Recent research has shown that emotion influences postural control. The objective of the present study was to establish whether or not postural threat influences postural and physiological responses to aversive visual stimuli. In order to investigate the coupling between emotional reactions, motivated behavior and postural responses, we studied the displacement of the subject's center of pressure (COP) and the changes in electrodermal activity (EDA), heart rate (HR) and postural muscle activation. Thirty-two participants (15 males, 17 females; mean ± SD age: 21.4 ± 2.3) viewed affective and neutral pictures while standing still on a force platform in the presence or absence of postural threat. The HR and EDA data revealed that the emotional state varied as a function of the postural condition. The mean displacement in the anteroposterior (AP) axis was more rearwards in response to aversive stimuli that in response to neutral stimuli, in both the absence of postural threat (−0.65 mm and +0.90 mm for aversive and neutral stimuli, respectively) and the presence of postural threat (−0.00 mm vs. +0.89 mm, respectively). An aversive stimulus was associated with a shorter AP COP sway path than a neutral stimulus in the presence of a postural threat (167.26 mm vs. 174.66 mm for aversive and neutral stimuli, respectively) but not in the latter's absence (155.85 mm vs. 154.48 mm, respectively). Our results evidenced withdrawal behavior in response to an aversive stimulus (relative to a neutral stimulus) in the absence of postural threat. Withdrawal behavior was attenuated (but nevertheless active) in the presence of a postural threat.

Multivariate analysis showed that in comparison with controls, patients who developed metastases were more likely to possess previously established risk factors such as male gender, presence of ulceration and lesions of greater thickness. However, our analysis also demonstrated that a personal history of non-melanoma skin cancer (OR1⁄41.95, 95% CI: 1.08–3.52, P1⁄40.022) and of cancer other than skin (OR1⁄42.51, CI: 1.14–5.51, P1⁄40.037), two risk factors that have not been previously examined in detail, were also associated with metastasis. We also compared the 320 EM patients with the 70 LM patients to determine risk factors associated with early metastases. EM patients were more likely to have lesions of greater thickness (OR1⁄42.35, CI: 1.64–3.36, Po0.001), ulcerated lesions (OR1⁄43.58, CI: 1.40–9.18, P1⁄40.016) and a past medical history of non-melanoma skin cancer (OR1⁄44.83, CI: 1.04–22.39, P1⁄40.024) than LM patients.

Mackiewicz, A.; Testori, A.; Ferraresi, V.; Maio, M.; Garbe, C.; Guillot, B.; Gascon, P.; Gilde, K.; Camerini, R.; Cognetti, F. Author Information

The prognostic significance of spontaneous regression of primary melanoma is a controversial issue. Studies on sentinel lymph node status and circulating tumour cells may represent a step towards a better understanding. The clinical details of 269 melanoma patients who underwent sentinel lymph node biopsy were analysed. Correlation was sought between the parameters of the primary tumour, particularly tumours showing a partial intermediate level of regression, and sentinel lymph node status. The presence of circulating tumour cells was studied by reverse transcription-polymerase chain reaction for tyrosinase messenger RNA preoperatively in 94 patients. Of the examined tumours, 27.8% showed histological features of a partial intermediate level of regression. Regressive tumours were localized predominantly on the trunk (P=0.006), were significantly thinner (P<0.0000) and were less frequently ulcerated (P=0.003) than tumours without regression. Moreover, the majority of regressive melanomas were of the superficial spreading type (P<0.0000) and their sentinel node status was more favourable (P=0.026). We demonstrated the presence of circulating tumour cells in five of 26 (19.2%) regressive and 19 of 68 (29.4%) non-regressive tumours. The difference was not significant (P=0.32). By multivariate analysis, however, the Breslow thickness and ulceration of the primary tumour were predictors of the sentinel lymph node status, in agreement with literature data. A partial intermediate level of regression of the primary tumour did not affect unfavourably the sentinel lymph node status in our study. We failed to demonstrate a significant relationship between the presence of circulating tumour cells and either primary tumour regression or the sentinel lymph node status.

Aims: To compare the routinely used polyclonal anti-S100 and a mouse monoclonal anti-S100B antibody for their accuracy in the detection of the S100B expression profile (pattern and intensity) in a series of 67 primary (n = 37) and lymph node metastatic (n = 30) melanoma tissues. S100B is the lineage marker of malignant melanoma. Antibodies routinely used for melanoma diagnosis are not necessarily specific for this protein. Furthermore, clinical monitoring of melanoma progression is mostly based on the determination of serum S100B protein levels without knowing the actual expression level in the primary and/or metastatic tissue.Methods and results: The profile of expression patterns (focal, heterogenous and diffuse) as well as intensity ranges (+, ++ and +++) were similar for the two antibodies in melanoma tissues. However, comparison of the patterns and intensities on the basis of individual cases revealed a high frequency of discrepancies (50.7 and 58.2%, respectively). Severe discrepancy between the two antibodies in the determination of the S100B protein expression pattern (focal versus diffuse or focal versus heterogeneous) was relatively frequent; 13.4 and 11.9%, respectively. Furthermore, a similar rate of severe discrepancy was observed between the two antibodies in the determination of the intensity of S100B expression levels (+ versus +++ or + versus ++); 19.4 and 8.9%, respectively. Separate analysis of the primary tumours and metastases gave similar results.Conclusion: For the accurate determination of S100B protein expression in malignant melanoma it is highly recommended that a monospecific antibody is used.

The central role of T cells in antitumor immunity is well established. However, tumor progression, often seen in the presence of substantial lymphocytic infiltration, suggests that these T cells are not capable of mounting an effective immune response to control tumor growth. Evidence has accumulated that T lymphocytes infiltrating human neoplasms are functionally defective, incompletely activated, or anergic. Therefore, when characterizing the immune competent cells within lymphoid infiltrates of tumors, it is important to assess their activation state. We investigated the expression of two T-cell activation markers, interleukin 2 receptor alpha (CD25) and OX40 (CD134), by immunohistochemistry in primary cutaneous melanoma samples of 76 patients and analyzed it in relation to tumor stage and tumor progression (>5 years follow-up), as well as to patients' survival. We found that the degree of infiltration by CD25(+) and intratumoral OX40(+) lymphocytes showed a tendency to decrease in thicker melanomas. The frequency of samples with high numbers of peritumoral CD25(+) and OX40(+) cells was significantly lower (P = 0.0009 and P = 0.0087, respectively) in melanomas developing distant visceral metastases, compared with nonmetastatic or lymph node metastatic tumors. For both activation markers studied, high peritumoral densities were associated with longer survival by univariate analysis (P = 0.0028 and P = 0.0255 for CD25 and OX40, respectively), whereas peritumoral OX40(+) lymphocyte infiltration had an impact on survival also in multivariate analysis (P = 0.035). The results suggest that the presence of lymphocytes expressing the T-cell activation markers CD25 or OX40 shows correlation with tumor progression as well as with patients' survival in cutaneous malignant melanoma.

PURPOSE:To compare fotemustine and dacarbazine (DTIC) in terms of overall response rate (ORR) as primary end-point and overall survival, duration of responses, time to progression, time to occurrence of brain metastases (BM), and to assess safety and quality of life in patients with disseminated cutaneous melanoma.PATIENTS AND METHODS:Patients received either intravenous fotemustine 100 mg/m2 weekly for 3 weeks or DTIC 250 mg/m2/d for 5 consecutive days every 4 weeks (two cycles). Nonprogressive patients received a maintenance treatment every 4 weeks (fotemustine 100 mg/m2 or DTIC 250 mg/m2 for 5 days).RESULTS:Two hundred twenty-nine patients were randomly assigned to fotemustine or DTIC arms. The best ORR was higher in the fotemustine arm than in the DTIC arm in the intent-to-treat population (n=229; 15.2% v 6.8%; P=.043) and in full analysis set (n=221) (15.5% v 7.2%; P=.053). Similar median durations of responses (5.8 months with fotemustine v 6.9 months with DTIC) and time to progression (1.8 v 1.9 months, respectively) were observed. In patients without BM at inclusion, the median time to BM was 22.7 months with fotemustine versus 7.2 months with DTIC (P=.059). Median survival was 7.3 months with fotemustine versus 5.6 months with DTIC (P=.067). The main toxicity was grade 3 to 4 neutropenia (51% with fotemustine v 5% with DTIC) and thrombocytopenia (43% v 6%, respectively). No significant difference was noted for quality of life between arms.CONCLUSION:ORR was higher in the fotemustine arm compared to the DTIC arm in first-line treatment of disseminated melanoma. A trend in favor of fotemustine in terms of overall survival and time to BM was evidenced.

Objective: Serum S-100B is a reliable tumor marker of malignant melanoma, but efficient use is restricted to patients with metastatic disease. Therefore, the aim of our study was to assess serum S-100B levels at different stages of malignant melanoma and to compare these levels with the expression of the S-100B phenotype in primary tumors and lymph node metastases. Methods: Fifty-nine patients were included in this study; serum S-100B protein was measured using an immunoluminometric assay while the expression pattern in the primary tumor was determined by immunohistochemistry using an anti-S-100B monoclonal antibody. Results: Serum S-100B concentrations were significantly elevated in stage III (p = 0.01) patients, with normal levels in stage I–II. The most frequent S-100B protein expression pattern of the melanoma tissue was found to be diffuse staining observed in around half of the cases (52.5%) followed by heterogeneous (30.5%) and focal patterns (17%), being independent of the stage as well as the lymph node involvement. In stage I–II patients, the various staining patterns did not correlate with the serum concentration of the S-100B protein, while in stage III patients with heterogenous or diffuse S-100B staining patterns in tumor tissue, the serum marker concentration was significantly higher (p < 0.05) than in patients with focal staining. Furthermore, S-100B staining of the melanoma tissue also differed (low/negative, medium and strong staining), and serum marker concentrations corresponded to the pattern of the staining intensity. In stage I–II, only strong staining was associated with elevated serum S-100B concentrations while in stage III medium and strong staining was found to be associated with significantly higher serum marker concentrations compared to patients with tumors with low/negative staining (p < 0.05). Conclusions: In malignant melanoma characterized by focal and/or low S-100B staining in the tumor tissue determined by immunohistochemistry, S-100B monitoring in the serum may not suffice to detect disease progression.

5-S-Cysteinyldopa (5-S-CD) is a precursor of pheomelanin. S-100B protein is a low molecular weight, acidic, calcium binding, cytoplasmic protein. In this study, the concentration changes of serum 5-S-CD and S-100B protein in melanomas of all stages were examined in parallel and patients were monitored during and after treatment. Serum samples were taken from 478 melanoma patients on 1924 occasions. Of these, 180 cases were regularly monitored. Concentrations of 5-S-CD were determined by high performance liquid chromatography (HPLC), S-100B protein by immunoluminometric assay. The mean/median concentrations of 5-S-CD and S-100B protein in Stage I, II and III patients and in the control group ranged around the normal level. In Stage IV patients, 58.4/50.6% sensitivity, 100% specificity and 100/86.6% positive predictive values were obtained concerning S-100B protein and 5-S-CD, respectively. Recurrence was observed in 57/180 of the regularly monitored patients in Stages I, II and III. In 10/57 (17.5%) of these patients suffering from any type of disease progression increases in both marker levels preceded the detection of metastasis by conventional methods. We can confirm that changes in both marker concentrations correlated with the stages of the patient. The markers are most sensitive in Stage IV patients and also have a high specificity in these patients. In Stage IV melanoma patients, 5-S-CD and S-100B protein levels are independent significant prognostic factors. In almost one fifth of patients both marker levels increased before the detection of metastatic disease with other appropriate, routinely scheduled investigations. This study suggests that serial serum marker measurements in the management and follow-up of melanoma patients should be examined further.

Motility of tumor cells is the rate limiting potential of metastatic cells and is regulated by autocrine and paracrine factors. Autocrine motility factor/neuroleukin/phosphohexose isomerase (AMF) is one of the best characterized autocrine motogenic cytokines. Here we have studied its in vitro effects on several human melanoma cell lines and found that neither cell line exhibited mitogenic response to AMF at a concentration where motogenic response could be initiated. Similar to previous studies on murine melanoma, activation of the AMF receptor upregulated β3 while it downregulated β1 integrins at the cell surface, inducing an integrin phenotype characteristic for invasive/metastatic melanoma. The gp78/AMF receptor protein expression in human melanoma cell lines correlated to their in vivo spontaneous metastatic potential. Furthermore, in two out of three human melanoma lines the expression significantly increased in the primary tumor when spontaneous metastases developed (immunosuppressed newborn rat model versus SCID mice). In a prospective study we have also analyzed AMF receptor protein expression in primary tumors of 54 skin melanoma patients using IHC. These studies revealed three types of AMF receptor phenotype: weak, heterogenous and strong expression profile. While in thin tumors weak/heterogenous AMFR expression predominated, in thick tumors the strong expression profile was predominant. The connection between AMFR expression and the invasive/metastatic potential of melanoma was further supported by our observation that SSM melanoma in the vertical growth phase expressed this motility receptor more strongly than tumors in the radial growth phase.

5-S-cysteinyldopa is a precursor of melanin. Its serum and urinary level can reflect melanoma progression. In this study the concentration changes of 5-S-CD in melanomas of all stages were examined, and patients were monitored during and after treatment. Serum samples were taken from 479 melanoma patients with different Stages on 1924 occasions, from June 1996 to December 2000. Levels of 5-S-CD were determined by HPLC. The mean/median value of 5-S-CD in the Stage I-II-III patients and in the control group ranged around the normal level. Significant difference was found between Stage III and Stage IV as well as between patients with no evidence of disease and patients with tumor burden. In Stage IV 69.7% sensitivity, 61.5% specificity and 79.3% positive predictive value were evaluated. The survival of patients with normal 5-S-CD level (n=235) differed significantly from cases having elevated marker concentration (n=244). One hundred eighty cases were regularly monitored on 1210 occasions. Recurrence development was noticed in 57 patients. In 24.6% of these patients suffering from any type of disease progression the increasing marker level preceded the detection of metastasis by conventional methods. Serum 5-S-CD in Stage IV is sensitive enough to detect distant metastasis, and its predictive value has a great importance. It is a reliable marker for monitoring the clinical course in malignant melanoma.

BACKGROUND:5-S-cysteinyldopa (5-S-DC) is a precursor of melanin. Its serum and urinary level can reflect melanoma progression. In this study we examined the concentration changes of 5-S-CD in melanomas of different clinical stages and in patients with different symptoms of melanoma, during and after treatment. METHOD:Serum samples were taken from 252 melanoma patients on 765 occasions, from June 1996 to July 1998. Levels of 5-S-CD were determined by HPLC. RESULTS:The value of 5-S-CD in patients with primary melanoma and in patients without symptoms ranged around the normal level. There was a significant difference between the values of patients with or without symptoms. There was also a significant difference between the 5-S-CD values at clinical Stage I and Stage III, as well as at clinical Stage II and Stage III, respectively. Analysing the values of patients with symptoms we found a significant difference between the mean values of primary tumour and stage III, between values in lymph node metastasis and stage III, between values in lung metastasis and stage III. The tumour burden was found to correlate with a rising marker level. In 7% of the symptomatic patients that had a marker level under the upper limit, amelanotic primary tumour was detected. CONCLUSION:According to the high marker level in lung and liver metastases, the marker might be useful in monitoring both patients with disease free ocular melanomas, to detect liver metastasis and high-risk patients after surgical removal of the primary tumour to reveal lung metastases.