摘要:

&NA;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 &mgr;l 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.

ISSN:0960-8931    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

&NA;Our laboratory has synthesized two new phenolic thioether amines,N‐propionyl‐4‐S‐cysteaminylphenol (N‐Pr‐4‐S‐CAP) andN‐[2‐{(4‐propionyloxyphenyl)thio}ethyl] propionamide (N,O‐diPr‐4‐S‐CAP). These compounds, along with the previously described phenolic thioether amineN‐acetyl‐4‐S‐cysteaminylphenol (N‐Ac‐4‐S‐CAP) and its acetyl form (N,O‐diAc‐4‐S‐CAP), are tyrosine‐amine derivative analogues. The cytotoxicity of these compounds is thought to be tyrosinase dependent, which may make them suitable for targeted anti‐melanoma therapy since only melanocytes and their malignant counterparts contain this active enzyme. To further investigate this hypothesis, we performed MTT [3‐(4,5‐dimethylthiazol‐2‐yl)2,5‐diphenyltetrazolium bromide] assays to determine the cytotoxicity of these compounds in 10 different cell lines. Specifically, we examined to what extent cytotoxicity is related to tyrosinase and tyrosine hydroxylase activity using melanoma and neuroblastoma cells, which have a common metabolic pathway using tyrosinase and tyrosine hydroxylase, respectively. The most sensitive cell line was the highly Pigmented SK‐MEL‐23 melanoma cell line, which shows a very high tyrosinase activity with the highest melanin Pigmentation. KAN and SK‐NSH (two neuroblastoma cell lines), which have no tyrosinase activity but high tyrosine hydroxylase, were also sensitive. However, C32 (a non‐pigmented melanoma with a lower tyrosinase activity) was also sensitive, and MeWo (a moderately pigmented melanoma with a high tyrosinase activity) was less sensitive. This in vitro study may indicate that there is a non‐tyrosinase‐mediated mechanism of cytotoxicity for phenolic thioether amines in addition to the tyrosinase‐mediated one described previously.

ISSN:0960-8931    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

&NA;In this study we directly compared thein vitroresponses of T‐cells from normal donors and melanoma patients to Melan‐A27‐35and Melan‐A26‐35. These peptides have been previously used in peptide‐based vaccination studies. Following three stimulations with peptide‐pulsed antigenpresenting cellsin vitro,Melan‐A‐specific cytolytic T‐lym‐phocytes (CTLs) were generated from seven of 20 subjects; two of the seven subjects responded reproducibly to both Melan‐A27‐35and Melan‐A26‐35, three to only Melan‐A27‐35and two to only Melan‐A26‐35. However, CTLs generated with either Melan‐A27‐35or Melan‐A26‐35showed cross recognition, and both types of CTL could recognize naturally processed antigen displayed on HLA‐A2+ tumour cells. Furthermore, Melan‐A‐specific CTLs could also be generated by stimulating peripheral blood mononuclear cells with autologous melanoma cells. Our results suggest that some subjects may have a bias in their CTL repertoire which favours the generation of Melan‐A27‐35specific CTLs, while others may favour Melan‐A26‐35specific CTLs. It is also likely that CTL precursors capable of detecting both peptides may have different affinities to the two Melan‐A peptides. Since it is difficult to predict the CTL responses to Melan‐A peptide in a given individual, we suggest vaccinating with both Melan‐A27‐35and Melan‐A26‐35peptides in clinical trials.

ISSN:0960-8931    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

&NA;The effects of &bgr;‐radiation on melanoma implanted into the hamster's eye were investigated. Two Bomirski hamster melanomas (BHMs), differing in their melanin content, were compared with regard to their radiosensitivity to ruthenium‐106 (106Ru) radiation. Tumours growing in the iris were irradiated with 3, 6 or 10 Gy of106Ru given as a single dose or in four fractions at 24 h intervals. Tumour growth kinetics and distant metastases were studied, and the eyeballs were examined histologically. Dose‐dependent delay of tumour growth was observed in both melanomas. After treatment with a dose of 6 Gy, the Ab amelanotic tumours grew 2.6 times slower, and the Ma melanotic tumours 1.4 times slower than untreated ones. The location of metastases differed in the two tested lines — pigmented metastases were found mainly in the lungs, while unpigmented metastases were found mainly in the kidneys. Histopathological analysis showed signs of blood vessel damage such as endothelial cells swelling, erythrocyte extravasation and tumour necrosis. This last finding increased with the rising dose of &bgr;‐radiation. Pigmented tumours were found to be two times more resistant to &bgr;‐radiation than amelanotic ones. The pattern of metastases of BHMs is determined by the type of melanoma (Ab or Ma). Exposure to &bgr;‐radiation from106Ru did not significantly affect either the number or size of metastases except at a dose of 10 Gy. This dose caused a statistically significant decrease in the number of metastases in the Ma melanotic subline.

ISSN:0960-8931    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

&NA;We have previously reported that the presence of cutaneous dysplastic naevi is a risk factor for uveal melanoma. In the present study our goal was to determine the incidence of different histopathological features of uveal melanoma among 91 patients with or without cutaneous dysplastic naevi. Statistical analysis revealed that the presence of cutaneous dysplastic naevi in uveal melanoma patients is associated with an increased incidence of the prognostically worst forms of uveal melanoma (epithelioid or mixed cell type melanomas). The relative risk was 5.97 (95% confidence interval 1.61‐22.14). Our results suggest that the presence of cutaneous dysplastic naevi is not only a risk factor but also a prognostic factor for uveal melanoma.

ISSN:0960-8931    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

&NA;The aim of this study was to evaluate the potential of the paramagnetic metalloporphyrin Mn‐TPPS4 (using Gd‐DTPA as the reference) for magnetic resonance imaging (MRI) of pigmented malignant melanoma in an animal model. High resolution MRI (2.0 T, 2.0 cm surface coil, T1‐weighted FLASH two‐dimensional sequence) was performed on 15 mice (C57b16) with intracutaneous implanted melanoma (B16F1) before and after intravenous administration of Gd‐DTPA (Magnevist, Schering AG, Berlin, Germany) and Mn‐TPPS4(Porphyrin Products, Logan, Utah, USA). The images were evaluated quantitatively by calculating the percentage enhancement, the slope of the signal intensity‐to‐time curves, the percentage increase in the signal intensity, and the signal‐to‐noise and contrast‐to‐noise ratios. The qualitative evaluation was accomplished by visual assessment of the enhancement, the demarcation of the tumours from the surrounding tissue, and the homogeneity of the tumours. Contrast medium‐enhanced images showed an increase in signal intensity for all the tumours, with no significant difference between the contrast media. Specific accumulation of the contrast media in the melanoma could not be proved. Demarcation of tumours from the surrounding tissue is better after administration of contrast media; regressive changed areas were better depicted.

ISSN:0960-8931    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

&NA;Isolated limb perfusion (ILP) with melphalan is used to treat recurrent melanoma. This study aimed to develop a microdialysis technique for melphalan tissue concentration measurement during ILP. The effects of melphalan concentration (50‐600 &mgr;g/ml), microdialysis flow rate (0.55‐17.5 &mgr;l/min), probe length (5‐50 mm) and temperature (25‐41.5°C) onin vitrorecovery were studied. In addition,in vivorecovery was measured in rat hindlimbs perfused with melphalan using 50 mm microdialysis probes implanted subcutaneously and into muscle. Both dialysate and tissue sample melphalan concentrations were determined by high performance liquid chromatography. Thein vitrorecovery of melphalan was not affected by melphalan concentration or temperature, but increased with probe length and decreased with flow rate. The melphalan concentrations in subcutaneous and muscle dialysates were not significantly different. A linear relationship was found between tissue dialysate concentrations and actual tissue concentrations of melphalan (r2= 0.97). Microdialysis is a potential method for tissue drug monitoring which may assist in the efficacious use of cytotoxics in human ILP.

ISSN:0960-8931    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

&NA;The biological mechanisms of chemoimmunotherapy efficacyin vivohave not been fully clarified; furthermore, few data are available to predict its efficacy on the basis of clinical and immunological pretreatment factors. In this paper, pre‐ and post‐treatment serum levels of cytokines (interleukin [IL]‐6, IL‐10, IL‐12 and neopterin) and soluble IL‐2 receptors (sIL‐2R), as well as circulating levels of T‐cell and NK subpopulations, were analysed according to clinical outcome in 66 advanced metastatic melanoma (MM) patients treated with subcutaneous IL‐2 in association with interferon‐&agr;, cisplatin and tamoxifen. Our purpose was to correlate the immune modifications during treatment with the clinical response and to define pretreatment factors with predictive value for clinical outcome. The overall response rate was 35%, with a median overall survival of 11.3 months. During treatment, responding patients showed a common marked increase in IL‐12 (mainly released by activated macrophages), sIL‐2R and neopterin serum levels, associated with high levels of total lymphocytes and circulating natural killer lymphocytes; progressing patients were characterized by an increase in IL‐6 serum levels (directly related to the increase in tumour burden). Multivariate analysis showed that high pretreatment IL‐12 levels (P = 0.05) and, to a lesser extent, lactate dehydrogenase levels in the normal range (≤ 450 U/I; P = 0.061) are independent favourable prognostic factors for survival. Our results show that macrophage activation in an immunostimulating way either before or during treatment is associated with a better clinical response and improved survival in advanced MM patients treated with IL‐2‐based chemoimmunotherapy.

ISSN:0960-8931    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

&NA;A phase II study was performed to evaluate the efficacy of cisplatin combined with interleukin‐2 and interferon‐&agr;2b administered subcutaneously to patients with metastatic malignant melanoma (MMM). Between April 1994 and January 1999, 87 patients with MMM and a WHO performance status of ≤ 2 were entered into the study. The first 42 patients had prophylactic cimetidine; the other 45 patients did not. An overall response rate of 27% was achieved in the 82 patients evaluable for response. The median response duration was 7.0 months (range 4.4‐29.0 months). The median survival for all patients was 10.1 months (range 0.4‐64.9+ months). Toxicity was substantial but generally manageable and usually reversed on dose reduction or temporary interruption of treatment. Two patients (2%) died of treatment‐related toxicity. No difference in response or survival was seen in the patients treated with or without cimetidine. In multivariate analysis, lactate dehydrogenase level (P < 0.001), number of metastatic sites (P = 0.014) and performance status (P = 0.035) was shown to be independent prognostic factors for survival. This high dose interleukin‐2 subcutaneous regimen resulted in a small fraction of long‐term survivors. The response and survival results were not superior to other studies using lower and less toxic interleukin‐2 doses.

ISSN:0960-8931    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

&NA;Although spine metastasis from melanoma is an uncommon event, it can pose a complex management problem. The presentation and natural history of melanoma metastatic to the spine has not been described in the medical literature. We have conducted a review of the records of 133 patients with melanoma metastatic to the spine in order to obtain retrospective data on demographic information, clinical presentation, disease course and survival. Patients with cutaneous, ocular and mucosal melanoma were all represented, but those with primary cutaneous tumours of the trunk were more prevalent than expected. Other sites of metastatic disease were present in nearly all patients and metastases to other skeletal sites were not unusual. Pain was the most common presenting symptom. The radiographic diagnosis was generally made easily by plain radiographs, computed tomography or magnetic resonance imaging, with the most frequent finding being a destructive lesion. Bone scan gave false‐negative results 15% of the time. The median survival for the group was 4 months. It is concluded that melanoma metastatic to the spine represents a late event in the evolution of this illness. Palliation should be the goal of treatment, but symptom management should be individualized, bearing in mind the short anticipated survival of these patients.

ISSN:0960-8931    

出版商:OVID    

年代:2000

数据来源: OVID