Melanoma: Burg G

Dummer R, Panizzon R, Bloch PH, Burg G, Anonymous00029. · Department of Dermatology, University Hospital of Zurich, Zürich, Switzerland. · Dermatology. · Pubmed #15604544 No free full text.

Abstract: Melanoma is the most common lethal cutaneous neoplasm. In order to harmonize treatment and follow-up of melanoma patients, guidelines for the management of melanoma in Switzerland have been inaugurated in 2001. These have been approved by all Swiss medical societies involved in the care of melanoma patients. New data necessitated changes concerning the safety margins (reduction to maximally 2 cm) and modifications of the recommendations of follow-up.

Dummer R, Bösch U, Panizzon R, Bloch PH, Burg G, Anonymous00035. · Department of Dermatology, University Hospital of Zürich, Switzerland. · Dermatology. · Pubmed #11549807 No free full text.

Abstract: Melanoma is the most common lethal cutaneous neoplasm. There is major controversy over the best management of this malignancy. In order to harmonize treatment and follow-up of melanoma patients, guidelines for the management of melanoma in Switzerland have been inaugurated. They have been approved by all Swiss medical societies involved in the care of melanoma patients.

Dummer R, Burg G. · No affiliation provided · J Eur Acad Dermatol Venereol. · Pubmed #11305369 No free full text.

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Burg G. · No affiliation provided · Ther Umsch. · Pubmed #10420806 No free full text.

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Dummer R, Beyeler M, Morcinek J, Burg G. · Dermatologische Klinik, UniversitätsSpital Zürich. · Praxis (Bern 1994). · Pubmed #14526630 No free full text.

Abstract: The skin is the organ most commonly affected by malignancies. Various cancers of the skin show a dramatic increase in incidence over the last decades. Epithelial skin tumors are most frequently, e.g., basal cell carcinoma and the squamous cell carcinoma with its precursors, the actinic keratoses. Melanoma, which is extremely difficult to treat in advanced tumor stages, is dreaded. Besides that, there are other epithelial malignant diseases, e.g. Morbus Bowen and adnexal tumors originating from the skin appendices. Mesenchymal malignant neoplasias such as Morbus Kaposi, angiosarcomas and other dermal sarcomas, are rare. Since the majority of malignant neoplasms is removable and curable by a simple surgical intervention, the knowledge of the different skin tumors is essential for non-dermatologist.

Böni R, Schuster C, Nehrhoff B, Burg G. · Department of Dermatology, University Hospital of Zürich, Gloriastrasse 31, CH-8091 Zürich, Switzerland. · Neuro Endocrinol Lett. · Pubmed #12163848 No free full text.

Abstract: The skin is the most common site of malignancy. Due to several mostly unknown factors, the frequency of skin tumors is increasing. Except for malignant melanoma, reliable statistical data on the frequency of skin tumors are scarce. Discussion on the epidemiology of skin tumors may take different aspects and factors into consideration: (1) histogenetic type; (2) race, (3) sex; (4) age, (5) localization; (6) environment. Moreover, precancerous conditions also may play an important role in this context. Epithelial tumors, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most frequent tumors of the skin. Figures show a wide range between 40 and over 700 or 5 and 250 respectively per 100 000 inhabitants per year depending on the country or area of report. Malignant melanoma is more frequently seen in Caucasians living in sunny regions (40) than in northern countries or in dark skinned races (4-12 per 100 000 per year), representing 4% of all skin tumors, but being responsible for 79% of skin cancer deaths. Other types of skin tumors like cutaneous lymphoma, Kaposi sarcoma, lipomas, adnexal tumors etc. are either not reported regularly and reliable epidemiologic data is not available, or are rare cutaneous tumors (taken all together < 1%).

Dummer R, Nestle FO, Burg G. · Dermatologische Klinik, Universitätsspital Zürich. · Dtsch Med Wochenschr. · Pubmed #11076264 No free full text.

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Dummer R, Nestle FO, Hofbauer G, Burg G. · Dermatologische Klinik, Universitätsspital Zürich. · Ther Umsch. · Pubmed #10420816 No free full text.

Abstract: Therapy of metastatic melanoma still remains difficult. All therapeutic strategies have to consider the individual patient's condition and number and localisation of the metastases. Solitary metastases in lung, CNS, soft tissues and lymph nodes have to be removed by surgery. Multiple metastases are treated with a systemic chemoimmunotherpy. Promising approaches use interleukin-2, interferons, DTIC, temozolamide, vindesine and cisplatin. Radiotherapy is the treatment of first choice for bone and CNS metastases. These therapeutic strategies have improved the prognosis of metastatic melanoma. Additional multi-center trials and experimental approaches will help to reach the goal of a curative systemic therapy for metastatic melanoma.

Böni R, Burg G. · Dermatologische Klinik, Universitätsspital Zürich. · Schweiz Med Wochenschr. · Pubmed #10413820 No free full text.

Abstract: Many studies using different approaches and sets of data have concluded that there is a significantly increased risk of malignant melanoma in patients with atypical moles. For clinical identification, the features of ABCD's (Asymmetry, Border, Colour, Dimension) are used, the "ugly duckling" sign (the naevus that does not resemble its "brother naevi"), dermatoscopy and digital approaches. After excision, histologic criteria are used to identify naevi with architectural changes. It has recently been possible to identify allelic losses within known tumour suppressor genes in microdissected atypical moles, using microdissection and loss of heterozygosity analysis, thus providing additional evidence for the concept of the atypical mole as a precursor lesion of melanoma.

Hofbauer GF, Baur T, Bonnet MC, Tartour E, Burg G, Berinstein NL, Dummer R. · Department of Dermatology, University Hospital Zürich, Zürich, Switzerland. · Melanoma Res. · Pubmed #18337646 No free full text.

Abstract: Immunotherapy employs cytokines for modifying local inflammatory reactions. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to activate dendritic cells, macrophages, and granulocytes leading to clinical trials using GM-CSF-based cancer vaccine approaches. Interleukin-2 (IL-2) is an important T cell stimulatory cytokine approved as exogenous antitumor agent. The ALVAC viral vector system uses a recombinant canarypox virus for local gene expression. We report a phase I clinical trial using intratumoral administration of ALVAC GM-CSF or ALVAC IL-2 in skin metastases of melanoma or leiomyosarcoma. ALVAC GM-CSF and ALVAC IL-2 were injected at 107.12 and 106.92, 50% cell culture infectious dose in eight metastases with acceptable tolerability. Local and systemic inflammatory reactions were observed. The transgene determined the local infiltrate: GM-CSF induced monocyte and macrophage enrichment of the peritumoral inflammatory infiltrate, whereas IL-2 increased local T lymphocytes. Stable disease of injected lesions was seen after ALVAC GM-CSF application, whereas ALVAC IL-2 treatment led to partial regression in three out of eight injected tumors, accompanied by decreased expression of melanocytic antigens. Local GM-CSF expression could be induced. In summary, ALVAC GM-CSF and ALVAC IL-2 injections are safe and can mediate local biologic and immunologic effects.

Schadendorf D, Ugurel S, Schuler-Thurner B, Nestle FO, Enk A, Bröcker EB, Grabbe S, Rittgen W, Edler L, Sucker A, Zimpfer-Rechner C, Berger T, Kamarashev J, Burg G, Jonuleit H, Tüttenberg A, Becker JC, Keikavoussi P, Kämpgen E, Schuler G, Anonymous00068. · Skin Cancer Unit, German Cancer Research Center & University Hospital Mannheim, Mannheim. · Ann Oncol. · Pubmed #16418308 links to  free full text

Abstract: BACKGROUND: This randomized phase III trial was designed to demonstrate the superiority of autologous peptide-loaded dendritic cell (DC) vaccination over standard dacarbazine (DTIC) chemotherapy in stage IV melanoma patients. PATIENTS AND METHODS: DTIC 850 mg/m2 intravenously was applied in 4-week intervals. DC vaccines loaded with MHC class I and II-restricted peptides were applied subcutaneously at 2-week intervals for the first five vaccinations and every 4 weeks thereafter. The primary study end point was objective response (OR); secondary end points were toxicity, overall (OS) and progression-free survival (PFS). RESULTS: At the time of the first interim analysis 55 patients had been enrolled into the DTIC and 53 into the DC-arm (ITT). OR was low (DTIC: 5.5%, DC: 3.8%), but not significantly different in the two arms. The Data Safety & Monitoring Board recommended closure of the study. Unscheduled subset analyses revealed that patients with normal serum LDH and/or stage M1a/b survived longer in both arms than those with elevated serum LDH and/or stage M1c. Only in the DC-arm did those patients with (i) an initial unimpaired general health status (Karnofsky = 100) or (ii) an HLA-A2+/HLA-B44- haplotype survive significantly longer than patients with a Karnofsky index <100 (P = 0.007 versus P = 0.057 in the DTIC-arm) or other HLA haplotypes (P = 0.04 versus P = 0.57 in DTIC-treated patients). CONCLUSIONS: DC vaccination could not be demonstrated to be more effective than DTIC chemotherapy in stage IV melanoma patients. The observed association of overall performance status and HLA haplotype with overall survival for patients treated by DC vaccination should be tested in future trials employing DC vaccines.

Heinzerling L, Burg G, Dummer R, Maier T, Oberholzer PA, Schultz J, Elzaouk L, Pavlovic J, Moelling K. · Department of Dermatology, University of Zurich, CH-8091 Zurich, Switzerland. · Hum Gene Ther. · Pubmed #15703487 No free full text.

Abstract: Plasmid DNA encoding human interleukin 12 (IL-12) was produced under GMP conditions and injected into lesions of nine patients with malignant melanoma (stage IV) previously treated with both standard and nonstandard therapies. The treatment was based on efficacy in preclinical studies with melanoma in mice and gray horses. The DNA was applied in cycles, three injections per cycle, for up to seven cycles. Three therapy arms comprised low (2 mg), medium (4 mg), and high (10 to 20 mg) amounts of total DNA. The therapy was well tolerated. Three of nine patients experienced a clinical response: two stable disease and one complete remission. One patient receiving a low dose of DNA experienced a long-lasting stabilization of the disease for more than 3 years, whereas the other two responders received high doses of DNA. All patients but one (patient 9) experienced a transient response at the intratumoral injection site. Immunohistochemical staining of responder sections showed local reduction of angiogenesis and lymphocyte infiltrations. All patients, in particular the clinical and local responders (patients 3, 7, and 8), exhibited an antigen-specific immune response against MAGE-1 and MART-1, which in some cases preexisted. Biopsies of responders showed some increase in IL-12, IP-10, and IFN-(). Serum levels revealed fluctuations. The results show that intratumoral injection of DNA produced some beneficial clinical effect. DNA encoding a cytokine may be useful as a therapeutic or adjuvant against various human cancers.

Hauschild A, Weichenthal M, Balda BR, Becker JC, Wolff HH, Tilgen W, Schulte KW, Ring J, Schadendorf D, Lischner S, Burg G, Dummer R. · Department of Dermatology, University of Kiel, St Georg Hospital,Hamburg, Germany. · J Clin Oncol. · Pubmed #12885805 No free full text.

Abstract: PURPOSE: Low-dose interferon alfa (IFNalpha) has been shown to have limited effects in the adjuvant treatment of patients with intermediate- and high-risk primary melanoma. We hypothesized that a combination regimen with low-dose interleukin-2 (IL-2) may improve survival prospects in these patients. PATIENTS AND METHODS: After wide excision of primary melanoma without clinically detectable lymph node metastasis (pT3 to 4, cN0, M0), 225 patients from 10 participating centers were randomly assigned to receive either subcutaneous low-dose IFNalpha2b (3 million international units [MU]/m2/d, days 1 to 7, week 1; three times weekly, weeks 3 to 6, repeated all 6 weeks) plus IL-2 (9 MU/m2/d, days 1 to 4, week 2 of each cycle) for 48 weeks, or observation alone. The primary end point was prolongation of a relapse-free interval. RESULTS: Of the 225 enrolled patients, 223 were found to be eligible. Median follow-up time was 79 months. All evaluated prognostic factors were well balanced between the two arms of the study. Relapses were noticed in 36 of 113 patients treated with IFNalpha2b plus IL-2 and in 34 of 110 patients with observation alone. Five-year disease-free survival of those who had routine surgery supplemented by IFNalpha2b and IL-2 treatment was 70.1% (95% confidence interval [CI], 61.3% to 78.9%), compared with 69.9% in those receiving surgery and observation alone (95% CI, 60.7% to 79.1%) in the intention-to-treat analysis. Evaluation of the overall survival did not show any difference between treated and untreated melanoma patients (P =.93). CONCLUSION: Adjuvant treatment of intermediate- and high-risk melanoma patients with low-dose IFNalpha2b and IL-2 is safe and well tolerated by most patients, but it does not improve disease-free or overall survival.

Dummer R, Bergh J, Karlsson Y, Horowitz JA, Mulder NH, Huinink DTB, Burg G, Hofbauer G, Osanto S. · Department of Dermatology, University Hospital of Zürich, Switzerland. · Cancer Gene Ther. · Pubmed #10917210 links to  free full text

Abstract: p53 mutations are common genetic alterations in human cancer. Gene transfer of a wild-type (wt) p53 gene reverses the loss of normal p53 function in vitro and in vivo. A phase I dose escalation study of single intratumoral (i.t.) injection of a replication-defective adenoviral expression vector containing wt p53 was carried out in patients with metastatic melanoma or breast cancer with increased p53 protein immunoreactivity in pretreatment tumor biopsies. The biological activity of the injected wt p53 was assayed by reverse transcriptase-polymerase chain reaction in tumor tissue. A total of six (five melanoma and one breast adenocarcinoma) patients were treated at dose levels dependent upon tumor size/dose escalation sequence. Five of six patients became positive for the transfer of wt p53 into tumor tissue 2 days after injection of the vector. Of the four patients assayed, all developed anti-adenoviral antibodies. Adverse reactions associated with i.t. injection were mild, with no obvious correlation between the incidence, severity, or relationship of the events and drug dose. p53 gene therapy by i.t. injection of a replication-defective adenoviral expression vector is safe, feasible, and biologically effective (with respect to transduction frequency) in patients with either metastatic melanoma or breast cancer.

Gächter T, Mühleisen B, Schärer L, Dummer R, Burg G, Hofbauer GF. · Department of Dermatology, University Hospital of Zürich, Zürich, Switzerland. · J Cutan Med Surg. · Pubmed #17274934 No free full text.

Abstract: BACKGROUND AND OBJECTIVE: We studied the weight of decision-making on clinical assessment of melanocytic lesions judging benign, atypical, and malignant lesions; common mistakes; and total removal rates, comparing dermatologists with nondermatologists. METHODS: Of 11,246 histopathology specimens, 3,768 had a clinical assessment of melanocytic lesions. Histopathologic diagnosis served as the gold standard. RESULTS: Benign nevi were assessed most accurately (77%). Dermatologists assessed benign nevi better (p < .0001). The accuracy of clinical assessment in atypical nevi and melanoma was lower (23% and 42%, respectively). Seborrheic keratosis was the most common mistaken diagnosis. Complete removal of clinically benign nevi, atypical nevi, and melanoma was 84%, 90%, and 89%. Decision-making impaired clinical assessement of melanocytic lesions by 5% for dermatologists and 9% for nondermatologists. CONCLUSION: The accuracy of clinical assessment of melanocytic lesions is high for benign nevi, with dermatologists outperforming nondermatologists. Clinicians overestimated malignant potential. Complete removal was more frequent in suspicious lesions. Clinical decision-making impaired assessment by 5 to 9%.

Beyeler M, Waldispuhl S, Strobel K, Joller-Jemelka HI, Burg G, Dummer R. · Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. · Dermatology. · Pubmed #17033166 No free full text.

Abstract: BACKGROUND: Early detection of melanoma recurrence is essential for the patient's prognosis. The serum S100 level may be a useful tool to detect relapse early. OBJECTIVE: To compare the efficacy of imaging techniques and serum S100 in the early detection of melanoma progression. This is the first report of a comparison of a serum marker with an imaging tool in the follow-up of melanoma patients. METHODS: From 1992 to 2003, we screened 192 patients suffering from melanoma recurrence after a disease-free interval. Of those, 127 patients were identified whose S100 levels had been assessed parallel to imaging procedures. RESULTS: Serum S100 was elevated in 37% of patients at the time of relapse. In stage III, 32% of the patients had elevated S100 levels whereas in case of progression to stage IV, 48% of the patients presented with increased S100. In 5.5% of patients, S100 was the first indicator of disease progression. Imaging procedures lead to detection of melanoma recurrence in 26.8%. CONCLUSION: A rising level of serum S100 is a specific and sensitive marker of melanoma progression.

Hofbauer GF, Hatta N, Daigle I, Hemmi S, Spanaus Schlapbach K, Willers J, Burg G, Simon HU, Dummer R. · Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. · Dermatology. · Pubmed #16286739 No free full text.

Abstract: BACKGROUND: Apoptotic pathway aberrations are reported as important tumor progression factors in melanoma. OBJECTIVE: Effect of soluble Fas ligand (sFasL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on short-term cultured melanoma cell viability from different stages of melanoma. RESULTS: Recombinant human FasL reduced viability after 18 h in a dose-dependent manner in 4 of 5 cell cultures from primary tumors and 1 of 9 cell cultures from metastatic melanoma (67.5 vs. 96.4%, p = 0.007). DNA fragmentation on flow cytometry confirmed apoptosis. Incubation with TRAIL had no effect on melanoma cell viability. Immunohistochemistry showed Fas in 3 of 4 primary and in 6 of 7 metastatic lesions, no FasL in primary lesions, and FasL in 5 of 7 metastatic lesions. CONCLUSION: Melanoma short-term cell cultures from primary tumors show decreased viability under FasL, but not TRAIL stimulation rather than short-term cell cultures derived from metastases.

Urosevic M, Braun B, Willers J, Burg G, Dummer R. · Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. · Exp Dermatol. · Pubmed #15946236 No free full text.

Abstract: The efficiency of melanoma immunotherapy appears to depend on both melanoma- and immune system-specific factors. Melanoma-specific factors include melanoma-associated antigen (MAA) expression as well as HLA class I molecule expression. We investigated the expression of five MAA - Melan-A/MART-1, tyrosinase, gp100, MAGE-1 and MAGE-3 - by means of FACS analysis in 50 melanoma cell cultures and compared them to the cultures of human foreskin-derived melanocytes and melanoma cell line UKRV-Mel2. Melan-A, tyrosinase and gp100 expression was frequently reduced in melanoma cell cultures, compared to that in foreskin melanocytes, whereas MAGE-1 and MAGE-3 expression showed variable degree of upregulation, compared to that in foreskin melanocytes. The expression of all tested MAA demonstrated high interindividual variability. We further show that cell cultures derived from the same tissue sample are oligoclonal in nature, by demonstrating the presence of up to three cell populations bearing distinct MAA profile. Analysing samples derived from the same patient but each at a different time point, we show that MAA expression profile changes over time either in positive (increase) or in negative (decrease) direction. Finally, we demonstrate that brain metastasis-derived cell cultures significantly overexpress Melan-A and MAGE-3, compared to primary tumours and other metastatic sites (P-value range: 0.05-0.001). Elucidation of the MAA expression patterns and the kinetics within the same patient as well as during the course of the disease may help improve current and develop new immunotherapeutic strategies.

Gerlini G, Tun-Kyi A, Dudli C, Burg G, Pimpinelli N, Nestle FO. · Department of Dermatological Sciences, University of Florence Medical School, Florence, Italy. · Am J Pathol. · Pubmed #15579430 links to  free full text

Abstract: CD1 molecules are expressed by antigen-presenting cells such as dendritic cells and mediate primary immune responses to lipids and glycolipids which have been shown to be expressed by various tumors. Glycolipids are expressed by melanoma cells but, despite their immunogenicity, no efficient spontaneous immune responses are elicited. As IL-10 has previously been shown to down-regulate CD1a on dendritic cells and is known to be expressed by various melanoma cell lines, we investigated if melanoma-derived IL-10 could down-regulate CD1 molecule expression on dendritic cells as a possible way to circumvent immune recognition. We found that CD1a, CD1b, CD1c, and CD1d were significantly down-regulated on dendritic cells in metastatic (n = 10) but not in primary melanoma lesions (n = 10). We further detected significantly higher IL-10 protein levels in metastatic than in primary melanomas. Moreover, supernatants from metastatic melanomas were significantly more effective in down-regulating CD1 molecules on dendritic cells than supernatants from primary melanoma cultures. This effect was blocked using a neutralizing IL-10 antibody in a dose dependent manner. Our findings suggest that metastatic but not primary melanomas can down-regulate CD1 molecules on infiltrating dendritic cells by secreting IL-10 which may represent a novel way to escape the immune response directed against the tumor.

Murer K, Urosevic M, Willers J, Selvam P, Laine E, Burg G, Dummer R. · Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. · Melanoma Res. · Pubmed #15305155 No free full text.

Abstract: The lack of melanoma-associated antigen (MAA) expression has been associated with the reduced overall survival in melanoma patients. In order to investigate whether the MAA expression detected on cell cultures established from melanoma patients might relate to the overall survival in these patients, we screened primary cell cultures derived from 37 melanoma metastases for the expression of five known MAA: Melan-A, tyrosinase, gp-100, MAGE-1 and MAGE-3 by polymerase chain reaction (PCR) and fluorescence-activated cell sorting (FACS). MAA expression detected by PCR was found at a high percentage in evaluated melanoma cell lines: 25 of 28 (89%) were positive for Melan-A, 22 of 28 (79%) were positive for tyrosinase, 26 of 28 (93%) were positive for gp-100, and 18 of 28 (64%) were positive for MAGE-3 expression. Using the FACS method the percentage of MAA-positive cell lines was much lower: 14 of 31 (45%) cell lines were positive for Melan-A, eight of 31 (26%) were positive for tyrosinase, 13 of 31 (42%) were positive for gp-100, six of 31 (19%) were positive for MAGE-1, and 14 of 31 (45%) were positive for MAGE-3 expression. Kaplan-Meier survival analysis demonstrated that the patients whose cell lines were positive for Melan-A expression by PCR had significantly longer overall survival time as Melan-A PCR-negative cases (P=0.0038). This could not be shown for any of the markers tested by FACS. Our results suggest that the expression of Melan-A/MART-1 in patient-derived cell cultures may help to identify a group of melanoma patients with prolonged survival.

Meier S, Baumert BG, Maier T, Wellis G, Burg G, Seifert B, Dummer R. · Department of Dermatology, University Hospital of Zurich, Switzerland. · Onkologie. · Pubmed #15138346 No free full text.

Abstract: AIM: We wanted to determine the factors influencing survival in a retrospective review of patients with melanoma brain metastases to permit more specific recommendations regarding therapy. PATIENTS AND METHODS: We reviewed the data of 100 patients treated at the Department of Dermatology and Radiation Oncology, University of Zurich, and the Klinik im Park, Zurich. Information on potential prognostic factors (age, sex, location of the primary tumor, Clark level, Breslow index, histological type, number of brain metastases, stage at initial diagnosis, location of brain metastases, and therapy) was collected from the medical records of 100 patients treated between 1966 and 2002. Univariate and multivariate analyses were performed to identify significant prognostic factors. RESULTS: The overall median survival time was 4.8 months, with 6-month, 1-year and 2-year survival percentages of 36, 14 and 5%, respectively. Univariate analysis indicated that survival correlated significantly with radiotherapy (partial and whole brain), surgery, stereotactic radiosurgery, chemotherapy, Clark level and Breslow index. Treatment with temozolomide (p = 0.052) and number of brain metastases (p = 0.07) failed to be statistically significant. Multivariate analysis confirmed radiotherapy (partial and whole brain), surgery, stereotactic radiosurgery, chemotherapy and the location of brain metastases as independent and significant prognostic factors of survival. The remaining factors did not reach statistical significance in multivariate analysis. CONCLUSION: Radiotherapy, chemotherapy and especially surgery and stereotactic radiosurgery seem to significantly prolong survival, as shown by multivariate analysis. Treatment with temozolomide will possibly play an important role in the future management of patients with brain metastases from cutaneous melanoma, but further prospective studies to verify this assumption are urgently needed.

Hafner J, Schmid MH, Kempf W, Burg G, Künzi W, Meuli-Simmen C, Neff P, Meyer V, Mihic D, Garzoli E, Jungius KP, Seifert B, Dummer R, Steinert H. · Department of Dermatology, Institute of Social and Preventive Medicine, University Hospital of Zurich, CH-8091 Zurich, Switzerland. · Br J Dermatol. · Pubmed #15099363 No free full text.

Abstract: BACKGROUND: Baseline staging in patients with primary cutaneous malignant melanoma (MM) is routine, but the diagnostic accuracy and the impact on clinical outcome are still unclear. OBJECTIVES: To evaluate the sensitivity and specificity of baseline staging in the early detection of regional lymph node metastases or distant metastases in patients with MM. METHODS: One hundred consecutive patients with MM of Breslow's tumour thickness over 1.0 mm were enrolled. All patients had an extensive baseline staging including physical examination, ultrasound (US) of the abdomen and regional lymph nodes, chest X-ray, whole-body positron emission tomography (PET) and sentinel lymph node biopsy. The sensitivity and specificity of detection of macroscopic or microscopic metastases in the regional lymph nodes or at distant sites were calculated for each method. RESULTS: Sentinel lymph node biopsy was positive in 26 patients. US detected two of 26 histologically tumour-positive sentinel nodes (sensitivity 8%, specificity 88%) and PET two of 26 (sensitivity 8%; specificity 100%). There were three lymph node metastases with a diameter > 4 mm. All of them were found suspect at physical examination. Two of them were detectable with US, two with PET, and all were identified with either US or PET. Nine patients had suspect findings at distant sites, which were all false positive on further investigation (specificity of the combined staging procedures 91%). At 18 (6-37) months' follow-up, five of 26 (19%) patients with a positive sentinel node and four of 74 (5%) of patients with a negative sentinel node had recurrent or progressive disease. CONCLUSIONS: The combination of physical examination and lymph node US detects the great majority of patients with macroscopic lymph node metastasis (approximately 3% of patients at baseline). Only 10% of patients who have a histologically tumour-positive sentinel node are macroscopically detectable. Altogether, approximately 25% of patients have a positive sentinel node biopsy, among 90% microscopic. The value of whole body staging at baseline remains limited, since distant metastases can hardly ever be detected. The survival benefit of baseline staging and surveillance in patients with cutaneous MM remains to be established by comparative prospective trials.

Kazakov DV, Kutzner H, Rütten A, Michal M, Requena L, Burg G, Dummer R, Kempf W. · Unit of Dermatopathology, Department of Dermatology, University Hospital, Zürich, Switzerland. · Am J Dermatopathol. · Pubmed #15024190 No free full text.

Abstract: The differentiation of melanoma from certain benign melanocytic lesions on histologic grounds alone may sometimes be difficult. The anti-MAGE antibody 57B was suggested to be a useful adjunct in differentiating melanoma from nevi. Our aim was to study MAGE immunoreactivity with B57 in benign melanocytic lesions that have not been investigated to this end so far. One hundred six benign melanocytic lesions were stained with the monoclonal antibody 57B. They included deep-penetrating nevus (n = 6), desmoplastic nevus (n = 9), halo nevus (n = 10), persistent melanocytic nevus (n = 12), common blue nevus (n = 17), cellular blue nevus (n = 8), cellular blue nevus with microalveolar pattern (n = 3), desmoplastic cellular blue nevus (n = 6), epithelioid blue nevus (n = 2), sclerotic blue nevus (n = 3), and clonal nevus (n = 30). Fifty-two lesions (49%) demonstrated various patterns of MAGE immunoreactivity, with clonal nevi and deep-penetrating nevi showing the most consistent staining. In conclusion, MAGE immunoreactivity detected by the monoclonal antibody 57B in formalin-fixed, paraffin-embedded tissue can be observed in benign melanocytic lesions, and therefore this antibody cannot be used in the differential diagnosis between melanoma and nevi.

Hofbauer GF, Burkhart A, Schüler G, Dummer R, Burg G, Nestle FO. · Department of Dermatology, University Hospital Zürich, Switzerland. · J Immunother. · Pubmed #14676635 No free full text.

Abstract: Melanoma-associated antigens are at the center of many immunotherapeutic trials in melanoma. Little is known about the impact of antigen expression on the natural course of disease. We stained 110 cases of primary melanoma with a median follow-up of 13 years (range 10-18 years) for melanoma-associated antigens gp100, MelanA/MART-1, MAGE-3, tyrosinase, and for HLA class I molecules. Of 91 cases evaluated, we found immunoreactivity for gp100, MelanA/MART-1, and tyrosinase in 88%, 80%, and 87% of primary tumors, respectively, for MAGE-3 in 37% and for HLA class I in 86% of primary tumors. Loss, that is, heterogeneous expression within primary tumors, was most pronounced for gp100 (73% of primary tumors) and least for MAGE-3 (27% of primary tumors). MelanA/MART-1 and tyrosinase expression loss was 58% and 59% of primary tumors, respectively. There was a high rate of expression loss for HLA class I (74%). Univariate and multivariate statistical analysis of expression in primary tumors and loss of melanoma antigens as well as HLA class I in individual primary tumors showed no significant correlation to overall survival. Loss of gp100 and loss of tyrosinase expression showed a negative survival trend over homogeneous expression of these antigens, although not reaching statistical significance (P = 0.08 and P = 0.09, respectively). We conclude that loss of melanoma antigen expression as well as HLA class I expression is a frequent observation in primary melanoma. However, no statistically significant correlation between loss of these antigens in individual primary tumors and negative impact on overall survival was found in our cohort.

Bogdan I, Smolle J, Kerl H, Burg G, Böni R. · Department of Dermatology, University Hospital, 8091 Zürich, Switzerland. · Melanoma Res. · Pubmed #12690309 No free full text.

Abstract: It has been shown that the co-occurrence of melanoma and pre-existing naevus is not a random event and that acquired naevi may be precursors of melanoma. A critical area of chromosomal loss at 9p21 has been implicated in the genesis of malignant melanoma, representing a site of frequent somatic chromosomal deletions in melanoma. Allelic deletions within this chromosomal region most often include the tumour suppressor gene p16. The objective of this study was to search for allelic deletions on chromosome 9p21 in naevus cell clusters. A microdissection-based approach was used to analyse 30 archived primary cutaneous melanomas and associated naevi for loss of heterozygosity (LOH) at 9p21 using the polymorphic DNA markers D9S171 and IFNA. LOH was detected in 10 out of 27 informative naevi (37%) at D9S171 and in eight out of 19 (42%) at IFNA in the dissected naevus cell clusters, and in nine out of 27 (33%) at D9S171 and seven out of 19 (36%) at IFNA in the associated melanomas. In eight out of 46 (17%) cases, LOH was detected simultaneously in the naevus and the associated melanoma using both markers. Our results suggest a causal relationship for the development of melanoma within a pre-existent associated naevus. These data support the hypothesis that lesions within 9p21 play an important role in early melanoma development, since these genetic alterations are found in histologically benign melanoma-associated naevi.