Autologous cell vaccine as a post operative adjuvant treatment for high-risk melanoma patients (AJCC stages III and IV). The new American Joint Committee on Cancer.
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This study evaluates the overall survival and disease free survival of melanoma patients that were treated with an autologous melanoma cell vaccine, administered as a post-operative adjuvant. Included are 43 patients with totally resected metastatic melanoma (28-AJCC stage III, 15-AJCC stage IV), with a median follow up of 34 months (6-62). The treatment consisted of eight doses of a vaccine made of 10-25x10(6) autologous melanoma cells either released from the surgical specimen or grown in cell cultures. Tumour cells were conjugated with hapten dinitrophenyl, mixed with Bacille Calmette Guerin and irradiated to 110 Gy. Both disease free survival and overall survival were found to be correlated with intensity of evolving delayed type hypersensitivity to subcutaneous injection of unmodified melanoma cells. Patients with a delayed type hypersensitivity reaction of > or =10 mm had a median disease free survival of 17 months (mean 35 months) and a mean overall survival of 63 months (median not reached). In contrast, patients with a negative or weak delayed type hypersensitivity had a median disease free survival of 9 months (relative risk of recurrence=4.5, P=0.001), and a median overall survival of 16 months (relative risk of death=15, P=0.001). Stage III patients with a positive delayed type hypersensitivity reaction had an improved disease free survival of 16 months and a mean overall survival of 38 months, whereas patients with a negative delayed type hypersensitivity had a median disease free survival of 7 months (relative risk=4.5, P=0.02) and a median overall survival of 16 months (relative risk=9.5, P=0.005). The adjuvant administration of autologous melanoma vaccine was associated with improved disease-free and overall survival to selected patients who successfully attained anti-melanoma reactivity as detected by positive delayed type hypersensitivity reactions to unmodified melanoma cells. (+info)
Uveal metastatic carcinoma in human immunodeficiency virus infection.
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We report the occurrence of uveal metastatic carcinoma in two patients with longstanding HIV infection presenting with decreased visual acuity. In the first case, a 49-year-old man with a 6-year history of HIV infection presented with a 4-5 month history of blurred vision in his right eye. In the second case, a 53-year-old man with a 5-year history of HIV infection presented with a 3-week history of distorted and blurred vision in both eyes. In both cases, a choroidal metastatic carcinoma was ultimately discovered. To our knowledge, these are the first reported cases of metastatic uveal carcinoma in individuals with HIV infection. Currently, there have been dramatic improvements in treatment for HIV infection and longer survival times of infected individuals. This fact, together with reported increased frequencies and aggressiveness of carcinomas in HIV-infected individuals will likely result in increasing occurrences of uveal metastases from primary carcinomas in HIV. (+info)
Hemodynamic parameters in blood vessels in choroidal melanoma xenografts and rat choroid.
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PURPOSE: Choroidal melanoma is the most common primary ocular cancer among the adult population. To avoid enucleation, there has been a concerted effort to develop therapies that spare the affected eye and the patient's vision. Blood flow helps shape the tumor's microenvironment, plays a key role in the tumor's response to many different types of therapy, and is necessary for delivery of chemotherapeutic agents. To rationally design new therapies and optimize existing treatments, it is essential to learn as much as possible about blood flow and the microcirculation in this tumor. In recent years, much has been discovered about the anatomy of the microvasculature and the dynamics of overall blood flow in choroidal melanoma, but little is known about the factors that determine microvascular blood flow. In this study hemodynamic parameters in individual microvessels of a human choroidal melanoma xenograft were compared with those same parameters in a normal rat choroid. METHODS: Nude, athymic WAG/RijHs-rnu rats were used in this study. The human choroidal melanoma cell line OCM-1 was used to grow solid tumors subcutaneously in the flanks of donor rats. Small pieces of these tumors were then implanted into the choroidal space of recipient rats. After 6 to 8 weeks, the rats were anesthetized with a subcutaneous injection of urethane, and the sclera was exposed. Rhodamine-labeled liposomes and red blood cells (RBCs) labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) were injected intravenously. Epifluorescent, intravital microscopy was used to visualize the flow of fluorescent RBCs through individual vessels in the choroid or tumor. Flow through multiple vessels was recorded on videotape for later analysis. From the recordings, RBC flux, RBC velocity (V(c)), and microvascular hematocrit (HCT(m)) were determined. Similar experiments were performed in rats with no tumor growth, and these same parameters were calculated in normal choroidal vessels. RBC flow was characterized in 55 vessels in six OCM-1 tumors and in 153 choroidal vessels in five non-tumor-bearing rats. RESULTS: RBC flux was higher in larger tumor vessels (>30 micro m in diameter) compared with similarly sized choroidal vessels. There were no differences in the velocities of RBCs through the two types of vessels. HCT(m) was significantly higher in medium-sized (>20 micro m in diameter) and larger tumor vessels compared with normal choroidal vessels. CONCLUSIONS: These experiments demonstrate differences between hemodynamic parameters in normal choroidal microvessels and microvessels in choroidal melanoma in this animal model. Because HCT(m) is a key determinant of apparent viscosity, abnormally high HCT(m) in the tumor vessels would increase vascular resistance and decrease flow. This could have a negative impact on the tumor oxygen levels and on the ability to deliver drugs effectively. On the contrary, higher local HCT(m) has also been shown to increase oxygen delivery. The impact and interplay of these two effects on tumor oxygenation remain to be determined. (+info)
Clinicopathological correlation of polypoidal choroidal vasculopathy revealed by ultrastructural study.
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AIMS: To describe the clinical and histopathological findings in a patient with polypoidal choroidal vasculopathy. METHODS: A 76 year old Japanese man had a discrete, orange-red lesion of 1 disc diameter in the macula, with the fluorescein and indocyanine green angiographic and optical coherence tomographic findings compatible with polypoidal choroidal vasculopathy. He underwent a surgical removal of the macular lesion, followed by light and electron microscopic examinations. RESULTS: The histopathological examination revealed that the specimen consisted of degenerated retinal pigment epithelium-Bruch's membrane-choriocapillaris complex and inner choroid. A tortuous, unusually dilated venule was present adjacent to an arteriole with marked sclerotic changes, appearing to form arteriovenous crossing. These vessels seemed to represent native inner choroidal vessels, and had haemorrhage per diapedesis. Blood cells and fibrin filled the lumina of the vessels and accumulated in the extravascular spaces, indicating vascular stasis. CONCLUSION: Hyperpermeability and haemorrhage due to stasis of a dilated venule and an arteriole involved by sclerosis at the site where they cross in the inner choroid might cause oedema and degeneration of the tissue. Voluminous accumulation of blood cells and fibrin might generate elevation of tissue pressure sufficient to displace the weakened lesion anteriorly. The result suggests that the polypoidal vessels in this case represent abnormality in the inner choroidal vasculature. (+info)
Photodynamic therapy using verteporfin in circumscribed choroidal haemangioma.
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AIM: To investigate the safety and efficacy of photodynamic therapy with verteporfin in patients with choroidal haemangioma. METHODS: A non-randomised, prospective clinical investigation of 19 patients with symptomatic circumscribed choroidal haemangioma was performed. Unsuccessful pretreatment (external beam irradiation, laser photocoagulation) was performed in four patients. Patients were included when (1) subretinal exudation involving the fovea, (2) a decrease in visual function, and (3) additional symptoms (for example, metamorphopsia) were present. Photodynamic therapy (PDT) was performed with verteporfin at a concentration of 6 mg/m(2) body surface area and a light dose of 100 J/cm(2) at 692 nm. RESULTS: The mean follow up time was 10.6 months (2-24 months). The mean number of treatment sessions was 2.15 (range 1-5). Visual acuity improved by at least one line in 73.3%, by at least two lines in 42.1%, was stable in 21.1%, and decreased by one line in 5.2% of the patients. Exudation was completely resolved in 94.8% of the cases. Regression of tumour height was documented in all 19 tumours. Patients receiving any pretreatment before PDT, a visual acuity of 0.1 and less, a history of more than 30 months, and no significant response after the first PDT session, did not show any significant improvement. Cox regression analysis revealed that the number of PDT treatment sessions was inversely associated with the improvement in visual acuity of at least two lines. No recurrences and no local or systemic side effects were observed during the follow up time. CONCLUSION: PDT using verteporfin is a safe and effective therapy for the treatment of symptomatic choroidal haemangioma even in tumours located beneath the fovea. (+info)
MAP kinase-dependent degradation of p27Kip1 by calpains in choroidal melanoma cells. Requirement of p27Kip1 nuclear export.
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We investigated the status and the regulation of the cyclin-dependent kinases (CDK) inhibitor p27(Kip1) in a choroidal melanoma tumor-derived cell line (OCM-1). By contrast to normal choroidal melanocytes, the expression level of p27(Kip1) was low in these cells and the mitogen-activated protein (MAP) kinase pathway was constitutively activated. Genetic or chemical inhibition of this pathway induced p27(Kip1) accumulation, whereas MAP kinase reactivation triggered a down-regulation of p27(Kip1) that could be partially reversed by calpain inhibitors. In good accordance, ectopic expression of the cellular calpain inhibitor calpastatin led to an increase of endogenous p27(Kip1) expression. In vitro, p27(Kip1) was degraded by calpains, and OCM-1 cell extracts contained a calcium-dependent p27(Kip1) degradation activity. MAP kinase inhibition partially inhibited both calpain activity and calcium-dependent p27(Kip1) degradation by cellular extracts. Immunofluorescence labeling and subcellular fractionation revealed that p27(Kip1) was in part localized in the cytoplasmic compartment of OCM-1 cells but not of melanocytes, and accumulated into the nucleus upon MAP kinase inhibition. MAP kinase activation triggered a cytoplasmic translocation of the protein, as well as a change in its phosphorylation status. This CRM-1-dependent cytoplasmic translocation was necessary for MAP kinase- and calpain-dependent degradation. Taken together, these data suggest that in tumor-derived cells, p27(Kip1) could be degraded by calpains through a MAP kinase-dependent process, and that abnormal cytoplasmic localization of the protein, probably linked to modifications of its phosphorylation state, could be involved in this alternative mechanism of degradation. (+info)
Long-term risk of local failure after proton therapy for choroidal/ciliary body melanoma.
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PURPOSE: To quantitate long-term risk of local treatment failure after proton irradiation of choroidal/ciliary body melanomas and to evaluate risk of metastasis-related deaths after local failure. METHODS: We followed prospectively 1,922 patients treated at the Harvard Cyclotron between January 1975 and December 1996 for local recurrences of their tumors. Mortality surveillance was completed through June 1999. For analysis, patient follow-up continued until tumor regrowth was detected or, in patients without recurrence, until the date of the last dilated examination prior to April 1998. Actuarial methods were used to calculate rates of recurrence and metastatic deaths. Cox regression models were constructed to evaluate risk factors for these outcomes. RESULTS: Median ocular follow-up after irradiation was 5.2 years. Local recurrence was documented in 45 patients by ultrasound and/or sequential fundus photographs; in 17 more patients, the eye was enucleated due to suspected but unconfirmed tumor growth. Recurrences were documented between 2 months and 11.3 years after irradiation. The 5- and 10-year rates of regrowth, including suspected cases, were 3.2% (95% confidence interval [CI], 2.5%-4.2%), and 4.3% (95% CI, 3.3%-5.6%). Among the 45 documented recurrences, about one half (21) occurred at the margin, presumably due to treatment planning errors. The remaining cases represented extrascleral extensions (nine cases), ring melanomas (six cases), or uncontrolled tumor (nine cases). Recurrence of the tumor was independently related to risk of tumor-related death. CONCLUSION: These data, based on relatively long-term follow-up, demonstrate that excellent local control is maintained after proton therapy and that patients with recurrences experience poorer survival. (+info)
Diagnostic transvitreal fine-needle aspiration biopsy of small melanocytic choroidal tumors in nevus versus melanoma category.
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PURPOSE: To report an experience with fine-needle aspiration biopsy of selected small melanocytic choroidal tumors during the interval from April 13, 1983, through January 19, 2001. METHODS: Retrospective descriptive case series report of 34 patients with a small melanocytic choroidal tumor (maximal diameter, < or = 10 mm; thickness, > or = 1.5 mm but < or = 3 mm) evaluated diagnostically by transvitreal fine-needle aspiration biopsy prior to treatment. None of the tumors had invasive features at the time of biopsy. RESULTS: Patients ranged in age from 26 to 73 years (mean, 50.9 years). The evaluated choroidal tumors had a mean maximal basal diameter of 8.0 mm and a mean maximal thickness of 2.4 mm. Eighteen of the 34 tumors (52.9%) had been documented to enlarge prior to biopsy. Biopsy was performed in all cases using a 25-gauge hollow lumen needle and a transvitreal approach via a pars plana puncture site. The biopsy yielded a sufficient aspirate for cytodiagnosis in 22 of 34 cases (64.7%). In these cases, the tumor was classified as malignant melanoma in 16 (47.1% of total), intermediate lesion in 4 (11.8%), and benign nevus in 2 (5.9%). The 12 tumors that yielded an insufficient aspirate and the four lesions that yielded intermediate cells continued to be classified as "nevus versus melanoma" and were monitored periodically for growth or other changes. Four of the 12 tumors that yielded an insufficient aspirate for cytodiagnosis and all four lesions that yielded intermediate cells were eventually reclassified as small choroidal melanomas and treated. The remaining eight tumors that yielded an insufficient aspirate and the two tumors that yielded benign nevus cells were classified as benign nevi at the most recent follow-up evaluation. CONCLUSIONS: Fine-needle aspiration biopsy showed that a substantial proportion of small melanocytic choroidal tumors likely to be classified clinically as small choroidal melanomas in many centers were in fact benign nevi or intermediate lesions. (+info)