Primary staging and follow-up in melanoma patients--monocenter evaluation of methods, costs and patient survival.

In a German cohort of 661 melanoma patients the performance, costs and survival benefits of staging methods (history and physical examination; chest X-ray; ultrasonography of the abdomen; high resolution sonography of the peripheral lymph nodes) were assessed at initial staging and during follow-up of stage I/II+III disease. At initial staging, 74% (23 out of 31) of synchronous metastases were first detected by physical examination followed by sonography of the lymph nodes revealing 16% (5 out of 31). Other imaging methods were less efficient (Chest X-ray: one out of 31; sonography of abdomen: two out of 31). Nearly 24% of all 127 first recurrences and 18% of 73 second recurrences developed in patients not participating in the follow-up programme. In follow-up patients detection of first or second recurrence were attributed to history and physical examination on a routine visit in 47 and 52% recurrences, respectively, and to routine imaging procedures in 21 and 17% of cases, respectively. Lymph node sonography was the most successful technical staging procedure indicating 13% of first relapses, but comprised 24% of total costs of follow-up in stage I/II. Routine imaging comprised nearly 50% of total costs for follow-up in stage I/II and in stage III. The mode of detecting a relapse ('patient vs. doctor-diagnosed' or 'symptomatic vs asymptomatic') did not significantly influence patients overall survival. Taken together, imaging procedures for routine follow-up in stage I/II and stage III melanoma patients were inefficient and not cost-efficient.

[Extensive ulcerated basalioma. Irradiation with ionizing radiation after electrocautery debridement]. / Ausgedehntes exulzeriertes Basaliom. Bestrahlung mit dem Dermopan nach elektrokaustischer Planierung.

Soft X-Ray (Dermopan) is an effective and gentle treatment for large basal cell carcinomas of the face. It is an useful alternative to extensive and often cosmetically unsatisfactory surgery, especially in large basal cell carcinomas covering an area of more than 4 cm2. A 79-year-old man presented with a 4,5-year history of an extensive basal cell carcinoma on the right temple, which was treated by soft x-ray after removal of excessive tumor tissue with electrocautery. A total dosage of 48 Gy was employed.

[Postherpetic erythema exsudativum multiforme with peri-nevus collection of annular outbreaks]. / Postherpetisches Erythema exsudativum multiforme mit perinävaler Anordnung der kokardenförmigen Effloreszenzen.

A 10 year old boy with postherpetic erythema multiforme developed an unusual arrangement of target lesions around all preexisting melanocytic nevi on his trunk. This is the first description of a perineval erythema multiforme.

[Penicillin allergy as a diagnostic problem. Overview and personal studies]. / Penizillinallergie als ein diagnostisches Problem. Eine Ubersicht und eigene Untersuchungen.

BACKGROUND AND OBJECTIVE: Penicillin allergy is a common clinical problem. The distinction between penicillin and para-infectious exanthems is difficult. We investigated the reliability of the history, as well as the sensitivity and specificity of skin tests and specific IgE levels. PATIENTS/METHODS: 160 patients with a history of penicillin allergy were retrospectively evaluated in the outpatient department of a dermatological clinic. RESULTS: Nearly 50% were diagnosed as allergic to penicillin by detection of specific IgE or skin test. About 60% of the patients with immediate type reactions, and 72% with maculo-papular erythema showed positive reactions in skin tests. Significantly more patients were diagnosed as allergic to penicillin by intradermal testing than by prick testing (p < 0.05). The sensitivity of the specific IgE RAST was 17.9%; the specifity, 89.5%. For the prick test the sensitivity was 8.2%; the specificity 90.8%. For the intradermal test the sensitivity was 26%; the specifity 69.7%. CONCLUSIONS: We suggest a step by step procedure to detect penicillin allergy making the diagnostic results as valid as possible.

Effect of pentoxifylline on sunburn cell formation in a novel supravital human skin model.

BACKGROUND/AIM: The aim of this study was to determine whether pentoxifylline (Pf) has an effect on sunburn cell (SBC) formation in humans. METHODS: A novel supravital human skin model was used. Normal skin samples were placed on gauze in completed RPMI 1640 Medium and remained vital for 48 h. Three concentrations of Pf (7.5, 15.0 and 30.0 microg/ml) were tested. After 2 h, each skin sample was irradiated with 120 mJ/cm2 of UVB. After 24-h incubation, the samples were formalin fixed, paraffin embedded and sections were stained with haematoxylin-eosin. RESULTS: The mean count of SBC (10.43 +/- 1.35 (SEM)) was significantly higher in the control group (without Pf) compared with its mean count in 7.5 microg/ml Pf (5.18 +/- 0.62, P < 0.001), or 15.0 microg/ml Pf (5.79 +/- 1.70, P < 0.001), or 30.0 microg/ml Pf (4.37 +/- 1.47, P < 0.001). CONCLUSION: Pentoxifylline reduced SBC formation in our supravital human skin model. It presumably acts as an antioxidant agent.

Interferential current is effective in palmar psoriaris: an open prospective trial.

Interferential current (IFC) has been shown to improve psoriasis in a small case series. So far no formal clinical trial had been conducted. As IFC is associated with slight prickling sensations a blinded study design was not feasible. Therefore, an open type prospective study was conducted with the assumption of 18% spontaneous remission rate. A response rate of 50% or less was judged as indicating no effect (hypothetical control), while 80% or more was considered as success (alternative hypothesis). In this "quasi-controlled" study 12 patients with therapy resistant palmar psoriasis received local treatment with IFC during a 12 week period. Treatment was performed at low current density in two daily sessions, each of 6 minutes duration. Erythema, scaling, induration, fissures and pustules were recorded in separate scores every 4 weeks. Response of a patient was judged positive when the total score of these criteria was reduced at least by two points at the end of treatment. After 12 weeks of treatment, 11 of 12 patients were cured or showed marked remission with the median overall score reduced by 4 points. An interim analysis was performed in order to decide whether the results had already reached significance (a < 0.05). The analysis revealed a statistically significant response rate of 90% (95% confidence interval 62-99%). These results are highly encouraging and should focus attention on this new therapy modality, which, in contrast to other treatments is not associated with side effects and discomfort.

Forms of epithelial differentiation of draining sinus in acne inversa (hidradenitis suppurativa).

The draining sinus is a late complication of several forms of severe acne, leading to extensive, periodically inflamed lesions that are undermined by a system of fistulas, supposed to be of follicular origin. We investigated the expression of various cytokeratins (CKs) and desmosomal proteins in the draining sinus of acne inversa (hidradenitis suppurativa) using monoclonal antibodies in immunohistochemistry on paraffin-embedded sections. We were able to define three different phenotypes of stratified squamous epithelia covering the sinus tracts. Type I epithelium was cornifying and characterized by the presence of CK 10, desmogleins 1-3 and desmocollins 1-3 in an epidermis-like pattern. Type II epithelium was non-cornifying, negative for CK 10 and positive for CK 13. It was negative for desmocollin 1 but strongly immunopositive for desmoglein 1 suprabasally and for desmoglein 2 in the basal cells. Type III epithelium was non-cornifying and strongly inflamed. It was marked by the presence of CK 7, CK 19 and desmoglein 2 and the absence of CK 10, desmoglein 1 and desmocollin 1. In both type II and III epithelium, desmoglein 3, desmocollin 2 and desmocollin 3 showed an inverted staining pattern as compared with normal epidermis and type I epithelium. Desmoglein 2 and CK 5/14 always remained restricted to the basal cell layer. Antibodies against CK 6 and CK 13/15/16 were immunopositive in all three phenotypes and CK 17 was predominantly immunolocalized to suprabasal layers of type II and III epithelium. The three phenotypes are characterized as pathological stratified squamous epithelia reflecting the dynamic process of inflammation, proliferation and stratification taking place in acne inversa.

Microinjection of an antibody against HSP 72 in keratinocytes to study acute UV injury.

First, a method of microinjection of antibodies in primary human keratinocytes in culture was established. Second, in acute UV irradiation, the physiological role of heat shock protein (HSP) 72 in keratinocytes was studied with this method. Primary human keratinocytes in culture were injected with "controls" as fluorescent dyes, phosphate buffered saline (PBS), an irrelevant secondary antibody and an antibody against a protein with known protective function in UV erythema, HSP 72. UV irradiation was applied and survival, colony forming and immunohistochemistry for injected and non-injected keratinocytes were evaluated in a time course. Puncturing the plasma membrane with injections of "controls" as FITC, PBS and the IgG anti-mouse antibody did not result in reflux of injected material or any alteration in morphology or colony-forming ability for 24 h. Keratinocytes injected with an mAb to HSP 72 without UV irradiation survived microinjection for up to 12 days, while surprisingly, more than double of injected and irradiated ones died after 12 h compared to not injected and irradiated ones. Moreover, microinjection of the antibody to HSP 72 in the nucleus resulted in a loss of the immunohistochemical labeling for HSP 72 in these cells after 12 h. Microinjection of the "controls" did not harm the survival, forming of colonies and expression of HSP 72 in keratinocytes for 24 h. In contrast, microinjection of an mAb against HSP 72 led to an increase in cell death after UV irradiation, confirming that HSP 72 is important for UV protection. Microinjection of antibodies in human keratinocytes in culture might allow the study of the physiological role of some proteins.

Heat shock protein HSP 27 is expressed in all types of basal cell carcinoma in low and high risk UV exposure groups.

HSP 27, a marker of differentiation and proliferation, helps the cell in repair processes after environmental stress such as heat, UV-irradiation and oxidative stress. So far, its role on carcinogenesis is not yet understood. HSP 27 was studied immunohistochemically in different types of primary, untreated basal cell carcinoma (BCC) in two populations with different UV exposure habits: descendents from Germany, "Pommern", living in Brazil (Pommeranos, n = 15), rural workers with high UV exposure and Germans from the region Baden-Württemberg with indoor jobs (n = 14). Age distribution and type of BCC were similar between the Pommeranos and the Germans. Specimens of BCC (n = 15 solid, n = 6 keratotic, n = 4 adenoid, n = 4 fibrotic) were evaluated in cryostat and paraffin sections for HSP 27, HSP 72 and bcl-2. In Pommeranos in Brazil (UV high risk group) versus (vs) inhabitants from Baden-Württemberg (UV low risk group), HSP 27 was expressed in 93% vs 79% in all histological subclasses, HSP 72 in 20% vs 21% and bcl-2 in 93 % in both groups. Antibodies against HSP 27, but not HSP 72, labeled BCC of all types. In contrast to the lack of HSP 27 in squamous cell carcinoma reported in the literature, we found HSP 27 and bcl-2 positive cells in BCC which might characterize the tumour as relatively benign and slow progressing.

Meloxicam in acute UV dermatitis--a pilot study.

The non-steroidal anti-inflammatory drug (NSAID) meloxicam is a preferential cyclooxygenase-2 (COX-2) antagonist. The UV protective potential of this drug was studied to compare it with the reported beneficial effects of such preferentially COX-1 specific NSAIDs as indomethacin and acetylsalicylic acid in the literature. In a pilot study (open-label, non-randomized, non-controlled, unblinded), 10 patients received UV irradiation with the minimal erythema dose (MED), first with meloxicam (7.5 mg/die) to reduce post-operative pain and second without ingestion of meloxicam. The factor of UV protection was evaluated. In six of ten patients meloxicam showed no benefit, whereas four of ten patients had a 1.3- up to 3-fold UV protection. In this study, the benefit in UV protection of meloxicam as a preferential COX-2 antagonist was not above the reported benefit of the "old" COX-1 inhibiting NSAIDS.

Conversion of psoriasis patients from the conventional formulation of cyclosporin A to a new microemulsion formulation: a randomized, open, multicentre assessment of safety and tolerability.

OBJECTIVE: To assess the safety, tolerability and efficacy of a new cyclosporin A (CyA) microemulsion formulation, Sandimmun Neoral (Neoral), in patients with severe psoriasis that was stable on CyA administered as Sandimmun (SIM). METHODS: In this 24-week, open, randomized, prospective, multicentre trial, 28 patients continued on the same dosage of SIM, while 30 converted to Neoral at 2.5 mg/kg/day or a dosage equivalent to their pre-conversion SIM dosage. During the study, dosages could be adjusted to maintain efficacy, because of adverse events or after disease stabilization. The maximum permitted dosage for either formulation was 5.0 mg/kg/day. Primary efficacy criteria were change in Psoriasis Area and Severity Index (PASI) from baseline and time to relapse. RESULTS: The dosage was increased to maintain efficacy in 22 patients (Neoral 13; SIM 9) and 20 dose reductions for safety were required (Neoral 14, SIM 6). In both groups, PASI scores remained stable throughout and relapses were primarily a result of dosage reduction after disease stabilization. No significant difference was found between groups in the proportion of patients remaining relapse-free. Adverse events were recorded in 20 patients receiving Neoral and 14 receiving SIM. Most drug-related events were of mild or moderate severity and reflected the known CyA side-effect profile. Dose titration guidelines ensured that mean blood pressure and serum creatinine concentrations remained stable in both groups. CONCLUSIONS: If the guidelines for CyA use are followed and the Neoral dosage does not exceed 5 mg/kg/day, conversion of stable patients with severe psoriasis from SIM to Neoral should present no clinically relevant safety or tolerability problems and efficacy of treatment is maintained.

Efficacy of the fixed 1.2% clindamycin phosphate, 0.025% tretinoin gel formulation (Velac) and a proprietary 0.025% tretinoin gel formulation (Aberela) in the topical control of facial acne.

BACKGROUND: A formulation containing agents affecting the non-inflammatory as well as the inflammatory lesions of acne vulgaris at the same time would be efficient, probably showing a high efficacy and possibly a considerable shortening of the duration of treatment. One single formulation would simplify drug administration thereby enhancing patient compliance and possibly leading to improved therapeutic results. In two studies this seems to have been corroborated for the fixed clindamycin phosphate-tretinoin gel formulation. OBJECTIVE: This study was designed to assess whether the recently developed fixed formulation of 1.2% clindamycin phosphate and 0.025% tretinoin in a gel base (Velac), further referred to as Clindamycin phosphate Tretinoin Gel is at least as effective as a proprietary 0.025% tretinoin gel formulation (Aberela, Janssen Cilag Ab, Sollentuna, Sweden; further defined as tretinoin) showing an additional anti-inflammatory effect in the treatment of moderate to severe acne vulgaris. METHODS: In a double-blind, randomised study 72 patients were treated with CTG and 73 with tretinoin gel in a once daily regimen for 12 weeks. Responses, irritation as well as possible systemic and other adverse effects were recorded after 4, 8 and 12 weeks of treatment and the improvement, compared to baseline, assessed in all included patients. An additional assessment of the safety parameters was carried out at week 2. Parameters of efficacy were the various acne lesion counts, the overall acne severity grade and the calculated totals of acne lesion counts. RESULTS: CTG was statistically significantly more effective than tretinoin at the P = 0.05 level in the papular and the total mean inflammatory lesion counts as well as in the estimated or calculated mean overall acne severity scores. CTG and tretinoin gel were equally effective in the remaining parameters: open and closed comedones, the calculated total mean comedone, the pustule as well as the nodule lesion counts. The onset of action was faster for CTG than for tretinoin gel and evident in all assessed parameters except in open comedone lesion counts. In the calculated total mean acne lesion counts, half of all acne lesions had disappeared by week 6 of treatment with CTG, whereas this was recorded at week 9 for tretinoin gel. No clinically relevant changes in the parameters of safety as a consequence of treatment were observed, although the burning component of irritation was shown to be significantly less for CTG than for tretinoin gel. The observed adverse effects were considered minor. Treatment had to be discontinued in five patients on CTG and three on tretinoin. CONCLUSION: The addition of clindamycin to tretinoin, as in CTG, enhances the comedolytic efficacy of tretinoin in moderate to severe acne of the face, maintaining at the same time its anti-inflammatory efficacy thus accelerating resolution of all types of acne lesions without affecting the safety of response to both components.

Expression of heat shock protein 27 in chromomycosis.

We report on a 58-year-old woman with long-lasting (36 years) chromomycosis on the foot and secondary self-inoculation from foot to hand 4 years ago. Mycological classification was performed after culture on Sabouraud glucose agar. We used haematoxylin and eosin and Giemsa staining and an antibody to heat shock protein (HSP) 27 (Stress Gen, Clone G3.1) on paraffin-embedded and cryostat specimens of chromomycosis. The mycological culture revealed the fungus Fonsecaea pedosoi. Histopathology revealed dermal fibrosis with persistent fungi (Medlar bodies), numerous mast cells and pseudoepitheliomatous hyperplasia. Immunohistochemically, HSP 27 was positively identified in F. pedrosoi. Moreover, in differentiating keratinocytes in the pseudoepitheliomatous lesions of chromomycosis, HSP 27 was increasingly expressed from basal layers to stratum spinosum in the epidermis but not in keratinocytes directly bordering Medlar bodies. In chromomycosis, HSP 27 is expressed, in accordance with its role as a marker of differentiation and proliferation, in keratinocytes and also in F. pedrosoi. It remains unknown if these results might explain the therapeutic efficacy of hyperthermic treatment.

Immunohistochemical characterization of HSP, alpha-MSH, Merkel cells and neuronal markers in acute UV dermatitis and acute contact dermatitis in vivo.

OBJECTIVE: To study the immunoneurocrine network in inflammatory dermatoses, we investigated histochemically acute UV and acute contact dermatitis. METHODS: Antibodies were applied to frozen and paraffin specimens of human skin after irradiation (n = 10), to positive patch tests (n = 10) and controls (n = 10) against: HSP 70, 72, 27, neuronal polypeptides (alpha-MSH, NSE, bombesin, PGP 9.5, NGF, NGF-R) and intermediate filaments (peripherin, NF 200, CK 19, 20). RESULTS: HSPs and alpha-MSH were upregulated in UV dermatitis in the epidermis compared to contact dermatitis and normal skin. Sunburn cells did not express HSPs or alpha-MSH in UV dermatitis. Neuronal markers and HSP 27 labeled more nerve fibers in UV than in contact dermatitis, except the increased staining for NGF, NGF-R and alpha-MSH in nerve fibers in contact dermatitis. In UV dermatitis, 50% of Merkel cells were suprabasal, but in contact dermatitis, basal, rounded and reduced in number. CONCLUSIONS: Merkel cells, HSPs and markers of neuroinflammation are of different importance in UV and contact dermatitis in vivo.

Clinicopathological and prognostic relevance of Rap1-GAP expression in melanocytic tumors.

Rap1-GAP protein has been identified as an inactivator of Rap1 activity, a putative endogenous antagonist of Ras proteins. The Rap1-GA1 locus maps to 1p36.1-35, the region which may harbor a gene for familial melanoma. In the present immunohistochemical study we analyzed the clinicopathological and prognostic relevance of Rap1-GAP expression in 60 benign and 103 malignant melanocytic tumors. Cytoplasmic immunoreactivity was detected in the cells of 27/60 nevi (45%) and 59/103 melanomas (57%). In the latter group the frequency of Rap1-GAP expression increased (P < 0.05) with the thickness of primary tumors and was highest in metastatic lesions. Rap1-GAP protein was detected in 15/19 subsequently recurring primary melanomas (79%) but only in 32/67 tumors (47%) of patients who remained free of disease (P < 0.05) for at least 6 years. Five out of six recurring thin melanomas (< 2 mm) were found to be immunoreactive. Although being no indicator for malignant transformation of melanocytic lesions, Rap1-GAP overexpression may represent a useful marker for identifying thin high-risk melanomas. Cytoplasmic expression of Rap1-GAP has also been observed in the cells of skin appendages and in keratinocytes, particularly in suprabasal layers of the epidermis. Therefore, Rap1-GAP is likely to be associated with cellular growth and/or differentiation. However, the present study did not provide evidence that this gene, despite its chromosomal localization, represents an early melanoma gene.

[Dermatology]. / Dermatologie.

The dermatotherapy of the past 30 years made enormous progress. It is focused on frequent diseases as acne, atopic dermatitis, psoriasis and mycoses. Research will provide us during the next years with additional therapeutic tools on chronic inflammation and in wound healing.