[Cutaneous radiation syndrome after accidental skin exposure to ionizing radiation]. / Kutanes Strahlensyndrom nach akzidenteller Exposition des Hautorgans mit ionisierenden Strahlen.

Accidental exposure of the human skin to single doses of ionizing radiation greater than 3 Gy results in a distinct clinical picture, which is characterized by a transient and faint erythema after a few hours, then followed by severe erythema, blistering and necrosis. Depending on severity of damage, the latter generally occurs 10-30 days after exposure, but in severe cases may appear within 48 hrs. Between three and 24 months after exposure, epidermal atrophy combined with progressive dermal and subcutaneous fibrosis is the predominant clinical feature. Even years and decades after exposure, atrophy of epidermis, sweat and sebaceous glands; telangiectases; and dermal and subcutaneous fibrosis may be found and even continue to progress. For this distinct pattern of deterministic effects following cutaneous accidental radiation exposure the term "cutaneous radiation syndrome (CRS)" was coined in 1993 and has been accepted by all international authorities including IAEA and WHO since 2000. In contrast to the classical concept that inhibition of epidermal stem cell proliferation accounts for the clinical symptomatology, research of the last three decades has demonstrated the additional crucial role of inflammatory processes in the etiology of both acute and chronic sequelae of the CRS. Therefore, therapeutic approaches should include topical and systemic anti-inflammatory measures at the earliest conceivable point, and should be maintained throughout the acute and subacute stages, as this reduces the need for surgical intervention, once necrosis has occurred. If surgical intervention is planned, it should be executed with a conservative approach; no safety margins are needed. Antifibrotic measures in the chronic stage should address the chronic inflammatory nature of this process, in which over-expression TGF beta-1 may be a target for therapeutic intervention. Life-long follow-up often is required for management of delayed effects and for early detection of secondary malignancies, which must be searched for especially in the borderline areas between clinically symptomatic and asymptomatic skin.

Progressive growth of fish tumors after transplantation into thymus-aplastic (nu/nu) mice.

The nude mouse does not reject xenografts of malignant and nonmalignant tissues of mammalian or avian origin, due to a deficiency of functional T-lymphocytes. In this study, tissue from a cold-blooded vertebrate, a teleost fish, was for the first time successfully transplanted to Swiss albino nu/nu mice. Malignant melanotic melanoma of Xiphophorus transplanted to nude mice showed progressive growth and could be serially passaged. In vitro culture experiments revealed that the fish tumor cells adapt to the physiological conditions of the mammalian host, most obviously to the body temperature. On the other hand, fish-specific morphological characters and biochemical features, e.g., expression of a melanoma-associated antigen, were retained. This experiment demonstrates the enormous capacity of the melanoma cells to adapt to severe changes in their environment, which even enables them to overcome the physiological barriers between such taxonomically distant vertebrate groups as fish and mammals.

Interlaboratory evaluation of a new reverse transcriptase polymerase chain reaction-based enzyme-linked immunosorbent assay for the detection of circulating melanoma cells: a multicenter study of the Dermatologic Cooperative Oncology Group.

PURPOSE: Reverse transcription-polymerase chain reaction (RT-PCR)-based detection of tyrosinase mRNA is the most frequently used laboratory method for the detection of circulating tumor cells in melanoma patients. However, previously published results showed considerable variability in the PCR positivity rates. MATERIALS AND METHODS: We designed a collaborative study to assess the sensitivity, specificity, and clinical relevance of a new standardized RT-PCR-based enzyme-linked immunosorbent assay (ELISA) for the detection of circulating melanoma cells. Blood samples of healthy donors mixed with cells of a melanoma cell line were prepared in a blinded fashion, and aliquots were sent to seven participating laboratories experienced in RT-PCR. RESULTS: The results demonstrate a high sensitivity (1 melanoma cell/mL blood) and specificity (no false-negatives and 7.4% [2 of 28] false-positives) of the assay and a satisfactory rate of interlaboratory reproducibility. The analysis of aliquots of blinded samples derived from 60 melanoma patients identified tyrosinase mRNA in 17 of 60 (28.3%): three (20%) of 15 stage I patients, two (13.3%) of 15 stage II patients, five (35.7%) of 14 stage III patients, and seven (43.8%) of 16 stage IV patients. The interlaboratory reproducibility of positive samples, however, was extremely low and indicates the presence of low amounts of target mRNA. CONCLUSION: Reverse transcriptase-PCR ELISA has a high sensitivity and specificity for the detection of tyrosinase mRNA in peripheral blood cells. The low interlaboratory reproducibility for the detection of tumor cells in blood samples of melanoma patients, however, raises the question of relevance of this assay for clinical use.

[Indications and safety aspects of vacuum-assisted wound closure]. / Indikationen und Sicherheitsaspekte der Vakuumtherapie.

Problem wounds continue to challenge medical care. In recent times, good results have been achieved through the application of negative pressure wound therapy. This approach, known as vacuum-assisted wound closure (VAC) involves the use of a defined,controlled negative pressure over a polyurethane or polyvinyl sponge placed in the wound. The wound effluent is evacuated continuously. The result is an improvement of microcirculation, and wound healing is enhanced. Animal experiments have confirmed an increase in cell growth. The basis for surgical wound management continues to be appropriate debridement. In this connection, negative pressure therapy, as a supportive measure, has proved to have major advantages over traditional methods of wound management, advantages that need to be further investigated clinically and experimentally. Consideration of the safety aspects and risk factors associated with the procedure can contribute to the optimization of therapeutic safety.

Chromosome 7 aneusomy. A marker for metastatic melanoma? Expression of the epidermal growth factor receptor gene and chromosome 7 aneusomy in nevi, primary malignant melanomas and metastases.

Receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR) play an important role in a variety of malignant neoplasias, making the search for aberrations in the relevant chromosomes an important issue. Differential expression of the EGFR gene was investigated by reverse transcriptase (RT)-PCR on tissue samples of normal skin, nevi, primary melanomas, and melanoma metastases. The EGFR gene is located on chromosome 7p12.3-p12.1. To determine the number of chromosomes 7 in cell nuclei of the mentioned tissue samples we performed fluorescence in situ hybridization (FISH) on touch preparations, using a DNA probe that hybridizes specifically to the centromeric region of chromosome 7. Additionally, chromosome 7 number in interphase nuclei was determined in short-term primary cell cultures of nevi, primary melanomas, and metastases. The highest EGFR gene expression frequency was found in melanoma metastases. By FISH we detected the highest fraction of cell nuclei with more than two chromosomes 7 in the group of metastases. Our results suggest that overexpression of the EGFR gene might play an important role in metastasis of malignant melanoma. This is well reflected by polysomy 7, possibly accounting for an increased EGFR gene copy number.

Ionizing radiation induces human intercellular adhesion molecule-1 in vitro.

Intercellular adhesion molecule-1 (ICAM-1) plays a central role in various inflammatory reactions and its expression is readily induced by inflammatory stimuli such as cytokines or ultraviolet irradiation. We have investigated the effect of ionizing radiation (IR) on human ICAM-1 expression in human cell lines and skin cultures. ICAM-1 mRNA levels in HL60, HaCaT, and HeLa cells were elevated at 3-6 h after irradiation and increased with doses from 10-40 Gy. The rapid induction of ICAM-1 occurred at the level of transcription, was independent of de novo protein synthesis, and did not involve autocrine stimuli including tumor necrosis factor-alpha and interleukin-1. IR also induced ICAM-1 cell surface expression within 24 h. Immunohistologic analysis of cultured human split skin revealed ICAM-1 upregulation on epidermal keratinocytes and dermal microvascular endothelial cells 24 h after exposure to 6 Gy. In conclusion, we propose ICAM-1 as an important radiation-induced enhancer of immunologic cell adhesion, which contributes to inflammatory reactions after local and total body irradiation.

Interleukin-8 receptor-mediated chemotaxis of normal human epidermal cells.

Normal human keratinocytes show chemotactic behavior towards interleukin-8 (IL-8). Under physiological conditions this cytokine seems to be present in an equilibrium between monomeric and dimeric forms, as indicated by Western blotting data. Radioligand binding studies suggest that keratinocyte chemotaxis is mediated by receptors specific for IL-8 dimers. IL-8 receptor-specific mRNA can be detected in a keratinocyte cell line by polymerase chain reaction.

Coexpression patterns of EGFR, HER2, HER3 and HER4 in non-melanoma skin cancer.

The receptor tyrosine kinases (RTKs) epidermal growth factor receptor (EGFR), HER2, HER3 and HER4 are involved in the pathogenesis of multiple human malignant neoplasias. However, their role in the carcinogenesis of basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) remains to be elucidated. In order to further define the role of these RTKs, 56 human skin tissue samples of normal skin, BCC and SCC were studied by conventional and differential and quantitative reverse transcriptase-polymerase chain reaction (rtPCR). EGFR and HER3 were predominantly expressed in the BCCs and SCCs, while HER2 was ubiquitously expressed. HER4 was not expressed in any sample. Since in vitro studies have provided compelling evidence that heterodimer formation of these receptors are associated with different signal transduction processes, coexpression patterns might be decisive for the induction and maintenance of a malignant phenotype. These results confirm this concept: isolated HER2 expression and EGFR/HER2 were predominantly found in normal skin, while HER2/HER3 and the triple expression of EGFR/HER2/HER3 were seen more frequently in the BCCs and SCCs compared with normal skin (50% and 40% compared with 26%, respectively). The activation of HER3, in addition to EGFR and HER2, might therefore be associated with the malignant phenotype. However, due to the small numbers in this study, further confirmation of the patterns is needed.

Interferon gamma in survivors of the Chernobyl power plant accident: new therapeutic option for radiation-induced fibrosis.

BACKGROUND: One of the remarkable clinical consequences of the Chernobyl accident was skin involvement, leading to extensive cutaneous fibrosis. Apart from surgery, no established treatment is available. METHODS: A group of survivors, working in or present at the accident site on April 26, 1986, and a few days thereafter, were examined, treated, and followed-up in 6-month intervals from September 1991 to November 1995. Eight individuals were identified as suffering from excessive cutaneous fibrosis. Skin thickness was measured with high-frequency (20 MHz) ultrasound in a clinically well-defined target skin lesion, in addition to histologic confirmation of radiation fibrosis. Interferon gamma was scheduled for all patients on a low-dose regimen (3 x 50 microg/week s.c.). In 2 patients, interferon was discontinued after the first injection, due to withdrawal of consent. In 6 patients, interferon was continued for 30 months, with 1 injection weekly for a further 6 months. Treatment was discontinued in November 1994. Four patients in the treated group and 1 of the 2 patients treated only once ("untreated patients") were reexamined 1 year later. RESULTS: In all individuals treated for 36 months, a significant (p < 0.005) reduction of radiation fibrosis could be determined, in contrast to a significant (p < 0.005) increase in the 2 untreated patients. Follow-up 1 year after discontinuation of the interferon treatment demonstrated significant (p < 0.005) recurrence of fibrosis. CONCLUSION: Low-dose interferon appears to be a safe and effective treatment of cutaneous radiation fibrosis following accidental exposure to high doses of ionizing radiation. Long-term supportive therapy may be required.

Interferon-gamma in 5 patients with cutaneous radiation syndrome after radiation therapy.

BACKGROUND: Irradiation can cause acute inflammatory responses as well as chronic fibrotic alterations of the skin. Cutaneous radiation fibrosis evokes a complex of therapeutic problems. However, therapeutic options, apart from surgical approaches, are limited. PATIENTS AND METHODS: Five female patients suffering from severe cutaneous fibrosis were treated with interferon-gamma on a low-dose regimen, 3 x 100 microg/week subcutaneously for 6 months, then once per week for another 6 months. In 4 patients, skin thickness was measured with high-frequency (20 MHz) ultrasound in a clinically well-defined target skin lesion. In 1 patient, nuclear magnetic resonance imaging was performed to quantify the extent of cutaneous radiation fibrosis and to monitor the therapeutic outcome. RESULTS: All patients suffered from radiation-induced cutaneous fibrosis. Additionally, in 1 patient, a fistula, as assessed by lymph vessel scintigraphy, and in another patient a radiation ulcer was diagnosed. In all patients, reduction of radiation-induced fibrosis could be documented. Both fistula and radiation ulcer regressed completely under interferon-gamma therapy. CONCLUSION: Low-dose interferon-gamma therapy is a new and effective treatment modality for cutaneous radiation fibrosis caused by radiation therapy. The positive impact of interferon-gamma on our patients warrants randomized double-blind trials on therapy of radiation fibrosis.

Transcriptional regulation of the human IL5 gene by ionizing radiation in Jurkat T cells: evidence for repression by an NF-AT-like element.

Eosinophilia is often observed in patients with parasitic infections and atopic diseases like allergic asthma and atopic dermatitis. Additionally, it is a typical feature of the inflammatory reaction after therapeutic and accidental exposure to ionizing radiation. This uniquely specific phenomenon regulated by the cytokine interleukin 5 (IL-5) suggests specific control for IL5 gene expression. In this study, we generated promoter-CAT constructs containing different human IL-5 promoter regions spanning from positions -507 to +43. Transfection experiments in Jurkat T cells revealed that the promoter sequence from -57 to +43 was required for constitutive and inducible IL-5 promoter activity. Low baseline CAT activity could be enhanced by treatment with phenylmercuric acetate (PMA) or the combination of PMA and calcium ionophore. The promoter region between positions -97 and +43 showed responsiveness to low-dose X rays. Electrophoretic mobility shift assays demonstrated that the region from -117 to -97 was responsive to irradiation. Transcription factors specifically bound to this sequence showed a dose-dependent response to single doses of X rays between 1 and 8 Gy. Competition analysis indicated that the protein-DNA complexes at this region were related to the nuclear factor of activated T cells (NF-AT). Further confirmation was obtained by the addition of specific antibodies into protein-DNA reactions. For the first time, we have demonstrated that specific DNA binding of NF-ATp at the promoter region from -117 to -97 is involved in transcriptional regulation of the human IL5 gene in response to ionizing radiation.

Increased expression of the epidermal growth factor receptor in human epidermal keratinocytes after exposure to ionizing radiation.

The effect of exposure of human epidermal keratinocytes to ionizing radiation, both in vivo and in vitro, on the expression of the epidermal growth factor receptor (EGF-R) was studied on the protein, mRNA, and functional levels. Quantitative fluorometry of short-term organ cultures incubated with a monoclonal antibody against human EGF-R revealed a dose-dependent increase of EGF-R expression 24 h after irradiation with 4 and 6 Gy, with an additional increase after 48 h. In biopsy specimens from patients undergoing radiation therapy a markedly increased expression could be determined by quantitative fluorometry during radiation therapy which wa still considerably above the baseline level 4 weeks after termination of treatment. Radioligand binding assays demonstrated a 50% increase in 125I-EGF binding to primary keratinocytes and A431 cells, at doses of 1 Gy, with a further increase after 72 and 96 h. Northern blots were performed with total RNA from two human epidermal cell lines (SCLII and A431). In A431 cells, increased EGF-R transcript levels could be detected 48 h after irradiation. In cells of the SCLII cell line, EGF-R expression was not affected by irradiation. These results were confirmed by semiquantitative polymerase chain reaction of primary cultured keratinocytes, demonstrating an increase of transcripts of EGF-R 24 h after irradiation with single doses of 6 Gy. Thus exposure to ionizing radiation leads to an increased expression of functionally intact EGF-R in human keratinocytes, at the protein and mRNA levels, both in vitro and in vivo; we hypothesize that this effect is part of a stress program of epidermal cells in response to ionizing radiation, ensuring rapid repopulation of irradiated areas.

The outcome of local radiation injuries: 14 years of follow-up after the Chernobyl accident.

The Chernobyl nuclear power plant accident on April 26, 1986 was the largest in the history of the peaceful use of nuclear energy. Of the 237 individuals initially suspected to have been significantly exposed to radiation during or in the immediate aftermath of the accident, the diagnosis of acute radiation sickness (ARS) could be confirmed in 134 cases on the basis of clinical symptoms. Of these, 54 patients suffered from cutaneous radiation syndrome (CRS) to varying degrees. Among the 28 patients who died from the immediate consequences of accidental radiation exposure, acute hemopoietic syndrome due to bone marrow failure was the primary cause of death only in a minority. In 16 of these 28 deaths, the primary cause was attributed to CRS. This report describes the characteristic cutaneous sequelae as well as associated clinical symptoms and diseases of 15 survivors of the Chernobyl accident with severe localized exposure who were systematically followed up by our groups between 1991 and 2000. All patients presented with CRS of varying severity, showing xerosis, cutaneous telangiectasias and subungual splinter hemorrhages, hemangiomas and lymphangiomas, epidermal atrophy, disseminated keratoses, extensive dermal and subcutaneous fibrosis with partial ulcerations, and pigmentary changes including radiation lentigo. Surprisingly, no cutaneous malignancies have been detected so far in those areas that received large radiation exposures and that developed keratoses; however, two patients first presented in 1999 with basal cell carcinomas on the nape of the neck and the right lower eyelid, areas that received lower exposures. During the follow-up period, two patients were lost due to death from myelodysplastic syndrome in 1995 and acute myelogenous leukemia in 1998, respectively. Other radiation-induced diseases such as dry eye syndrome (3/15), radiation cataract (5/15), xerostomia (4/15) and increased FSH levels (7/15) indicating impaired fertility were also documented. This study, which analyzes 14 years in the clinical course of a cohort of patients with a unique exposure pattern, corroborates the requirement for long-term, if not life-long, follow-up not only in atomic bomb survivors, but also after predominantly local radiation exposure.

Nitric oxide inhibits tissue factor synthesis, expression and activity in human monocytes by prior formation of peroxynitrite.

OBJECTIVE: Nitric oxide (NO) has antithrombotic properties by regulating platelet function, whereas direct effects on plasmatic coagulation are rarely described. In sepsis and inflammation, when synthesis of NO, oxygen radicals and toxic metabolites is crucial, the expression of tissue factor (TF) on monocytes stimulated by lipopolysaccharides (LPS) induces intravascular coagulation. This study was performed to examine the influence of NO and the NO-dependent metabolite peroxynitrite on LPS-induced TF expression and activity in human monocytes. DESIGN: Experimental study. SETTING: Laboratory for cell biology. METHODS: Human peripheral blood mononuclear cells were isolated from buffy coats by gradient centrifugation. The NO-releasing compounds SIN1 and NOC18 were used under different conditions. TF antigen was assayed by flow cytometry, and its activity by a clotting assay. TF-mRNA was measured by reverse transcriptase polymerase chain reaction (RT-PCR-ELISA). MEASUREMENTS AND RESULTS: Whereas NOC18, a pure NO donor, had no effect, SIN1, releasing both NO and superoxide (O2-), reduced TF expression and activity in a dose- and time-dependent manner; superoxide dismutase (SOD) reversed the SIN1-mediated effect. Adding the O2(-)-deliberating system hypoxanthin/xanthin oxidase (which had no significant effect per se) to NOC18, or using the NO and O2- reaction product peroxynitrite resulted in a reduction of TF expression. RT-PCR-ELISA indicated upregulation of TF-mRNA by SIN1 with a peak at 500 microM; higher doses had less effect. CONCLUSION: These data demonstrate an influence of NO on LPS-induced TF expression in monocytes by prior formation of peroxynitrite; furthermore, the balance between NO and O2- seems to play a crucial role.

Radiation lentigo. A distinct cutaneous lesion after accidental radiation exposure.

BACKGROUND: Accidental exposure of skin to ionizing radiation leads to long-term alterations such as fibrosis, keratosis, and teleangiectasias. Also, noncharacteristic hyperpigmentation and hypopigmentation may be noted. OBSERVATIONS: A distinct lesion is described on the calves of a white male survivor of the 1986 nuclear accident at Chernobyl, Ukraine. Several years after the accident at Chernobyl, characteristic pigmented macules developed in the areas of skin that had previously been exposed to ionizing radiation: there was a marked, sharply demarcated lentiginous hyperpigmentation of epidermal and basal keratinocytes and melanocytes, as well as an increase in the number of melanocytes. No cellular atypia was noted. CONCLUSIONS: This case demonstrates the potential of high single doses of ionizing radiation to induce pigmented lesions with similar clinical and histological features as they have been described after exposure to natural UV radiation or radiation from a tanning bed or sunlamp or after therapy with oral psoralen with long-wave UV-A radiation (PUVA), described as solar, tanning bed, and PUVA lentigines. The absence of cellular atypia may account for a favorable prognosis and enables clear distinction from more serious diagnoses such as lentigo maligna melanoma.

Ionizing radiation induces, via generation of reactive oxygen intermediates, intercellular adhesion molecule-1 (ICAM-1) gene transcription and NF kappa B-like binding activity in the ICAM-1 transcriptional regulatory region.

Ionizing radiation produces reactive oxygen intermediates in mammalian tissues and may serve as a model system for the investigation of the biologic effects of free radicals. We have previously shown that the adhesion molecule ICAM-1 is induced by ionizing radiation, and here we have investigated the molecular mechanisms responsible. ICAM-1 mRNA and cell surface expression was induced in HeLa and HaCaT cells after exposure to ionizing radiation. This induction was blocked by preincubation with the antioxidants PDTC and N-acetyl cysteine. ICAM-1 promoter activity was assessed by transiently transfecting HeLa cells with CAT-reporter gene constructs containing sequential ICAM-1 5' deletions. ICAM-1 5' fragments -1162/+1 (relative to the transcription start site) and -277/+1 displayed increased promoter activity when cells were exposed to ionizing radiation, but no induction was seen in a -182/+1 construct associating positions -277 to around -182 with inducibility by ionizing radiation. Nuclear extracts from HaCaT cells were tested in mobility shift assays using an NF kappa B-like binding site of the ICAM-1 5' region (positions -186/-177). There was marked enhancement of DNA-protein complex forming in extracts from irradiated versus untreated cells. Incubation of cells with antioxidants prior to irradiation prevented the radiation-dependent increase in complex formation. We conclude that reactive oxygen intermediates are involved in ICAM-1 induction by ionizing radiation. The ionizing radiation-induced, antioxidant-inhibitable binding at the ICAM-1 NF kappa B-like binding site is consistent with the view that NF kappa B is a pro-oxidant transcription factor.

Accidental radiation exposure and azoospermia.

Seven Georgian male soldiers (19-25 years old) had accidentally been exposed to radiation by Cs-137 between April 1996 and May 1997. No information about the exact time and duration of exposure was available. All patients presented with the subacute stage of Cutaneous Radiation Syndrome with deep painful ulcers on different body sites, predominantly on the legs. Semen analyses showed complete azoospermia in 4 patients, with elevated follicle-stimulating hormone (FSH) in 3 and elevated luteinizing hormone (LH) in 2 of them. One patient had severe oligozoospermia of 7 million sperm per mL, with normal sperm motility and morphology; his FSH and LH levels were elevated. One patient had complete normozoospermia, and the seventh patient had polyzoospermia of 340 million per mL; both of these patients had normal serum hormone levels. Only the patient with oligozoospermia reported a history of delayed testicular descent; his physical examination showed relatively soft and small testicles and a varicocele with considerable reflux. The physical andrological examinations were normal in the other 6 patients. It is very likely that the azoospermia in the 4 patients can be attributed to the radiation accident. In conclusion, it is essential to perform andrological examinations in patients who have been exposed to radiation even if there are only cutaneous injuries detectable, as a high percentage of them can show azoospermia.

Detection of herpes simplex virus and varicella-zoster virus in clinical swabs: frequent inhibition of PCR as determined by internal controls.

BACKGROUND: PCR-based detection of microorganisms is widely used for diagnostic purposes. Most routine PCR applications do not control for inhibition of PCR, thus leading to false-negative results. METHODS AND RESULTS: One hundred eighteen swab samples obtained from skin and mucosa were investigated for the presence of herpes simplex virus (HSV), varicella-zoster virus (VZV), and the control gene betaglobin by internally controlled PCR with purified and unpurified DNA in parallel. With unpurified DNA, inhibition of PCR was detected in 23% of betaglobin PCRs, 25% of VZV PCRs, and 16% of HSV PCRs versus 3% each for purified DNA. Approximately 20% of the samples with positive results for HSV or VZV had negative or inhibited results using unpurified DNA. CONCLUSION: These results indicate that PCR from clinical swab specimens should be performed exclusively with internal controls because the positive control alone cannot exclude PCR inhibition in individual samples. Purification of DNA will decrease, but not exclude, PCR inhibition.

S100 beta is a more reliable tumor marker in peripheral blood for patients with newly occurred melanoma metastases compared with MIA, albumin and lactate-dehydrogenase.

Lactate-dehydroxynase (LDH) has been described as a leading blood parameter in patients with melanoma metastases. However, recent data indicates that levels of S100 as well as melanoma inhibiting activity (MIA) in peripheral blood, correlate with melanoma progression. The aim of this study was to evaluate tumor markers S100, MIA, LDH and albumin in peripheral blood of 373 melanoma patients. 284 patients presented with in-situ or UICC stage I/II, and 89 with stage III/IV (54 tumor-free, 29 with newly occurred metastases). For newly occurred metastases, sensitivity was highest for S100 in peripheral blood (0.86), followed by MIA (0.80), LDH (0.48), and albumin (0.15). Specificity for albumin (0.99) and LDH (0.98) was higher than for S100 (0.91) and MIA (0.62). This data indicate that S100 in peripheral blood as compared to MIA, LDH and albumin appears to be the most appropriate tumor marker for newly occurred melanoma metastases.