摘要:

Different types of melanin pigments have recently been identified and recognized as critical determinants of the photosensitivity of individuals. Eumelanin, the black to brown melanin pigments, are believed to protect against ultraviolet-induced cell damage, while phaeomelanin, the reddish brown variant, is thought to be photosensitizing. The relative, qualitative and absolute amount of melanin production under stimulation of solar radiation is likely to be genetically determined. The hypothesis of this study is that determination of these values can help in identifying those people who are less protected. However, these techniques must be evaluated at a population level and against traditional epidemiological measures. We assessed the amount and type of melanin in 195 subjects in four centres across Europe, relating the results to epidemiological measures such as skin characteristics, history of sunburns and number of naevi. The most important finding was that eumelanin and phaeomelanin have very different distributions in the population, being associated with other phenotype characteristics with different patterns. The relationship between phaeomelanin and eumelanin is linearly inverse in the range from black to dark blonde hair colour, while it is weakly directly proportional in the range from dark blonde to light blonde, with people with red hair showing a peculiar pattern. Phaeomelanin rather than eumelanin seemed to be independent of other skin characteristics. The results show the feasibility of a further study with an appropriate case-control design and accurate determination of melanin.

ISSN:0960-8931    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Nitric oxide (NO) is known to facilitate tumour metastasis through the promotion of angiogenesis, vascular dilation, platelet aggregation, etc. In the present study we explored its novel role in producing dysfunction of the host immune system in the metastasis of murine metastatic melanoma B16-BL6 cells. A significant reduction in the mixed lymphocyte reaction (MLR) was observed in the spleen cells from B16-BL6-bearing mice, but not in those from mice bearing the parent cell B16. When B16-BL6 cells were addedin vitroto the MLR, a significant decrease was also found, even when they were co-cultured with the lymphocytes in two compartments of a Transwell chamber separated by an 8.0 μm filter. The supernatant from cultured B16-BL6 but not B16 cells, which had a greatly increased NO activity, significantly inhibited concanavalin A- and lipopolysaccharide-induced lymphocyte proliferation. A remarkably higher expression of inducible NO synthase (iNOS) was detected in B16-BL6 cells than in B16 cells. Nω-Nitro-l-arginine (l-NNA), a NO synthase inhibitor and superoxide dismutase, significantly antagonized the above inhibition by B16-BL6 cells, while l-arginine, a NO precursor, and S-nitroso-N-acetyl-d,l-penicillamine, a NO donor, strengthened the inhibition. Furthermore, l-NNA significantly inhibited lung metastasis of B16-BL6 cells, while l-arginine tended to enhance the metastasis. The cytotoxicity of B16-BL6-specific T-cells was significantly decreased by pre-culture with B16-BL6 cells in a Transwell chamber or the culture supernatants of B16-BL6 cells, whereas l-iminoethyl-lysine, a selective inhibitor of iNOS, showed a significant recovery from the disease. These results suggest that NO released by metastatic tumour cells may impair the immune system, which facilitates the escape from immunosurveillance and metastasis of tumour cells.

ISSN:0960-8931    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The background for this study was reports in the literature of stronger fluorescence observed visually for melanomas compared with benign naevi in formalin-fixed paraffin-embedded sections. Our objective was to carry out a quantitative study of the phenomenon and to investigate if such an approach could be used in the detection of melanomas. Microscopic digital imaging was used to measure quantitatively the fluorescence intensity in specimens from 50 malignant melanomas, four basal cell carcinomas and 58 benign lesions. The mean fluorescence intensity of the melanomas was considerably higher than of the other lesions. For melanomas, the intensity depended both on the distance from the skin surface and the distance from the centre of the lesion. A simple algorithm based on the intensity threshold correctly classified the melanomas with a sensitivity of 74% and a specificity of 59%. Quantitative measurements of the fluorescence of the pigmented skin lesions fixed with formalin and embedded in paraffin can be a useful auxiliary tool for differentiating melanoma from other pigmented lesions histopathologically.

ISSN:0960-8931    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Several genes implicated in the development of various malignancies appear to be of minor relevance in melanoma. We therefore aimed to find a tumour suppressor candidate involved in this malignancy by comparing gene expression in uncultured primary melanoma specimens with those in acquired melanocytic naevi, from which quite often melanomas are known to arise. Applying the subtractive suppression hybridization technique, we generated a subtracted library of candidate genes downregulated in melanoma. Among the cDNA fragments identical to known genes, this library included a cDNA fragment 630 bp in length that is identical to the gene for the human protein phosphatase 2A (PP2A) regulatory subunit B (B56) γ isoform (PP2A-Bγ, PPP2R5C). On further evaluation of 15 primary melanoma and 16 acquired melanocytic naevus tissue specimens from independent patients using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis, expression of this gene was found to be suppressed in melanomas compared with naevi; the difference was statistically significant. As PP2A is known to be a major cellular serine–threonine phosphatase, and has been implicated not only in the regulation of cell growth and division but also in the control of gene transcription and growth factor signal transduction, alterations in the pattern of the regulatory subunits may affect substrate specificity and subcellular localization of the PP2A holoenzyme in melanoma cells.

ISSN:0960-8931    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Cyclooxygenase-II (Cox-II) overexpression is involved in the progression of various subtypes of cancer. We investigated the significance of Cox-II in the progression of malignant melanomas (MMs). Using immunohistology we determined that Cox-II isnotexpressed in 70 benign and malignant melanocytic tumours. Basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) were also analysed as controls: the BCCs were consistently Cox-II negative (n= 11), whereas the SCCs showed moderate to strong Cox-II expression in 53% (n= 17). Reverse transcription-polymerase chain reaction and Western blotting of MM cell lines and MM tissues confirmed the lack of Cox-II expression in MM. However,in vitrothe Cox-inhibiting non-steroidal anti-inflammatory drug (NSAID) sulindac sulphide (SIS) was significantly more effective in inducing apoptosis than sulindac sulphone (SOS), a derivative with a negligible effect on Cox (P< 0.01). The SIS doses needed for the induction of apoptosis were not significantly different in MM cell lines versus a Cox-II-positive colon carcinoma cell line (HT29). Furthermore, add-back experiments with high doses of the prostaglandins PGE2and PGF2β, major Cox-II products, did not abrogate this effect. We conclude that Cox-II expression is not involved in the progression of MM, and NSAID-induced apoptosis in MM cell lines seems to follow pathways independent of Cox-II. Nevertheless, Cox-II inhibitors are still candidates for therapy, though they act via an unknown mechanism.

ISSN:0960-8931    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Cutaneous and uveal melanoma both have a poor prognosis and chemotherapy is usually unsuccessful. We have previously reported the activity of a number of cytotoxic agents against metastatic cutaneous and primary choroidal uveal melanoma using anex vivoadenosine triphosphate (ATP)-based chemosensitivity assay (ATP-TCA). In this study we compare the results obtained with the two types of melanoma. Cutaneous melanoma deposits in skin and lymph nodes (n= 58) and choroidal melanomas (n= 77) were tested using the ATP-TCA. Analysis of the data based on an arbitrary threshold for sensitivity shows that both types of melanoma exhibit heterogeneity of sensitivity to all the agents and combinations tested. With all the single agents except gemcitabine, cutaneous melanomas showed greater sensitivity in the assay, though this did not achieve statistical significance. This was also true with the drug combinations, with the exception of treosulfan + gemcitabine, which had similar activity in each type of melanoma. Of all the single agents tested, doxorubicin (47% of specimens classed as sensitive), vinorelbine (43%), treosulfan (41%) and paclitaxel (33%) showed the greatest activity with cutaneous melanoma. In the uveal melanoma samples, mitoxantrone (33%), gemcitabine (22%) and treosulfan (21%) showed the greatest activity. In contrast to the cutaneous melanomas, 13% of the uveal melanomas were sensitive to paclitaxel, 4% were sensitive to doxorubicin and 11% were found to be sensitive to vinorelbine. Both tumour types showed greater sensitivity to combinations of cytotoxic agents. The combination of treosulfan + gemcitabine was universally effective, with 72% of cutaneous melanomas and 80% of uveal melanomas exhibiting activity at the level selected to indicate sensitivity in the assay, though this will not necessarily indicate a similar level of clinical sensitivity.

ISSN:0960-8931    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Nude rats bearing melanomas on their hindlimbs were treated by isolated limb infusion (ILI) with increasing doses (7.5–400 μg/ml) of melphalan. The response of tumours to treatment at the end of the observation period was graded, according to diameter, as complete response (CR), partial response (PR), no change (NC) or progressive disease (PD). No linear relationship between the dose of melphalan and the tumour response was observed. All doses above a threshold of 15 μg/ml achieved a PR or CR. The achievement of CR was not related to increased dose. Two major implications arise from this work. Firstly, the typically two- to three-fold increase in cytotoxic drug concentration given in high dose chemotherapy compared with standard drug concentration may not be sufficient to produce the expected increase in tumour response and possibly survival, and the controversial results of high dose chemotherapy in different studies may thus be explained. Secondly, since an increase in melphalan dose above a certain threshold does not greatly increase tumour response, the use of combination therapies would seem to be more likely to be effective than increased chemotherapeutic drug doses in achieving better tumour responses.

ISSN:0960-8931    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

In 2715 of 4524 patients with cutaneous melanoma treated surgically between 1968 and 1992 prognostic parameters were analysed for their value in predicting the occurrence of first progression. All of the 2715 patients developed only one invasive cutaneous melanoma during the follow-up period. Data concerning tumour thickness and mitotic index (maximum number of mitoses per square millimetre) of the cutaneous melanomas were determined. Between the characteristics age, tumour thickness, mitotic index, prognostic index (PI), sex, site of tumour, melanoma subtype and Clark level, the value of the mitotic index, as a prognostic parameter independent of tumour thickness, and the combination of mitotic index and tumour thickness were evaluated. The development of the first metastases was documented during a mean follow-up of 7.5 years. The majority of first recurrences occurred at regional lymph nodes and attempts have been made to identify those patients at risk of developing metastatic disease. The most effective parameters proved to be tumour thickness and mitotic index. For both parameters an independent prognostic influence was shown. The prognostic index, defined as the product of tumour thickness and number of mitoses per square millimetre, was re-evaluated and confirmed. A new modified prognostic index, defined as the product of square tumour thickness and mitotic index, proved to be even more useful for defining a subgroup of patients who are at risk of developing metastases and, therefore, might benefit from adjuvant therapy.

ISSN:0960-8931    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

This analytic (phase II) study aimed to investigate the hypothesis that the decline in serum melanoma-inhibiting activity (MIA) levels following initiation of treatment might have prognostic value. The mean serum lactate dehydrogenase (LDH), MIA and S100 levels in patients with malignant melanoma before treatment were higher than in the control group. Patients with visceral dissemination had much higher mean serum MIA levels than patients with nodal spread only. A regression model was constructed to analyse the prognostic factors in patients with advanced stage malignant melanoma. Therapy included surgical excision or lymph node dissection, hypofractionated radiotherapy, and immunotherapy or chemotherapy. Blood samples were collected within 24 h before the initiation of systemic treatment and two or three times more at 20–28 day intervals. Overall survival was investigated by univariate analysis, and correlation with clinical factors was compared using the log-rank test. Gender, primary tumour site, surgery, radiation therapy, serum S100 levels before systemic treatment and choice of chemotherapy were not correlated with the outcome. In addition to the stage of disease, low serum LDH levels before systemic treatment and a decline in serum MIA levels following initiation of systemic treatment predicted a favourable outcome. Metastasis to visceral organs was associated with higher serum MIA levels. Persistence of high serum MIA levels despite systemic treatment predicts an unfavourable prognosis.

ISSN:0960-8931    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Among patients with advanced melanoma, the development of autoimmune phenomena or of hypothyroidism during therapy has been associated with a favourable outcome. The objective of this study was to determine the prevalence of autoimmunity and of hypothyroidism in the melanoma population as a whole and to determine if these disease states confer a survival advantage for patients with metastatic disease. We report our findings in the uveal melanoma population. The study population (n= 91) consisted of all patients registered at this institution with the diagnosis of uveal melanoma during a 2 year study period. Eight (8.8%) had a systemic autoimmune disease; 12 (13.2%) were hypothyroid, including 9/46 (19.6%) females. Survival of the stage 4 patients was determined from diagnosis of the primary tumour (SvDx) and from diagnosis of metastatic disease (SvMt), and was compared to that of age/sex matched stage 4 controls. For autoimmune patients versus controls, the median SvDx was 111 months vs 37 months (P= 0.2734) and the median SvMt was 17 months vs 4 months (P= 0.0887). For the hypothyroid patients versus controls, the median SvDx was 58 months vs 49 months (P= 0.5348) and the median SvMt was 4 months vs 8 months (P= 0.2437). We conclude that there is a trend toward longer survival from the date of metastasis in uveal melanoma patients with a systemic autoimmune disorder, suggesting that systemic autoimmunity may play a role in modifying the activity of established metastases. This trend is not seen among the uveal melanoma patients with hypothyroidism. The high prevalence of hypothyroidism suggests a possible molecular interaction between the two disease processes.

ISSN:0960-8931    

出版商:OVID    

年代:2001

数据来源: OVID