Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study.

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.

Accuracy of the determination of S100B protein expression in malignant melanoma using polyclonal or monoclonal antibodies.

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.

Heterogenous S-100B protein expression patterns in malignant melanoma and association with serum protein levels.

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.

Use of serum 5-S-CD and S-100B protein levels to monitor the clinical course of malignant melanoma.

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.

Expression and function of the AMF receptor by human melanoma in experimental and clinical systems.

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 beta3 while it downregulated beta1 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.

Clinical significance of 5-S-cysteinyldopa monitoring in patients with malignant melanoma.

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.

Serum concentration of 5-S-cysteinyldopa in patients with 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.

[The role of intraoperative gamma-probe-guided sentinel lymph node biopsy in the treatment of malignant melanoma and breast cancer]. / Az intraoperatív gamma-próba által vezérelt örszem nyirokcsomó-biopszia jelentösége a melanoma malignum és az emlörák kezelésében.

In the treatment of malignant tumors regional lymphadenectomy is used for two purposes. It is used partly for staging the regional lymph nodes which is a significant and independent prognostic factor and determines the need for adjuvant oncologic treatment and partly for achieving locoregional disease control. Removal of tumor-free lymph nodes by regional lymph node clearance is unnecessary according to our current knowledge. Since the sensitivity and specificity of non-invasive clinical examinations are insufficient in predicting the nodal status the histological study of the regional lymph nodes cannot be abandoned. A new and minimally invasive surgical procedure, the mapping and removal of the first tumor draining lymph node, the sentinel node provides the possibility of pathological nodal staging without performing formal lymphadenectomy. Mapping of the sentinel node can be performed by the use of a radioisotope and intraoperative hand-held gamma-probe or a vital blue dye or a combination of these two. This latter method was used by the authors in 73 patients (25 with malignant melanoma and 48 with breast cancer). Sentinel lymph node biopsy was performed successfully in 92% of patients with melanoma and 90% of patients with breast cancer. In three breast cancer patients the sentinel node inaccurately predicted the axillary status as negative, but is was in 93% accurate in predicting the histologic nodal state. According to our preliminary experiences intraoperative gamma-probe guided sentinel lymph node biopsy is considered a feasible procedure in both malignant melanoma and breast cancer. More experiences are needed before introducing this method in the routine clinical practice.

Serum levels of S-100 protein and 5-S-cysteinyldopa as markers of melanoma progression.

Serum S-100 protein is widely used as a marker of melanoma and since 5-S-cysteinyldopa (5-S-CD) is a precursor of melanin its serum and urinary levels can reflect melanoma progression. In this study we examined the concentration changes of serum S-100 protein and 5-S-CD in 252 melanoma patients of different clinical stages. Serum samples were taken from 252 melanoma patients at 860 times, from June 1996 to July 1998. The serum S-100 protein was measured by the immunoluminometric assay, levels of 5-S-CD was determined by HPLC. The value of S-100 protein in patients with primary melanoma (0.11m mg/l) and in patients without symptoms (0.15 m mg/l) ranged around the normal level (0.01 0.12 m mg/l). There was a significant difference between the values of patients with or without symptoms. There was a similarly significant difference between the S-100 values of clinical Stage I (0.11 mg/l) and Stage III (2.91 mg/l) as well as between those of clinical Stage II (0.47 mg/l) and Stage III (2.91 mg/l), respectively. Analyzing the values of patients with symptoms we observed significant difference between the S-100 protein values of patients with primary tumor and those with solitary or multiple distant metastases. In case of 5-S-CD significant difference was found between clinical Stage I and III as well as clinical Stage II and III. Furthermore, there was a significant difference between the mean marker values of patients with primary tumor, lymph node, lung metastasis and clinical stage III.

[Determination of serum S-100 protein and 5-S-cysteinyl-DOPA levels in melanoma patients]. / S-100 protein és 5-S-ciszteinil-DOPA vizsgálata melanomás betegekben.

This was the first time that authors detected se-S-100 and 5-SCD values with patients with malignant melanoma in Hungary. They examined the change of serum S-100 and 5-SCD value parallel. Sera were obtained with 184 melanoma patients 326 times. Patients were ranked into groups on the basis of clinical symptoms: free of symptoms and suffering from it (primary tumour, regional lymph node metastasis, soliter or multiplex distant metastasis). On the basis of the initial results the following have been found: S-100 protein and 5-SCD serum levels had no prognostic value in patients with primary melanoma. Patients without symptoms showed values around the normal level. There was significant difference in both markers between patients with or without symptoms. Significant differences were found between clinical stage I and II, as well as in clinical stage II and III. In the case of S-100 protein there was significant difference between the values of patients with soliter and multiplex distant metastasis.

Tinea capitis caused by Microsporum canis in an adult.

The authors report a case of tinea capitis in a woman aged 49, with a previous history of discoid lupus erythematosus. The pathogenic agent was Microsporum canis. The patient was cured after two months therapy with griseofulvin and local antimycotics.

[Diabetic retinitis in children and adolescents and its relationship to regulation (author's transl)]. / Diabetische Retinopathie bei Kindern und Jugendlichen. Ihre Abhängigkeit von der Stoffwechseleinstellung.

Ninety diabetics between eight and 18 years of age, whose diabetes is controlled very carefully, were examined by fluorescein angiography in order to investigate the incidence and severity of diabetic retinitis. At 21% the percentage was markedly lower than that found by other workers, who control metabolism much less stringently. Also the severity of the retinitis was found to be much less pronounced in our examinations than in those carried out by other groups. Our results show that besides disposition the control of diabetes plays a decisive role in the development of diabetic retinitis in young diabetics.