Metastatic Ocular Melanoma Research Articles

Interferon alpha 2b decreases hepatic micrometastasis in a murine model of ocular melanoma by activation of intrinsic hepatic natural killer cells.

To investigate in a murine model the mechanism by which micrometastatic melanoma, which spreads from the eye to the liver, is controlled by interferon (IFN)-alpha 2b. Major histocompatibility (MHC) class I antigen (H-2, all haplotypes) expression in three murine melanoma cell lines (Queens, B16LS9, B16F10) was determined by flow cytometric immunophenotyping. The cell lines were heterotopically inoculated into the posterior compartments (PCs) of C57Bl/6 mice, and the mice were given intraperitoneal (IP) injections of IFN-alpha 2b or PBS for 1 or 4 days before enucleation at 7 days after inoculation. Groups of mice were made NK deficient or depleted with subcutaneous (s.c.) injection of anti-asialo GM1. The mice were killed at 28 days or 56 days (survival experiment) after inoculation, and the number of hepatic micrometastases was histologically determined. NK cells were isolated from the spleen and liver at necropsy, and propidium iodide labeled target-specific cytolysis was determined by flow cytometry. The micrometastases were evaluated for apoptosis and proliferation with TUNEL and MIB1 immunostaining, respectively, and TUNEL-to-MIB1 ratios were determined. Hepatic NK cells were immunostained with CD49b. MHC class I antigen was expressed in the three cell lines in the order of Queens < B16LS9 < B16F10. All cell lines grew, were confined to the PC, and formed hepatic micrometastases. A decrease in micrometastases, an increase in target-specific cytolysis, and an increase in survival correlated with decreased HLA class I expression by the melanoma cells. The IFN-alpha 2b treatment resulted in a boost of intrinsic hepatic NK cells, demonstrated in NK-deficient but not NK-depleted mice. The treatment effect corresponded to increased apoptosis (TUNEL)-proliferation (MIB1) ratios in the micrometastases. Immunostaining demonstrated an increased number of intrahepatic NK cells associated with the micrometastases in treated groups. Neoadjuvant IFN-alpha 2b results in decreased hepatic micrometastasis and increased survival time through increased intrinsic hepatic NK cell-mediated tumor apoptosis in a murine model of metastatic ocular melanoma.

Combined liver and pancreas resection with biochemotherapy for metastatic ocular melanoma.

Systemic therapy alone for metastatic melanoma is relatively ineffective, and surgical resection of metastases to a solitary site remains the best single treatment to improve survival. While cytoreductive surgery plus chemotherapy play a significant role in the management of advanced ovarian cancer, the precise role of surgery as an adjunct to systemic therapy for melanoma metastatic to multiple sites is not well defined. We report a patient with ocular melanoma metastatic to liver and pancreas treated by cytoreductive surgery consisting of mesohepatic resection, distal pancreatectomy, and portal node dissection, followed by biochemotherapy with dacarbazine and interferon alpha. The concept of cytoreductive surgery is reviewed, with particular attention to its use in the management of metastatic melanoma. The patient's postoperative course was unremarkable and she remains alive and asymptomatic with no detectable disease at 20 months' follow-up. Cytoreductive surgery as a part of an aggressive multidisciplinary approach may play a role in the treatment of cutaneous and ocular melanoma metastatic to multiple visceral sites. Data from well-designed, innovative clinical trials of cytoreductive surgery and biochemotherapy are required to determine the effectiveness of this multidisciplinary approach.

Troxacitabine, an l-Stereoisomeric Nucleoside Analog, on a Five-Times-Daily Schedule: A Phase I and Pharmacokinetic Study in Patients With Advanced Solid Malignancies

To assess the feasibility of administering troxacitabine, a unique L-nucleoside that is not a substrate for deoxycytidine deaminase-mediated catabolism, as a 30-minute intravenous (IV) infusion daily for 5 days. Patients with advanced solid malignancies were treated with escalating doses of troxacitabine as a 30-minute IV infusion daily for 5 days. Plasma and urine sampling was performed to characterize the pharmacokinetics and pharmacodynamics of troxacitabine. Thirty-nine patients received 124 courses of troxacitabine at eight dose levels ranging from 0.12 to 1.8 mg/m(2)/d. Severe neutropenia that was protracted (> 5 days) and/or associated with fever, and skin rashes were consistently experienced by heavily (HP) and minimally pretreated (MP) patients at doses exceeding 1.2 and 1.5 mg/m(2)/d, respectively. At troxacitabine doses > or = 1.2 mg/m(2)/d, treatment was often delayed 1 additional week for complete resolution of hematologic effects, resulting in lengthening of the treatment interval from every 3 to 4 weeks. Skin rash, palmar-plantar erythrodysesthesia, and thrombocytopenia were also observed and were occasionally severe, particularly at the highest doses. A patient with metastatic ocular melanoma experienced a partial response. Pharmacokinetics of troxacitabine were dose-independent; mean (SD) values for the volume of distribution at steady-state and clearance (Cl(s)) were 60 (32) L and 161 (33) mL/min, respectively, on day 1. After treatment on the fifth day, terminal half-life values averaged 39 (63) hours, and Cl(s) was reduced by approximately 20%, averaging 127 (27) mL/min. The principal mode of drug elimination was renal. Recommended doses for phase II studies of troxacitabine as a 30-minute infusion daily for 5 days every 4 weeks are 1.5 and 1.2 mg/m(2)/d for MP and HP patients, respectively. Broad disease-directed evaluations of troxacitabine on this schedule and possibly less frequent schedules are warranted.

Metastatic Ocular Melanoma to the Left Ventricle Inducing Near-Syncope Attacks in an 84-Year-Old Woman

Cardiac tumors may represent mechanical causes for syncope by limiting left ventricular filling and/or by obstructing the left ventricular outflow tract. Malignant melanoma is known to metastasize to the myocardium or pericardium, but there are only a very limited number of reports describing endocardial involvement by the tumor. We describe herein an 84-year-old woman who presented with daily near-syncope episodes, 9 years after treatment for a choroidal melanoma. The echocardiography and the pathologic examination revealed a metastatic melanoma. This is the first reported case of an ocular melanoma metastasizing to the heart and presenting as a left ventricular intracavitary pedunculated mass.

A new technique for implantation of tissue culture melanoma cells in a murine model of metastatic ocular melanoma

The aim of this study was to compare the transcorneal and transconjunctival techniques for the implantation of intraocular melanoma cells and development of metastasis in a murine model. Groups of C57BL/6 mice were given either transconjunctival or transcorneal inoculations of 2.5 × 105/2.5 μl tissue culture B16-LS9 melanoma cells into the intraocular posterior compartment (PC). The eyes were enucleated at 4-11 days post-inoculation and histologically examined. The mice were sacrificed 14 days after enucleation and necropsies were performed with histological evaluation for visceral metastases. Intraocular and extraocular tumour growth was present in all of the eyes inoculated via the transconjunctival route. Pulmonary metastases were found in this group if the eye was enucleated 7 or more days post-inoculation. The melanoma remained confined to the inside of the eye in the transcorneal group until day 7. Haematogenous metastases to the lung and liver developed from the intraocular melanoma in this group. Transcorneal inoculation of tissue culture melanoma cells into the murine PC provides a useful animal model for visceral metastasis of ocular melanoma.

A new technique for implantation of tissue culture melanoma cells in a murine model of metastatic ocular melanoma

The aim of this study was to compare the transcorneal and transconjunctival techniques for the implantation of intraocular melanoma cells and development of metastasis in a murine model. Groups of C57BL/6 mice were given either transconjunctival or transcorneal inoculations of 2.5 x 10(5)/2.5 microl tissue culture B16-LS9 melanoma cells into the intraocular posterior compartment (PC). The eyes were enucleated at 4-11 days post-inoculation and histologically examined. The mice were sacrificed 14 days after enucleation and necropsies were performed with histological evaluation for visceral metastases. Intraocular and extraocular tumour growth was present in all of the eyes inoculated via the transconjunctival route. Pulmonary metastases were found in this group if the eye was enucleated 7 or more days post-inoculation. The melanoma remained confined to the inside of the eye in the transcorneal group until day 7. Haematogenous metastases to the lung and liver developed from the intraocular melanoma in this group. Transcorneal inoculation of tissue culture melanoma cells into the murine PC provides a useful animal model for visceral metastasis of ocular melanoma.

Depletion of NK cell activity results in growth of hepatic micrometastases in a murine ocular melanoma model

PURPOSE. To study the role of natural killer (NK) cells in growth of spontaneous hepatic metastasis in a murine intraocular melanoma model. METHODS. Tissue culture B16-LS9 melanoma cells were analyzed by flow cytometry for MHC class I expression of all haplotypes and inoculated into the posterior compartment (PC) of one eye of C57BL6 mice. The eyes were enucleated at 12 days post-inoculation and histologically examined for tumor growth. One group of mice (n = 10) were given intraperitoneal injections of anti-asialo GM1 for NK cell depletion post-enucleation and a second group of mice (n = 9) served as controls. The mice were sacrificed at 24 days post-inoculation and necropsies were performed to determine the number and size of metastasis. RESULTS. The B16-LS9 cells failed to express MHC class I antigen. Tumor grew in the PC of all eyes and metastasized to the lungs and livers of all mice, with the average number of hepatic micrometastases greater in the NK depleted group versus the control group (p =. 009). There was no significant difference in the average number of pulmonary metastases in the treated versus the control group (p =. 072). Hepatic metastases grew to an average diameter of 600 µm in diameter in two NK depleted mice. CONCLUSIONS. NK depletion in this model of metastatic ocular melanoma results in increased number and growth of hepatic micrometastases.

Treatment of uveal melanoma metastatic to the liver. A review of the M.D. Anderson Cancer Center experience and prognostic factors

Background. Liver metastasis develops in approximately two-thirds of patients with recurrent uveal melanoma. Despite therapy, the median survival of those with liver metastasis is 5 to 7 months. The recognition of a grave prognosis associated with liver metastasis has led to evaluation of new modalities of therapy, including the use of regional therapies such as intrahepatic arterial chemotherapy and either embolization or chemoembolization of hepatic metastases. In this study, the results of an institutional experience over the past 2 decades are reviewed and prognostic factors that affect survival from the time the liver metastasis is diagnosed are assessed. Methods. In this study of 201 patients with uveal melanoma involving the liver who were treated at M. D. Anderson Cancer Center between 1968 and 1991, the authors retrospectively reviewed the cases and compared the results of systemic therapies, hepatic infra-arterial chemotherapies, and chemoembolization of liver metastases. Cox's multivariate analysis and stepwise logistic regression were then computed to determine significant prognostic variables. Results. The systemic therapies produced a response rate of less than 1%. Chemoembolization was the most effective treatment, inducing responses in 36% of patients. Survival curves were calculated using the life-table method of Kaplan and Meier. Patient-and tumor-related characteristics were examined and their relation to on survival from the time of diagnosis of liver metastasis was determined. Levels of serum alkaline phosphatase, total bilirubin, and lactic dehydrogenase plus response to treatment showed a strong relation to survival. In contrast, univariate analysis showed that patient age and gender, metastasis free interval, presence of extrahepatic metastasis, and type of therapy for liver metastasis did not influence survival. Multivariate stepwise regression analysis identified serum alkaline phosphatase and metastasis free interval as the main independent prognostic factors for survival after liver metastasis diagnosis. Conclusions. Of the three modalities of therapy used for choroidal melanoma metastatic to the liver, only chemoembolization using cisplatin-based regimens produced a meaningful response rate. Information from this analysis can be used to predict the outcome of patients with uveal melanoma metastatic to the liver. Patients with metastatic ocular melanoma confined to the liver should be treated with chemoembolization and should not be included in chemotherapy trials designed for cutaneous melanoma. Cancer 1995; 76:1665–70.

Metastatic Ocular and Cutaneous Melanoma: A Comparison of Patient Characteristics and Prognosis

Are metastatic ocular and cutaneous melanomas the same type of tumor? This question arises at the time of treatment of metastatic disease. Large studies of patients with metastatic cutaneous melanoma have shown a treatment response rate of greater than 21% with selected therapies. 1,2 A literature review suggests that only limited systemic evaluations of chemotherapy response of metastatic ocular melanoma have been reported. 3 We present results from a large database of multinational trials of chemotherapeutic treatment of metastatic melanoma that included patients with metastatic ocular melanoma. The trials were conducted by the Eastern Cooperative Oncology Group and were designed to evaluate the efficacy and toxic effects of various drug treatments for metastatic melanoma. Data for 713 patients were available for analysis. The median time from the first diagnosis to entry to the study was 20 months. Fifty-one patients had primary ocular melanoma, 402 had primary cutaneous melanoma, and 260

Treatment of uveal melanoma metastatic to the liver: a review of the M. D. Anderson Cancer Center experience and prognostic factors.

Liver metastasis develops in approximately two-thirds of patients with recurrent uveal melanoma. Despite therapy, the median survival of those with liver metastasis is 5 to 7 months. The recognition of a grave prognosis associated with liver metastasis has led to evaluation of new modalities of therapy, including the use of regional therapies such as intrahepatic arterial chemotherapy and either embolization or chemoembolization of hepatic metastases. In this study, the results of an institutional experience over the past 2 decades are reviewed and prognostic factors that affect survival from the time the liver metastasis is diagnosed are assessed. In this study of 201 patients with uveal melanoma involving the liver who were treated at M. D. Anderson Cancer Center between 1968 and 1991, the authors restrospectively reviewed the cases and compared the results of systemic therapies, hepatic intra-arterial chemotherapies, and chemoembolization of liver metastases. Cox's multivariate analysis and stepwise logistic regression were then computed to determine significant prognostic variables. The systemic therapies produced a response rate of less than 1%. Chemoembolization was the most effective treatment, inducing responses in 36% of patients. Survival curves were calculated using the life-table method of Kaplan and Meier. Patient- and tumor-related characteristics were examined and their relation to on survival from the time of diagnosis of liver metastasis was determined. Levels of serum alkaline phosphatase, total bilirubin, and lactic dehydrogenase plus response to treatment showed a strong relation to survival. In contrast, univariate analysis showed that patient age and gender, metastasis free interval, presence of extrahepatic metastasis, and type of therapy for liver metastasis did not influence survival. Multivariate stepwise regression analysis identified serum alkaline phosphatase and metastasis free interval as the main independent prognostic factors for survival after liver metastasis diagnosis. Of the three modalities of therapy used for choroidal melanoma metastatic to the liver, only chemoembolization using cisplatin-based regimens produced a meaningful response rate. Information from this analysis can be used to predict the outcome of patients with uveal melanoma metastatic to the liver. Patients with metastatic ocular melanoma confined to the liver should be treated with chemoembolization and should not be included in chemotherapy trials designed for cutaneous melanoma.

The prevalence and location of metastases from ocular melanoma: imaging study in 110 patients.

Ocular melanoma is characterized by an unpredictable clinical course, during which fulminant metastatic disease may occur after a prolonged disease-free interval. The purpose of this study was to determine the pattern of metastatic involvement in this disease. The clinical and radiologic findings in 110 patients with metastatic ocular melanoma were reviewed. The 54 men and 56 women were 24-79 years old (mean, 50 years) when the primary tumor was first diagnosed. Metastases were present in three patients at the time of first diagnosis and occurred in 107 patients 2 months to 36 years later (mean, 52 months). One hundred five patients died between 1 and 38 months after the onset of metastatic disease. Hepatic metastases developed in 101 patients (92%), and in 60 (55%) of these, the liver was the only organ involved initially. Pulmonary parenchymal metastases developed in 34 patients (31%), but in only four of them were metastases confined to the lungs. Twenty-five patients (23%) had bone involvement, mostly affecting the spine. Nineteen patients (17%) had skin or subcutaneous metastases, but in only two of them was this the initial finding. Nodal involvement was shown in 15 patients (14%), almost always associated with extensive hepatic metastases. Brain and adrenal metastases were seen in five and three patients, respectively. Hepatic involvement occurs in almost all patients who develop metastatic ocular melanoma, and the liver is the most common initial site of metastatic involvement. Metastases may develop after a long disease-free interval.

Survival in metastatic ocular melanoma.

Of 35 patients with metastatic ocular melanoma, 71.4% manifested liver involvement either initially (45.7%) or later in the course of the disease (25.7%). With liver involvement, the median survival was 2.2 months, whereas with pulmonary involvement it was 19.2 months after the first evidence of metastatic disease (P less than 0.01). Survival after recurrence varied also with age, those younger than 50 years having median survival of 14 months, with those 50 years or older having median survival 3.5 months (P less than 0.01). It also varied with the patient's sex, males having median survival 3 months after recurrence, and females 10.4 months (P less than 0.05). Younger patients and females had also longer disease-free intervals prior to recurrence. Surgical removal of metastases, when feasible, in combination with chemotherapy, seems to offer improved palliation, since a subsequent median survival thus of 18.4 months was observed with 3/15 patients alive disease-free 1 to 3 years later, while the median survival of 20 patients not treated with surgery was 2.5 months. Most of this difference in survival, however, is due to a difference in tumor load between the two groups, with patients subjected to surgery having lesser amounts of tumor and/or more favorable sites.

Ocular Metastases from Systemic Melanoma

We studied two patients, a 72-year-old man and a 27-year-old woman, with metastatic melanoma documented by cytologic examination of the ocular fluids. Neither patient had a clinically detectable ocular mass. Fine-needle aspiration with cytologic examination may be useful in the diagnosis of metastatic ocular melanoma.

The excretion of Thormählen positive melanogens in melanoma patients and its clinical significance

Thormählen positive melanogens (TPM) were determined in the urine of 585 primary and/or metastatic cutaneous melanoma patients, in 105 primary and/or metastatic ocular melanoma patients, in 100 patients suffering from other diseases with the exception of melanoma and in 72 healthly persons. On the basis of our results we can recommend the determination of the sum of TPM as sufficient for routine monitoring of patients in the course of malignant melanoma. The determination of TPM urinary excretion cannot substitute histological and clinical examinations in an early diagnosis of malignant melanoma, but it is very important and useful for a differential diagnosis and prognosis of malignant melanoma. TPM urinary excretion can be followed in melanoma patients also for the indication of further treatment and the evaluation of the response on chemotherapy or immunotherapy.