Melanoma: Volkenandt M

Garbe C, Hauschild A, Volkenandt M, Schadendorf D, Stolz W, Reinhold U, Kortmann RD, Kettelhack C, Frerich B, Keilholz U, Dummer R, Sebastian G, Tilgen W, Schuler G, Mackensen A, Kaufmann R. · University Department of Dermatology, Tübingen, Germany. · Melanoma Res. · Pubmed #18337653 No free full text.

Abstract: Systemic medical treatment of melanoma is administered in the adjuvant and palliative setting. Adjuvant therapy may be considered in patients with primary melanoma with more than 1.5 mm tumor thickness and with regional node metastasis. Presently no indication for systemic adjuvant chemotherapy or for adjuvant therapy with nonspecific immune-stimulatory agents outside controlled studies is seen. Interferon-alpha is the first substance in the adjuvant therapy of melanoma, which has shown to present a significant advantage to the patients in some prospective randomized studies. Good arguments for using adjuvant interferon-alpha therapy in high-risk melanoma patients exist. Both high-dose and low-dose interferon-alpha show promise. The major indications for systemic chemotherapy and chemoimmunotherapy are inoperable recurrent tumors, inoperable regional metastases and distant metastases (stage IV). As treatment in such situations is primarily palliative, the effect of any regimen on the quality of life must be carefully weighed. As a first line treatment, single agent therapy is recommended, as polychemotherapy or biochemotherapy did not show significant advantages for prolongation of survival; hence they are more toxic. An urgent need for development of new treatment modalities is necessary and general principles of experimental immunotherapy are outlined.

Garbe C, Hauschild A, Volkenandt M, Schadendorf D, Stolz W, Reinhold U, Kortmann RD, Kettelhack C, Frerich B, Keilholz U, Dummer R, Sebastian G, Tilgen W, Schuler G, Mackensen A, Kaufmann R. · University Department of Dermatology, Tübingen, Germany. · Melanoma Res. · Pubmed #18227710 No free full text.

Abstract: The primary treatment of a melanoma is surgical excision. An excisional biopsy is preferred, and safety margins of 1 cm for tumor thickness up to 2 mm and 2 cm for higher tumor thickness should be applied either at primary excision or in a two-step procedure. When dealing with facial, acral or anogenital melanomas, micrographic control of the surgical margins may be preferable to allow reduced safety margins and conservation of tissue. The sentinel lymph node biopsy should be performed in patients whose primary melanoma is thicker than 1.0 mm and this operation should be performed in centers where both the operative and nuclear medicine teams are experienced. In clinically identified lymph node metastases, radical lymph node dissection is considered standard therapy. If distant metastases involve just one internal organ and operative removal is feasible, then surgery should be seen as therapy of choice. Radiation therapy for the primary treatment of melanoma is indicated only in those cases in which surgery is impossible or not reasonable. In regional lymph nodes, radiation therapy is usually recommended when excision is not complete (R1 resection) or if the nodes are inoperable. In distant metastases, radiation therapy is particularly indicated in bone metastases, brain metastases and soft tissue metastases.

Heyn J, Placzek M, Ozimek A, Baumgaertner AK, Siebeck M, Volkenandt M. · Department of Surgery, Ludwig Maximilians University Munich, Germany. · Clin Exp Dermatol. · Pubmed #17376215 No free full text.

Abstract: Malignant melanoma (MM) of the anal region is an uncommon disease. In many cases, the disease is undetected or mistaken for a benign polyp or haemorrhoids until it reaches an advanced state. Owing to delayed diagnosis and early metastases, the prognosis is often poor. In contrast to melanomas of the skin, a history of sun exposure does not seem to have an impact in development of MM in this region. Anorectal melanomas (AM) are most common in the rectum, followed by the anal canal and anal verge. Ras mutations, especially in codon 61 of the N-ras oncogene, are common in CM and rare in melanomas of the vulva and anorectum. The diagnosis of an AM is usually made using a biopsy. Histopathological examinations show spindle-shaped and pleomorphic cells. Adjuvant immunohistological markers are the calcium-binding protein S-100, the melanoma antigen HMB-45, the melanoma-expressed protein Melan A, and microphthalmia-associated transcription factor (MiTF). To date, there are few published guidelines for the correct management of AM, and surgery remains the mainstay of treatment. We report on a 39-year old man who presented with a 5-week history of recurrent prolapse of an anal tumour. The tumour was histologically confirmed to be malignant melanoma.

Garbe C, Hauschild A, Volkenandt M, Schadendorf D, Stolz W, Kortmann RD, Kettelhack C, Frerich B, Keilholz U, Dummer R, Sebastian G, Tilgen W, Schuler G, Mackensen A, Kaufmann R. · Universitäts-Hautklinik Tübingen. · J Dtsch Dermatol Ges. · Pubmed #16638065 No free full text.

This publication has no abstract.

Blum A, Volkenandt M. · Hautklinik, Eberhard-Karls-Universität, Tübingen. · Dtsch Med Wochenschr. · Pubmed #12183799 No free full text.

Abstract: The current status, clinic, causes and prevention strategies of malignant tumours of the skin are described. Dermatologists, physicians and health professionals have made tremendous efforts to improve the public education and early detection of these tumours especially during the last decade. Further campaigns and continual medical education are demanded to continue this improvement for patients and public health system.

Hauschild A, Volkenandt M, Garbe C. · Klinik für Dermatologie, Venerologie und Allergologie, der Christian-Albrechts-Universität Kiel. · Dtsch Med Wochenschr. · Pubmed #11098240 No free full text.

This publication has no abstract.

Schäfer M, Messer T, Wegner U, Schmid-Wendtner MH, Volkenandt M. · Psychiatrische Klinik der Ludwig-Maximilians Universität München, München. · Hautarzt. · Pubmed #10501682 No free full text.

Abstract: Interferon-alpha (IFN-alpha) is of high interest in the adjuvant treatment of malignant melanoma. During long term treatment, psychiatric side effects play an important role and not infrequently lead to reduction or discontinuation of therapy. Most common are sleeping disturbance, agitation, weariness, sleepiness, irritability, social withdrawal and depression, which most often develop during the first three months of the therapy. Also more severe side effects may occur, like delirium, organic depression, psychotic episodes and organic personality change, which in some patients may even lead to suicidal thoughts or suicide attempts, which is illustrated in two case reports. Therapeutic intervention depend to the severity of side effects. Moderate depressive syndromes may successfully be treated by antidepressive drugs like serotonin reuptake inhibitors (SSRI), which may even allow continuation of IFN-alpha therapy. In patients with severe depression or organic personality changes with increased risk of suicide, immideate discontinuation of IFN-alpha therapy is mandatory and treatment in a psychiatric hospital must be considered.

Hauschild A, Volkenandt M. · Klinik für Dermatologie, Venerologie und Allergologie, Christian-Albrechts-Universität Kiel. · Ther Umsch. · Pubmed #10420815 No free full text.

Abstract: The goal of adjuvant therapy after routine surgery of malignant melanoma is the effective suppression of progression of disease caused by clinically inapparent micrometastases. While individual small and mostly retrospective clinical studies comparing adjuvant chemotherapy with untreated historical controls suggested a possible benefit for treated patients, large and multicenter prospective, randomized studies failed to clearly demonstrate a benefit for treated patients in regard to improvement of disease free or overall survival. Therefore, adjuvant chemotherapy can no longer be recommended for patients with malignant melanoma outside of controlled clinical studies. Current promising candidates for successful adjuvant therapy of patients with malignant melanoma are recombinant biological response modifiers, in particular interferons. Three randomized studies consistently reported a benefit in regard to relapse free survival for patients treated with interferon-alpha compared to untreated controls. However, the impact, on extension of overall survival ('cure') remains unclear. Furthermore, to date, no definitive data on the optimal dose and duration of interferon-alpha-therapy are available. Thus, patients with high risk of tumor progression should be enrolled in national and international prospective, randomized clinical trials, which may lead to valid data and clear recommendations about optimal adjuvant therapy.

Schaefer M, Horn M, Schmidt F, Schmid-Wendtner MH, Volkenandt M, Ackenheil M, Mueller N, Schwarz MJ. · Department of Psychiatry, Charité-University Medicine Berlin, Campus Charité Mitte, Schumannstr. 20/21, D-10117 Berlin, Germany. · Brain Behav Immun. · Pubmed #15331126 No free full text.

Abstract: Interferon-alpha (IFN-alpha) treatment is frequently complicated by symptoms of depression. The mechanism by which peripherally administered IFN-alpha enters and modulates the central nervous system remains unclear. The cell adhesion molecule ICAM-1 is involved in the regulation of blood-brain barrier (BBB) permeability. ICAM-1 expression was shown to increase during IFN-alpha treatment and recently the expression of ICAM-1 on vascular endothelial cells in the brain was found to be correlated with the development of depression. We therefore hypothesized that soluble ICAM-1 may be involved in the development of IFN-alpha associated depression. In a prospective study, serum levels of soluble ICAM-1 (double sandwich ELISA test) and symptoms of depression (SDS) were measured in 48 patients with malignant melanoma before and during adjuvant IFN-alpha treatment. Both, depression scores and the serum levels of sICAM-1 significantly increased after three months of IFN-alpha treatment compared to baseline levels (p < .001). Patients who developed depression (SDS-index scores > or = 50) after three months of treatment had higher sICAM-1 levels compared to non-depressed patients. Furthermore, sICAM-1 levels were positively correlated with SDS values (r = .367, p = .018). Our data provides evidence for an association between the induction of sICAM-1 and the development of symptoms of depression during IFN-alpha treatment, possibly by enhancing BBB-permeability.

Schmid-Wendtner MH, Brunner B, Konz B, Kaudewitz P, Wendtner CM, Peter RU, Plewig G, Volkenandt M. · Departments of Dermatology, Ludwig-Maximilians University, Munich, Germany. · J Am Acad Dermatol. · Pubmed #10954659 No free full text.

Abstract: Between 1987 and 1998, 64 patients with lentigo maligna (LM) (n = 42) or lentigo maligna melanoma (LMM) (n = 22) were treated by fractionated radiotherapy. In all 22 patients with LMM, excision of the nodular part of the LMM was performed before radiation of the residual lentiginous tumor. During the follow-up period of 1 to 96 months (mean, 23 months; median, 15 months), none of the 42 patients with LM displayed any signs of recurrence of LM after radiation therapy alone. Of the 22 patients with LMM, only 2 patients showed local recurrence of the tumor, salvaged by excision in both cases. One patient with LMM suffered from metastatic disease without local recurrence of the melanoma 44 months after radiation therapy. The cosmetic results of radiotherapy were good or excellent in the vast majority of patients, with only a few experiencing hypopigmentation or hyperpigmentation in the irradiated area. Fractionated radiation therapy with superficial x-rays is an effective method of treatment of LM associated with low morbidity and leading to clinical results comparable to those of surgical excision.

Hauschild A, Weichenthal M, Rass K, Linse R, Ulrich J, Stadler R, Volkenandt M, Grabbe S, Proske U, Schadendorf D, Brockmeyer N, Vogt T, Rompel R, Kaufmann R, Kaatz M, Näher H, Mohr P, Eigentler T, Livingstone E, Garbe C. · Department of Dermatology, University Hospital of Schleswig-Holstein, Campus Kiel, Schittenhelmstr 7, D-24105 Kiel, Germany. · J Clin Oncol. · Pubmed #19433681 No free full text.

Abstract: PURPOSE Interferon alfa (IFN-alpha) has shown clinical efficacy in the adjuvant treatment of patients with high-risk melanoma in several clinical trials, but optimal dosing and duration of treatment are still under discussion. It has been argued that in high-dose IFN-alpha (HDI), the intravenous (IV) induction phase might be critical for the clinical benefit of the regimen. PATIENTS AND METHODS In an attempt to investigate the potential role of a modified high-dose induction phase, lymph node-negative patients with resected primary malignant melanoma of more than 1.5-mm tumor thickness were included in this prospective randomized multicenter Dermatologic Cooperative Oncology Group trial. Six hundred seventy-four patients were randomly assigned to receive 4 weeks of a modified HDI scheme. This schedule consisted of 5 times weekly 10 MU/m(2) IFN-alpha-2b IV for 2 weeks and 5 times weekly 10 MU/m(2) IFN-alpha-2b administered subcutaneously (SC) for another 2 weeks followed by 23 months of low-dose IFN-alpha-2b (LDI) 3 MU SC three times a week (arm A). LDI 3 MU three times a week was given for 24 months in arm B. Results Of 650 assessable patients, there were 92 relapses among the 321 patients receiving high-dose induction as compared with 95 relapses among the 329 patients receiving LDI only. Five-year relapse-free survival rates were 68.0% (arm A) and 67.1% (arm B), respectively. Likewise, melanoma-related fatalities were similar between both groups, resulting in 5-year overall survival rates of 80.2% (arm A) and 82.9% (arm B). CONCLUSION The addition of a 4-week modified HDI induction phase to a 2-year low-dose adjuvant IFN-alpha-2b treatment schedule did not improve the clinical outcome.

Baumert J, Schmidt M, Giehl KA, Volkenandt M, Plewig G, Wendtner C, Schmid-Wendtner MH. · Department of Dermatology and Allergology, Ludwig-Maximilian-University Munich, Munich, Germany. · Melanoma Res. · Pubmed #19430403 No free full text.

Abstract: An elevated tumour thickness is strongly associated with an increased risk of mortality in melanoma patients. In the last few decades, an overall decrease of the tumour thickness to prognostically more favourable levels has been observed in several countries. Nevertheless, it is not clear whether this positive time trend occurred uniformly in specific subgroups of melanoma patients. Therefore, we aimed to assess time trends of tumour thickness by age group, tumour site and melanoma subtype. The study population consisted of 6475 patients with histologically proven primary invasive cutaneous melanomas seen at the Department of Dermatology and Allergology at the Ludwig-Maximilian-University Munich between 1977 and 2000. Age-adjusted time trends were assessed using linear and logistic regression analysis. Overall, a positive time trend with a decreasing tumour thickness was observed during the observation period in most subgroups. However, no significant time trend was observed in patients with a melanoma on the feet or with a nodular or acrolentiginous melanoma. The almost constant high tumour thickness of these patients might be caused by underaddressing the specific traits of these melanomas in earlier prevention campaigns. An important goal for the upcoming years should consist of a positive time trend with a decreasing tumour thickness in these subgroups.

Garbe C, Schadendorf D, Stolz W, Volkenandt M, Reinhold U, Kortmann RD, Kettelhack C, Frerich B, Keilholz U, Dummer R, Sebastian G, Tilgen W, Schuler G, Mackensen A, Kaufmann R, Hauschild A. · Sektion Dermatologische Onkologie, Universitäts-Hautklinik, Liebermeister Strasse 25, D-72076 Tübingen, Germany. · J Dtsch Dermatol Ges. · Pubmed #18801142 No free full text.

This publication has no abstract.

Garbe C, Hauschild A, Volkenandt M, Schadendorf D, Stolz W, Reinhold U, Kortmann RD, Kettelhack C, Frerich B, Keilholz U, Dummer R, Sebastian G, Tilgen W, Schuler G, Mackensen A, Kaufmann R. · University Department of Dermatology, Tübingen, Germany. · Melanoma Res. · Pubmed #17992123 No free full text.

Abstract: Melanoma is a malignant tumor that arises from melanocytic cells and primarily involves the skin. The most important exogenous etiological factor is exposure to ultraviolet irradiation. Diagnosis of melanoma is based primarily on its clinical features, and the A-B-C-D rule is useful in identifying pigmented lesions, which are suspicious for melanoma (Asymmetry, Border irregular, Color inhomogeneous and Diameter more than 5 mm). Dermoscopy is very helpful in clarifying the differential diagnosis of pigmented lesions. About 90% of melanomas are diagnosed as primary tumors without any evidence for metastasis. The tumor-specific 10-year survival for all such tumors is about 75-85%. The most important prognostic factors for primary melanoma without metastases are vertical tumor thickness (Breslow depth) as measured on the histological specimen, presence of histopathologically recognized ulceration, invasion level (Clark level) and identification of micrometastases in the regional lymph nodes via sentinel lymph node biopsy. The current tumor node metastasis classification for the staging of primary melanoma is based on these factors. Melanomas can metastasize either by the lymphatic or by the hematogenous route. About two-thirds of metastases are originally confined to the drainage area of regional lymph nodes. A regional metastasis can appear as satellite metastases up to 2 cm from the primary tumor, as intransit metastases in the skin between the site of the primary tumor and the first lymph node and as regional lymph node metastases. In the stage of regional metastasis, the differentiation between micrometastasis and macrometastasis and the number of lymph nodes involved are crucial. As soon as distant metastasis develops, prognosis depends on the site of the metastasis and on the lactate dehydrogenase levels in the blood. The frequency and extent of follow-up examinations is based on the initial tumor parameters. In thin primary melanomas up to 1-mm tumor thickness, clinical examinations at 6-month intervals are sufficient and in thicker primary melanomas, at 3-month intervals. Lymph node sonography as well as determination of the tumor marker protein S100beta are recommended. Additionally, in the stage of regional metastasis, whole body imaging should be performed every 6 months; in the stage of distant metastasis, surveillance has to be scheduled individually.

Friebe A, Schwarz MJ, Schmid-Wendtner M, Volkenandt M, Schmidt F, Horn M, Janssen G, Schaefer M. · Department of Psychiatry, Charité, Campus Mitte, Berlin, Germany. · J Immunother. · Pubmed #17414324 No free full text.

Abstract: Immunomodulatory therapy with interferon-alpha (IFN-alpha) often leads to neuropsychiatric side effects, especially depression. An activation of the immune system is discussed to trigger neurotransmitter changes and depressive illness. So far, few data are available about biologic markers, who may predict the individual risk for developing depressive symptoms during IFN-alpha therapy. The aim of the present study was to investigate the predictive role of certain immunologic markers for the development of IFN-alpha-induced depression. We hypothesized that patients characterized by a proinflammatory and TH1-accentuated immune response before treatment might have an increased risk for developing depressive mood changes. Thirty-three melanoma patients were prospectively investigated during adjuvant treatment with IFN-alpha-2a/2b (3 x 3 Mio units/wk). Depressive mood changes were assessed with the self-rating depression scale (SDS, Zung-scale) before and during IFN-alpha treatment. Serum concentrations of soluble tumor necrosis factor-R1 (sTNF-R1), soluble interleukin-6R (sIL-6R), sIL-4R, and neopterin were measured before and after 3 months of treatment. sIL-6R, which was negatively associated with SDS scores, significantly predicted higher depression scores in the first 3 months of IFN-alpha treatment. sTNF-R1, which was positively associated with SDS scores, significantly predicted the development of late depressive symptoms after 6 months of therapy. In contrast to the initial hypothesis, patients characterized by high sTNF-R1 and low sIL-6R baseline levels, indicating an anti-inflammatory condition before therapy, had a higher vulnerability for depression during IFN-alpha therapy.

Baumert J, Plewig G, Volkenandt M, Schmid-Wendtner MH. · Department of Dermatology and Allergology, Ludwig-Maximilian-University, Munich, Germany. · Br J Dermatol. · Pubmed #17381454 No free full text.

Abstract: BACKGROUND: Prognosis of patients with melanoma is strongly associated with tumour thickness at time of diagnosis. Therefore, knowledge of patient characteristics and behaviour associated with a high tumour thickness is essential for the development and improvement of melanoma prevention campaigns. OBJECTIVES: The present study aimed to identify sociodemographic, clinical and behavioural factors associated with high tumour thickness according to Breslow. METHODS: The study population consisted of 217 patients with histologically proven primary invasive cutaneous melanomas seen at the Department of Dermatology and Allergology at the Ludwig-Maximilian-University Munich, Germany, between January 1999 and January 2001. Personal interviews were conducted by two physicians to obtain information on sociodemographic characteristics and on patients' knowledge of melanoma symptoms, sun behaviour, delay in diagnosis and related factors. Multivariate linear and logistic regression analysis with stepwise variable selection was used to identify risk groups with a high tumour thickness. To assess possible effect modifications, interaction terms were included in the regression analysis. RESULTS: The median tumour thickness was 0.8 mm (interquartile range 0.5-1.6). Fifty-seven patients (26%) had tumour thickness >1.5 mm. In a multivariate linear regression analysis, patients living alone and patients with a low educational level showed a significantly greater tumour thickness. The relation of melanoma knowledge to tumour thickness was modified by the melanoma subtype: whereas lack of melanoma knowledge led to an increased tumour thickness for the subtypes superficial spreading melanoma, lentigo maligna melanoma and unspecified malignant melanoma, no significant effect was estimated for the subtypes nodular melanoma (NM) and acrolentiginous melanoma (ALM). Sex, age, self-detection of melanoma, patient delay and professional delay were not significantly associated with the tumour thickness in multivariate linear regression. Similar results were found in multivariate logistic regression. CONCLUSIONS: An increased tumour thickness was found in subjects living alone and having a low educational level. These subjects should be targeted in future prevention campaigns in a more focused way. Further efforts are necessary to improve knowledge and earlier detection of melanoma subtypes NM and ALM.

Giehl KA, Nägele U, Volkenandt M, Berking C. · Department of Dermatology, Ludwig-Maximilian University of Munich, Munich, Germany. · J Cutan Pathol. · Pubmed #17214848 No free full text.

Abstract: BACKGROUND: Basic fibroblast growth factor (bFGF) and stem cell factor (SCF) are essential growth factors for melanocytes which carry the receptors FGFR-1 for bFGF and c-kit for SCF. Because both factors may be involved in melanoma development, the expression of bFGF/FGFR-1 and SCF/c-kit was investigated in melanocytic tumors of different progression stages. METHODS: Fifty primary melanomas and 44 melanocytic nevi were analyzed for the expression of SCF, c-kit, bFGF, and FGFR-1 by immunohistochemistry. RESULTS: In melanoma, SCF and c-kit were expressed in 76 and 84%, respectively, and coexpressed in 66%. bFGF and FGFR-1 were expressed in 45 and 86%, respectively, and coexpressed in 46%. In melanocytic nevi, SCF was expressed in 23% and c-kit in 70% while coexpression was more common in dysplastic (39%) than non-dysplastic subtypes (8%). bFGF and FGFR-1 were expressed in 55 and 67%, respectively, while coexpression was found in 47% but varied considerably between different histological subtypes. CONCLUSIONS: SCF and c-kit were frequently expressed by melanomas and dysplastic nevi suggesting an autocrine growth mechanism as described for bFGF. In both nevi and melanoma, c-kit was almost exclusively found in the epidermis while bFGF was more common in the dermis. Thus the growth factor/receptor expression seems to depend on the cutaneous localization of the melanocytic tumors.

Mössner R, Anders N, König IR, Krüger U, Schmidt D, Berking C, Ziegler A, Brockmöller J, Kaiser R, Volkenandt M, Westphal GA, Reich K. · Department of Dermatology, Georg-August-University, Von-Siebold-Strasse 3, 37075, Göttingen, Germany. · Arch Dermatol Res. · Pubmed #17072629 No free full text.

Abstract: Variations in the melanocortin-1 receptor (MC1R) and in the glutathione-S transferase genes mu1 (GSTM1) and theta 1 (GSTT1) have been reported to influence UV sensitivity and melanoma risk. MC1R is one of the major genes that determine skin pigmentation because the melanocortin-1 receptor regulates eumelanin synthesis. GSTT1 and GSTM1 are enzymes expressed in the skin that detoxify products of oxidative stress reactions caused by UV irradiation. In this study variations in the MC1R, GSTM1 and T1 genes were analyzed in 347 healthy subjects and 322 patients with cutaneous malignant melanoma by direct cycle sequencing, RFLP and multiplex PCR. Important phenotypic characteristics of the study participants were obtained to assess whether genetic associations occurred independently of phenotypic risk factors for melanoma. We found an association of the MC1R D84E and R151C polymorphisms with melanoma (odds ratios for carriage of the rare allele 4.96, 95% CI [1.06-23.13], P = 0.032, and 1.69, 95% CI [1.12-2.55], P = 0.013, respectively). Melanoma risk increased with the number of variant MC1R alleles carried by an individual (P = 0.003). In a multivariate model, however, only the D84E polymorphism influenced melanoma risk independently of the risk factors fair skin type, high nevus count and high age (P = 0.047). There was no effect of homozygous GST M1 or T1 deletions on melanoma risk. In contrast to previous data, there was no evidence that GSTM1 deficiency influences melanoma risk in the subgroup of individuals with red or blond hair.

Stadler R, Luger T, Bieber T, Köhler U, Linse R, Technau K, Schubert R, Schroth K, Vakilzadeh F, Volkenandt M, Gollnick H, Von Eick H, Thoren F, Strannegård O. · Department of Dermatology, Academic Medical Centre, Minden, Germany. · Acta Oncol. · Pubmed #16760174 No free full text.

Abstract: In a prospective, controlled, randomised, multicentre study 252 patients with totally resected cutaneous melanoma (248 in stage II-III and 4 in stage IV) were either treated with two doses of dacarbazine (DTIC) followed by a 6-month treatment with 3 MU thrice weekly of highly purified natural interferon-alpha (n = 128; arm A) or received no adjuvant treatment (n = 124; arm B). Treatment was well tolerated. After a median follow-up of 8.5 years ITT analysis showed that the difference in survival was statistically significant with respect to melanoma-related deaths (HR = 0.65, CI = 0.46-0.97, p = 0.022) and close to significance with respect to overall survival (HR 0.71, CI 0.49-1.00, p = 0.052). The risk reduction of melanoma-associated death, calculated by Cox proportional hazards modelling, after adjusting for identified predictive variables, was almost 50% (p = 0.002). The overall efficacy of the treatment appeared to be mainly attributable to effects observed in patients with deep and/or metastasizing tumours (HR 0.60, CI 0.40-0.90, p = 0.013).

Mössner R, Meyer P, Jankowski F, König IR, Krüger U, Kammerer S, Westphal G, Boettger MB, Berking C, Schmitt C, Brockmöller J, Ziegler A, Stapelmann H, Kaiser R, Volkenandt M, Reich K. · Department of Dermatology, Georg-August-University, Von-Siebold-Strasse 3, D-37075 Göttingen, Germany. · Cancer Lett. · Pubmed #16713673 No free full text.

Abstract: There is strong evidence to suggest that the peroxisome proliferator-activated receptor (PPAR)-gamma, a member of the nuclear receptor family of transcriptional regulators, mediates tumor suppressive activities in a variety of human cancers. Recently, PPARgamma agonists were found to inhibit growth of melanoma cell lines. Here, we tested the possibility that variations in the gene encoding PPARgamma (PPARG) influence melanoma risk. Two variations of PPARG (P12A[rs1801282] and C161T [rs3856806]) were investigated in two independent case-control studies with a total of 832 melanoma patients and 790 control individuals. In the first study, homozygous carriers of the rare *T allele of the C161T polymorphism in exon 6 of PPARG were significantly more common among patients with melanoma than among healthy subjects (6.0 vs. 2.0%; P=0.0096) and this association was independent of clinical risk factors such as skin type and nevus count (odds ratio 5.18; 95% confidence interval 1.68-15.96; P=0.0041). This finding, however, could not be replicated in the second case-control study. We therefore conclude that the investigated PPARG polymorphisms are not likely to constitute a significant risk factor for the development of melanoma among German Caucasians.

Blankenburg S, König IR, Moessner R, Laspe P, Thoms KM, Krueger U, Khan SG, Westphal G, Berking C, Volkenandt M, Reich K, Neumann C, Ziegler A, Kraemer KH, Emmert S. · Department of Dermatology, Georg-August-University, Goettingen, Germany. · Carcinogenesis. · Pubmed #15731165 links to  free full text

Abstract: Individuals with the rare DNA repair deficiency syndrome xeroderma pigmentosum (XP) are sensitive to the sun and exhibit a 1000-fold increased risk for developing skin cancers, including cutaneous melanoma. Inherited polymorphisms of XP genes may contribute to subtle variations in DNA repair capacity and genetic susceptibility to melanoma. We investigated the role of three polymorphic alleles of the DNA repair gene XPC in a hospital-based case-control study of 294 Caucasian patients from Germany who had cutaneous melanoma and 375 healthy cancer-free sex-matched Caucasian control subjects from the same area. We confirmed that the XPC intron 9 PAT+, intron 11 -6A, and the exon 15 2920C polymorphisms are in a linkage disequilibrium. Only 1.6% of the 669 donors genotyped were discordant for these three polymorphisms. The allele frequencies (cases: controls) were for intron 9 PAT+ 41.7%:36.9%, for intron 11 -6A 41.8%:37.0% and for exon 15 2920C 41.3%:37.3%. Using multivariate logistic regression analyses to control for age, skin type and number of nevi, the three polymorphisms were significantly associated with increased risks of melanoma: OR 1.87 (95% CI: 1.10-3.19; P = 0.022), OR 1.83 (95% CI: 1.07-3.11; P = 0.026), and OR 1.82 (95% CI: 1.07-3.08; P = 0.026), respectively. Exploratory multivariate analyses of distinct subgroups revealed that these polymorphisms were associated with increased risks for the development of multiple primary melanomas (n = 28). The results of our case-control study support the hypothesis that the intron 9 PAT+, intron 11 -6A and exon 15 2920C haplotype may contribute to the risk of developing cutaneous melanoma by increasing the rate of an alternatively spliced XPC mRNA isoform that skips exon 12 and leads to reduced DNA repair. Our results should be validated in independent samples in order to guard against false positive findings.

Blankenburg S, König IR, Moessner R, Laspe P, Thoms KM, Krueger U, Khan SG, Westphal G, Volkenandt M, Neumann C, Ziegler A, Kraemer KH, Reich K, Emmert S. · Department of Dermatology, Georg-August-University Goettingen, Von-Siebold-Strasse 3, 37075 Goettingen, Germany. · Eur J Hum Genet. · Pubmed #15494739 links to  free full text

Abstract: Xeroderma pigmentosum (XP) patients exhibit a 1000-fold increased risk for developing skin cancers including malignant melanoma. We investigated the role of three variant alleles of the DNA repair gene XPC and one variant allele of the XPG gene in a hospital-based case-control study of 294 Caucasian patients from Germany with malignant melanoma and 375 healthy control individuals from the same area matched by sex. The polymorphisms G1580A (XPC exon 8; Arg492His), T1601C (XPC exon 8; Val499Ala), G2166A (XPC exon 10; Arg687Arg), and C3507G (XPG exon 15; Asp1104His) were not in linkage disequilibrium. The allele frequencies (cases: controls) were for 1580A 6.29%: 5.63%, for 1601C 79.08%: 78.28%, for 2166A 26.19%: 28.13%, and for 3507G 79.86%: 78.61%. We found no association of the homozygous 1580A, 1601C, 2166A, and 3507G genotypes with increased risks of melanoma: OR 1.254 (95% CI: 0.486-3.217), OR 1.108 (95% CI: 0.629-1.960), OR 0.817 (95% CI: 0.490-1.358), and OR 1.168 (95% CI: 0.670-2.044), respectively. Exploratory analyses of subgroups of melanoma patients compared to all controls indicated no association of these genotypes with increased risks for development of multiple primary melanomas (n = 28), a negative family history for melanoma (n = 277), melanomas in individuals with a low number of nevi (n = 273), melanomas in individuals older than 55 years (n = 142), and melanomas thicker than 1 mm (n = 126).

Schmid-Wendtner MH, Baumert J, Plewig G, Volkenandt M. · Department of Dermatology and Allergology, Ludwig-Maximilian-University, Munich, Germany. · J Am Acad Dermatol. · Pubmed #15097949 No free full text.

Abstract: Seasonal patterns in diagnosis were examined in 7836 patients with cutaneous melanoma (clinical stage I and II) documented at the Department of Dermatology and Allergology at Ludwig-Maximilian-University in Munich, Germany, between 1977 and 2000. Of these patients, 2362 were first given a diagnosis in the summer months (June-August) and 1757 were first given a diagnosis in the winter months (December-February). A summer-to-winter ratio was determined for sex, age, anatomic tumor site, histopathologic subtype, and tumor thickness. The summer-to-winter ratio was 1.34 (95% confidence interval: 1.27-1.43) for all patients, with a ratio of 1.22 (95% confidence interval: 1.12-1.33) for men and 1.47 (95% confidence interval: 1.35-1.60) for women. The frequency of diagnosis of cutaneous melanoma was seasonal for all age classes, for all anatomic tumor sites, for all histopathologic subtypes except acrolentiginous melanomas, and for melanomas with a tumor thickness <3.0 mm. Comparing subgroups of the above-mentioned clinical and histopathologic parameters, significant differences could be observed for sex and anatomic tumor site. On the basis of this data, possible explanations for the diagnostic summer peak may be a greater awareness as a result of clothing habits in summertime or because of incurred sunburns in patients with skin type I and II, and the influence of public-health campaigns usually performed at the beginning of summer.

Schmid-Wendtner MH, Baumert J, Eberle J, Plewig G, Volkenandt M, Sander CA. · Department of Dermatology and Allergology, Ludwig-Maximilians University, Frauenlobstrasse 9-11, D-80337 Munich, Germany. · Br J Dermatol. · Pubmed #14616371 No free full text.

Abstract: BACKGROUND: Although survival in patients with thin melanomas (tumour thickness < or = 0.75 mm) is usually excellent, thin melanomas have the potential to metastasize. OBJECTIVES: To determine risk factors for the development of disease progression in patients with thin cutaneous melanomas. METHODS: A retrospective study was performed between 1977 and 1998 to identify risk factors for the development of disease progression in 2302 patients with cutaneous melanoma with tumour thickness < or = 0.75 mm, diagnosed and treated at the Department of Dermatology and Allergology, Ludwig-Maximilians University, Munich, Germany. The Kaplan-Meier method was used to estimate the influence of different clinical characteristics for the occurrence of first progression during 10 years of follow-up. RESULTS: An analysis of the data from 6298 patients with cutaneous melanoma identified 2302 patients (37%) who presented with cutaneous melanoma with a tumour thickness < or = 0.75 mm, without clinical signs of metastasis at initial diagnosis (clinical stage Ia). A small subgroup of our patients (77 of 2302) developed metastatic disease during the follow-up period. The estimated rate of occurrence of metastasis after 10 years of follow-up was 4.7%. The mean follow-up time was 62 months (median 46). Of these 77 patients, 16 experienced progression at the primary tumour site and 32 presented with regional lymph node metastases. Twenty-eight patients primarily developed systemic metastases (seven patients with and 20 without regional lymph node metastases, one patient with regional lymph node metastases and local recurrence). In one patient the primary site of metastatic disease was not reported. Clinical characteristics included age, sex of the patient and different subtypes of cutaneous melanoma: superficial spreading melanoma, nodular melanoma, acrolentiginous melanoma (ALM) and lentigo maligna melanoma (LMM). Male patients and patients with LMM or ALM were significantly over-represented (P = 0.02 and P = 0.002). In the group of 77 patients with thin melanomas (< or = 0.75 mm), local recurrence was over-represented as compared with those with melanomas > 0.75 mm. No difference in group was found for overall survival after the occurrence of lymph node metastasis as the first manifestation of disease progression. CONCLUSIONS: Thorough follow-up and skin examination is recommended for a subgroup of patients with thin tumours, which consists of male patients with LMM or ALM located in the head and neck region.

Schmid-Wendtner MH, Paerschke G, Baumert J, Plewig G, Volkenandt M. · Department of Dermatology and Allergology, Ludwig-Maximilian-University, 80337 Munich, Germany. · Melanoma Res. · Pubmed #12690303 No free full text.

Abstract: In several studies the early detection of locoregional metastases in patients with cutaneous melanomas has been shown to be of prognostic value. Physical examination alone often fails to detect locoregional metastases or cannot unambiguously classify palpable lymph nodes. This study aimed to evaluate the usefulness of high resolution ultrasonography for the early detection of locoregional metastases and to compare the sensitivity and specificity of ultrasound and physical examination. A prospective study was performed between January 1997 and June 1999 in 1395 patients (721 men and 674 women) with invasive cutaneous melanoma, treated and followed up at the Department of Dermatology and Allergology, Ludwig-Maximilian-University, Munich, Germany. A total of 2650 physical and ultrasound examinations of lymphatic drainage areas were performed, and lesions suspicious for metastases were excised and diagnosed by histopathology. The results of physical and ultrasound examinations were compared. Of the 2650 ultrasound examinations, metastases were suspected in 153, whereas 290 of the 2650 physical examinations were suspicious for metastatic disease. A total of 168 patients with suspicious lesions underwent surgery; histopathological examination revealed 112 melanoma metastases and 56 other diagnoses, including one second malignancy, one neurinoma, one haemangioma and 54 reactive lymph nodes. Ultrasonographic diagnosis of melanoma metastases had a sensitivity of 92.2% and a specificity of 98.2%, whereas diagnosis by physical examination had a sensitivity of only 51.3% and a specificity of 90.9%. Thus ultrasound examination was found to be highly effective and superior to physical examination for the early detection of locoregional melanoma metastases.