Robert J.; Walsh, Susan; Finn, Susan M.; Munzenrider, John E.; Spar, Myles

doi:10.1016/s0161-6420(91)32285-1

Cited by 326 publications

(221 citation statements)

References 27 publications

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“…In most cases, metastatic spread occurs within 5 years of initial diagnosis, but metastatic spread has, in exceptional cases, been recorded up to 42 years after diagnosis (Sheilds et al, 1985). Once detectable metastases have formed, the patient is unlikely to survive for more than a few months (Gragoudas, 1991).…”

Section: Discussionmentioning

confidence: 99%

Tamoxifen, 17β-oestradiol and the calmodulin antagonist J8 inhibit human melanoma cell invasion through fibronectin

Dewhurst

Gee²,

Rennie³

et al. 1997

Br J Cancer

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Summary Invasion through stromal extracellular matrix (ECM) is part of the complex, multistep process of tumour cell invasion and metastasis. Our group has previously demonstrated that calcium and calmodulin are important in another step in the metastatic cascadethat of attachment of cells to ECM. Interestingly, the non-steroidal anti-oestrogen tamoxifen (which also has calmodulin antagonist activity), used in the treatment of breast cancer and now in metastatic cutaneous melanoma, can inhibit the attachment of normal and neoplastic cells to ECM. In this study, we investigated whether such drugs, known to inhibit cell attachment, could also subsequently reduce their invasion through a layer of human fibronectin. We examined the ability of the specific calmodulin antagonist J8, tamoxifen and its two major metabolites, N-desmethyltamoxifen (N-des) and 4-hydroxytamoxifen (4-OH), as well as the pure anti-oestrogen ICI 182,780 and 17,Boestradiol to inhibit invasion of the human cutaneous melanoma cell line, A375-SM, uveal melanoma cells and uveal melanocytes. A375-SM cells and uveal melanoma cells showed a high level of invasion (15.2% and 33.7% respectively) compared with melanocytes (around 5%) under the experimental conditions used. Submicromolar concentrations of N-des, tamoxifen, J8 and 1 7,B-oestradiol significantly reduced the invasiveness of the A375-SM cell line. The uveal melanoma cells also showed similar inhibition, although at higher concentrations of these agents. 4-OH and ICI 182, 780 had little or no effect on invasion of A375-SM cells (these were not tested on uveal melanoma cells). All cells used in this study were found to be negative for type nuclear oestrogen receptors, reinforcing the possibility that tamoxifen and 17,-oestradiol can act via mechanisms unrelated to binding to classical oestrogen receptors to inhibit tumour cell invasion.Keywords: melanoma; invasion; calmodulin antagonists; tamoxifen; oestrogen The prognosis for patients with either cutaneous (Garbe et al, 1995) or uveal melanoma (Bedikian et al, 1981;Rajpal et al, 1983) is poor once these tumours have metastasized. Metastatic spread involves several different stages and, in escaping from the primary tumour and in forming distal metastatic deposits, neoplastic cells need to attach to and subsequently invade through stromal ECM (Albini and Colacci, 1993 for review). Metastatic melanoma cells express a greater range of adhesion molecules than their non-transformed precursor, the melanocyte (Mortarini and Anichini, 1993). Initial attachment of cells to ECM proteins then leads to a reorganization of the cell cytoskeleton to form focal adhesions (Van Leeuwen et al, 1994).In recent years, our laboratory has investigated the role of signal transduction systems in the early stages of cell attachment and shown that attachment of melanoma cells to ECM proteins appears to involve intracellular signalling systems, in particular calcium and calmodulin (MacNeil et al, 1992. We also demonstrated that tamoxifen and two of its major metabolites c...

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Section: Discussionmentioning

confidence: 99%

Tamoxifen, 17β-oestradiol and the calmodulin antagonist J8 inhibit human melanoma cell invasion through fibronectin

Dewhurst

Gee²,

Rennie³

et al. 1997

Br J Cancer

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“…4 Median survival in this group of patients is less than 1 year, and systemic and regional chemotherapy or ablative techniques do not seem to meaningfully impact the natural history of the disease. 5,6 Although tumor progression may be indolent, patients with hepatic metastases from neuroendocrine tumors often suffer the sequellae of hormonally active metastases, and strategies for effective palliation of extensive disease are needed. 7…”

Section: Introductionmentioning

confidence: 99%

Phase I Study of Hepatic Arterial Melphalan Infusion and Hepatic Venous Hemofiltration Using Percutaneously Placed Catheters in Patients With Unresectable Hepatic Malignancies

Pingpank

Libutti

Chang

et al. 2005

JCO

114

117

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Purpose-We conducted a phase I study of a 30-minute hepatic artery infusion of melphalan via a percutaneously placed catheter and hepatic venous hemofiltration using a double balloon catheter positioned in the retrohepatic inferior vena cava to shunt hepatic venous effluent through an activated charcoal filter and then to the systemic circulation. The purpose of the study was to demonstrate feasibility in an initial cohort and subsequently determine the maximum tolerated dose and doselimiting toxicity of melphalan.Patients and Methods-The initial cohort (n = 12) was treated with 2.0 mg/kg of melphalan before dose escalation to 3.5 mg/kg (n = 16). Total hepatic drug delivery, systemic levels, and percent filter efficiency were determined. Patients were assessed for hepatic and systemic toxicity and response.Results-A total of 74 treatments were administered to 28 patients. Twelve patients with primary and metastatic hepatic tumors received 30 treatments (mean, 2.5 per patient) at an initial melphalan dose of 2.0 mg/kg. At 3.5 mg/kg, a dose-limiting toxicity (neutropenia and/or thrombocytopenia) was observed in two of six patients. Transient grade 3/4 hepatic and systemic toxicity was seen after 19% and 66% of treatments, respectively. An overall radiographic response rate of 30% was observed in treated patients. In the 10 patients with ocular melanoma, a 50% overall response rate was observed, including two complete responses.Conclusion-Delivery of melphalan via this system is feasible, with limited, manageable toxicity and evidence of substantial antitumor activity; 3 mg/kg is the maximum safe tolerated dose of melphalan administered via this technique.

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“…Once hepatic metastases are established, survival is usually less than 12 months. 3 Conversely, iris melanomas, although less frequent, have a good prognosis and only rarely metastasise. 4 Uveal melanomas have been well characterised by cytogenetic studies, owing largely to their relatively simple karyotypes and ease of culture.…”

Section: Introductionmentioning

confidence: 99%

Multiple locations on chromosome 3 are the targets of specific deletions in uveal melanoma

Cross

Ganesh

Parpia

et al. 2005

Eye

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Survival of Patents with Metastases from Uveal Melanoma

Cited by 326 publications

References 27 publications

Tamoxifen, 17β-oestradiol and the calmodulin antagonist J8 inhibit human melanoma cell invasion through fibronectin

Tamoxifen, 17β-oestradiol and the calmodulin antagonist J8 inhibit human melanoma cell invasion through fibronectin

Phase I Study of Hepatic Arterial Melphalan Infusion and Hepatic Venous Hemofiltration Using Percutaneously Placed Catheters in Patients With Unresectable Hepatic Malignancies

Multiple locations on chromosome 3 are the targets of specific deletions in uveal melanoma

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