Adjuvant treatment with pegylated interferon α-2a versus low-dose interferon α-2a in patients with high-risk melanoma: a randomized phase III DeCOG trial.

BACKGROUND: Adjuvant treatment with interferon (IFN)-α-2a improved disease-free survival (DFS) and showed a trend for improving overall survival (OS) in melanoma. This trial was designed to examine whether PEG-IFN is superior to IFN with regard to distant metastasis-free survival (DMFS), DFS and OS. PATIENTS AND METHODS: In this multicenter, open-label, prospective randomized phase III trial, patients with resected cutaneous melanoma stage IIA(T3a)-IIIB (AJCC 2002) were randomized to receive PEG-IFN (180 µg subcutaneously 1×/week; 24 months) or IFN α-2a (3MIU subcutaneously 3×/week; 24 months). Randomization was stratified for stage, number of metastatic nodes, age and previous IFN treatment. The primary end point was DMFS; secondary end points were OS, DFS, quality of life (QoL) and tolerability. RESULTS: A total of 909 patients were enrolled (451 PEG-IFN versus 458 IFN). Neither 5-year DMFS [PEG-IFN 61.0% versus IFN 67.3%; hazard ratio (HR) 1.16, P = 0.21] nor 5-year OS (PEG-IFN 73.2% versus IFN 75.2%; HR 1.05, P = 0.70) nor 5-year DFS (PEG-IFN 57.3% versus IFN 60.9%; HR 1.09, P = 0.40) showed significant differences. Subgroup analyses in patients ± ulcerated primaries and of different tumor stages did not find differences in DMFS, OS or DFS between the treatment groups. One hundred and eighteen patients (26.2%) in the PEG-IFN and 61 patients (13.3%) in the IFN population did not receive the full dosage and length of treatment due to adverse events (P < 0.001). Leukopenia and elevation of liver enzymes were more common in the PEG-IFN arm (56% versus 23.5% LCP; 19.1% versus 9.4% AST; 33.0% versus 16.5% ALT). QoL was identical for nearly all domains. CONCLUSION: PEG-IFN did not improve the outcome over IFN. A higher percentage of patients under PEG-IFN discontinued treatment due to toxicity. CLINICAL TRIALSGOV IDENTIFIER: NCT00204529.

[Tap water iontophoresis]. / Leitungswasseriontophorese.

Since 1968, tap water iontophoresis has been employed as the method of choice for treating palmoplantar hyperhidrosis. Special electrodes also allow treatment of axillary hyperhidrosis. Tap water iontophoresis also can extend symptom -free intervals in dyshidrotic palmar eczema. The mechanism action is most likely a functional disturbance of the secretory mechanism of eccrine acini. During the induction phase, treatments are carried out once daily. Current direction may be switched before each treatment or, even better, kept constant until one side, preferably the dominant hand on the anode, is sweating normally. Then polarity is switched until both hands are adequately treated. During the weekly maintenance therapy, current direction is switched before each treatment. The most comfortable means of iontophoretic treatment employs pulsed direct current of high frequency (5-10 kHz) which is better tolerated than continuous direct current and also suitable for children. Side effects are minimal and transient. Only slight skin irritation or sensations of discomfort may occur during treatment. Electric burns and shocks can be avoided by following routine precautions. Contraindications for tap water iontophoresis are metallic implants, such as cardiac pacemakers, or orthopaedic joint or bone implants, if they are within the electric circuit. Defects in the skin barrier, which can not be protected by petrolatum or insulating tape, also represent a temporary contraindication. Treatment in pregnancy is contraindicated, since experience is lacking.

[Drug-induced alveolitis associated with infliximab/azathioprine therapy]. / Medikamenten-induzierte Alveolitis unterInfliximab-/Azathioprin-Therapie.

BACKGROUND: TNF-alpha is known to play a decisive role as a pro-inflammatory cytokine in several autoimmune conditions. Its neutralisation by TNF-alpha antagonists such as infliximab (Remicade), a chimeric monoclonal anti-TNF-alpha antibody, may be beneficial in patients with active disease. These anticytokine drugs have been approved and are being increasingly used in the therapy of rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriatic arthropathy and generalised psoriasis after established treatments have failed. Whenever therapy options are few, TNF-alpha antagonists are regarded as an effective, relatively safe and generally well-tolerated alternative, even if there is no detailed knowledge of their safety profile and possible long-term adverse events. In the respiratory tract an increased risk of viral, (myco-)bacterial, fungal and opportunistic infections has been observed. Furthermore, rare cases of severe fibrosing alveolitis in patients with concomitant immunosuppressant therapy or underlying lung disease have been reviewed recently. CASE: We present a case of drug-induced alveolitis following infliximab and azathioprine for the treatment of severe, generalised psoriasis and atopic eczema without pre-existing lung disease. Withdrawal of both drugs achieved clinical and functional stabilisation, and the addition of prednisolone resulted in a rapid improvement. CONCLUSION: As the pathophysiology of the pulmonary insult is unknown and since there are potentially serious adverse effects, we advise caution and close screening before and after initiation of TNF-alpha blockade, especially in patients with an underlying lung disease or with a combination of pneumotoxic agents.

Photopatch testing: a consensus methodology for Europe.

A group of interested European Contact Dermatologists/Photobiologists met to produce a consensus statement on methodology, test materials and interpretation of photopatch testing. While it is recognized that a range of local variables operate throughout Europe, the underlying purpose of the work is to act as an essential preamble to a Pan European Photopatch Test Study focusing particularly on sunscreen chemicals.

[Large nodular lymphomatoid papulosis associated with parakeratosis variegata]. / Grossknotige lymphomatoide Papulose in Assoziation mit einer Parakeratosis variegata.

A 63 year old man suffering from lymphomatoid papulosis in association with parakeratosis variegata over a period of 20 years is presented. This case is unusual in respect to long-standing history, the rare combination of the two entities, and the extraordinary size of the nodules of lymphomatoid papulosis. Extracorporal photopheresis has induced partial remission lasting up to nine months so far.

Results of photoprovocation and field studies on the efficacy of a novel topically applied antioxidant in polymorphous light eruption.

BACKGROUND: UVA-induced photooxidation is considered to play an essential role in the pathogenesis of polymorphous light eruption (PLE), and topical pretreatment of skin with alpha-glucosylrutin (AGR), a potent plant-derived antioxidant, has been shown to significantly suppress photoprovoked PLE eruption. AIM: In order to further elucidate the optimum pretreatment regimen and to investigate the efficacy and skin compatibility of topical preparations containing AGR under field conditions, two controlled clinical studies were conducted in PLE patients. METHODS: In the first study, photoprovocation of PLE was performed in 20 patients, using UVA irradiation (4 x 60-100 J/cm(2)), applied to four test sites at the individual areas of predilection. One site served as an untreated control. The remaining three sites received treatment with a SPF 15 sunscreen containing 0.25% AGR (Eucerin Gel Cream Phase 2) 30 minutes before irradiation. Two of these sites were additionally pretreated with the corresponding AGR-containing vehicle (Eucerin Gel Cream Phase 1) twice daily for 3 and 7 days, respectively. The second study was conducted as a controlled in-use-test in patients with PLE (n = 27) or acne aestivalis (n = 3), who had suffered from the disease during their last year's vacation. They were educated to apply the pre-sun preparation to the formerly affected skin areas twice daily for 1 week before their planned vacation and to use the SPF 15 sunscreen 30 minutes before each vacation sun exposure. Symptoms were recorded in patients' diaries throughout the vacation and documented by a physician after their return. RESULTS: In the first study, protection of skin with the SPF 15 sunscreen alone led to a significant prevention of PLE symptoms, especially itch, compared with the control area. Pretreatment further reduced the severity of PLE significantly and led to total prevention in 19 patients. In the second study, whereas 92.6% had reported severe and 7.4% mild PLE in the last year, there were currently only 7.4% severe cases, with 25.9% mild and 29.6% questionable cases; 37% had no symptoms at all. Also, two out of three acne aestivalis patients had diminished symptoms after treatment. CONCLUSION: The results confirm the prophylactic efficacy of the antioxidant AGR in PLE, applied as SPF 15 sunscreen alone or additionally to pretreatment with a corresponding pre-sun preparation, and also show an effect in acne aestivalis patients.

Photopatch testing: the 12-year experience of the German, Austrian, and Swiss photopatch test group.

BACKGROUND: In 1984, the German, Austrian, and Swiss Photopatch Test Group was founded to standardize the photopatch test procedure and to investigate photoallergic reactions, as well as the epidemiology of photoallergy, in central Europe. Therefore in a first test period from 1985-1990, 32 test substances were applied on the backs of patients suspected to be photosensitive. After evaluation of these data, some substances were dismissed, and others were additionally integrated into the test tray. Thus a modified test tray comprising 26 test substances was used for the second test period (1991-1997). OBJECTIVE: According to the standard photopatch test procedure defined in the first test period, the aim of this multicenter study was to apply compounds from the modified second test tray to a large group of photosensitive patients. After evaluation of the second test period (1991-1997), the outcome was compared with the results of the first period. On the basis of these results and influenced by concurrently published case reports, a third modified photopatch test tray has been established. METHODS: After the application of a duplicate test tray for 24 hours, one test site was irradiated with 10 J/cm(2) UVA, and the other test site served as the control area. Readings were performed immediately and 24, 48, and 72 hours after irradiation. Test reactions were qualitatively graded according to a 4-point scale and classified by the investigators of the participating centers. In 49 participating clinics 1261 photopatch tests were performed. All data were subjected to computer-assisted analysis by using a specially developed software to classify all positive test reactions as plain contact or photoinduced reactions (nonspecific, toxic, or allergic photoreactions) and to define substance-specific reaction patterns. RESULTS: In test period 1 data of 1129 patients were evaluated. From 2859 positive test reactions, 28.6% were excluded as plain contact reactions, 71.4% were found to be photoinduced reactions, and 3.8% were classified as photoallergic. In test period 2 data of 1261 patients were evaluated. One thousand four hundred fifteen positive test reactions were observed, and of these, 28.7% were excluded as plain contact reactions, 71.3% were classified as photoinduced reactions, and 8.1% were classified as photoallergic reactions. In both test periods nonsteroidal anti-inflammatory drugs, disinfectants, and phenothiazines represented the leading photoallergens in the evaluated central European region. By using computer-assisted reaction pattern analysis, substance-specific reaction patterns could be distinguished. These substance-specific reaction patterns comprised 4 main categories: the well-known decrescendo (phototoxic) and crescendo (photoallergic) reaction patterns, as well as a combined and a plateau pattern. CONCLUSION: The test modification after the first test period led to a notably reduced number of positive (mainly nonphotoallergic and thus nonrelevant) test reactions per patient in the second test period (from 2.6 to 1.1). In contrast, the percentage of photoallergic reactions increased significantly from 3.8% to 8.1% of all positive test reactions. Test modifications after the first test period led to a remarkably improved specificity of the photopatch test. Furthermore, substance-specific reaction patterns observed in test period 1 were confirmed in test period 2.

The photoprotective effect of ascorbic acid, acetylsalicylic acid, and indomethacin evaluated by the photo hen's egg test.

The aim of the present study was to evaluate the supposed photoprotective effects of ascorbic acid, acetylsalicylic acid, and indomethacin by the photo hen's egg test, a recently developed new model for phototoxicity. Therefore, in three independent experimental settings the blood vessel system of the embryo's yolk sac of 24 incubated hens' eggs (2 test groups) were exposed to 60 mJ/cm2 ultraviolet B (UVB) to induce severe phototoxic damage. Before UVB irradiation, one of these test groups was exposed additionally to one of the test substances and the other one to 0.9% sodium solution alone. To exclude plain toxic reactions, two additional test groups were exposed only to 0.9% sodium chloride solution or to one of the test substances alone. Over a test observation period of 24 h, the embryo lethality as well as the morphological changes of the yolk sac blood vessel system were observed. Ascorbic acid led to a significant and remarkable reduction of the UVB-induced damage. Acetylsalicylic acid also showed a significant but lower photoprotective capacity. In contrast, indomethacin showed no photoprotective effects in the photo hen's egg test.

The Outermost Stratum Corneum Layer is an Effective Barrier Against Dermal Uptake of Topically Applied Micronized Titanium Dioxide.

In order to help clarify the controversially discussed dermal uptake properties of micronized titanium dioxide (TiO _ 2), we conducted extensive in vitro dermal absorption studies with 'Franz-type' diffusion cells on excised porcine skin. After biopsies and chemical fixation, the overall localization of TiO _ 2 in the skin was analyzed by means of transmission electron microscopy (TEM). The lateral and vertical distribution of TiO _ 2 within the stratum corneum (SC) was investigated by tape stripping and subsequent scanning electron microscopy (SEM) in combination with energy dispersive X-ray analysis (EDXA). TiO _ 2 was found exclusively on the outermost SC layer. The surface deposit, as displayed by TEM, featured clearly distinguishable agglomerates as well as single particles with a characteristic cubic shape and a primary particle size of about 20-50 nm. Concurrently, SEM/EDXA micrographs first showed an even distribution of TiO _ 2 on the skin surface. After 10-fold stripping, however, TiO _ 2 was found to be localized only in the furrows and not on the partially removed ridges of the skin surface. SEM/EDXA micrographs of the adhesive tape strips revealed a characteristic pattern of stripped material and free regions. This pattern was an imprint of the skin's topography. Hence, tape stripping initially removed TiO _ 2 and SC layers only from the ridges and not from the deeper furrows. Continued stripping increasingly yielded material from the deeper contours of the SC surface. TiO _ 2 was found only in traces in the upper part of the follicle without any evidence of uptake into the follicular epithelium. This indicates that there is not any relevant penetration via the follicular route. We conclude that due to the microtopography of the skin, the strip number normally does not reflect the SC layer number. Accordingly, tape stripping results should always be interpreted with care, especially in the case of topically applied particles, as even higher numbers of subsequent strips may still sample material from the outermost SC layer of the deeper furrows, which could be interpreted falsely as penetrated material. Our results clearly demonstrate that TiO _ 2 homogeneously and completely covers the outermost SC layer. It is neither delivered to the SC nor to the underlying skin layers when applied topically to porcine skin in vitro in the cosmetic vehicle used here. These findings underscore the safety of this micronized inorganic UV filter.

Photo hen's egg test: a model for phototoxicity.

The aim of this investigation was to establish a new model for phototoxicity which is more advanced than the widely used cultures of yeasts, bacteria or cells of various origin, and at the same time to avoid animal testing. We studied the extraembryonal vasculature of the incubated hen's egg. This model was originally introduced by toxicologists as an alternative to the rabbit's eye irritation test (Draize test). In the photo hen's egg test, substances are applied to the embryo's yolk-sac blood vessel system at a non-toxic concentration and are irradiated with 5 J/cm2 ultraviolet A (UVA) (320-400 nm). Promethazine, haematoporphyrin, ciprofloxacin and 8-methoxypsoralen were tested in this system. Death of the embryo, membrane discoloration and haemorrhage are parameters for phototoxic damage, which were recorded during an observation period of 24 h. These well-known phototoxic substances induced pronounced damage of the yolk-sac membrane and blood vessels which was not found in the controls (test substance alone, UVA alone or untreated) using a 2 x 2 factorial test design. The photo hen's egg test serves as a valid screening model for substances supposed to be photosensitizers owing to a phototoxic mechanism.

Effects of topically applied antioxidants in experimentally provoked polymorphous light eruption.

BACKGROUND: Polymorphous light eruption (PLE) is the most common photodermatosis, with a prevalence of 10-20% in Western European countries and in the USA. Only few preventive measures for PLE exist, while its etiology and pathogenesis are still elusive. Recent theories on pathogenesis discuss the possible influence of oxidative stress. OBJECTIVE: The presented randomized, placebo-controlled, double-blind study examines for the first time the protective effect of 3 different topically applied antioxidative preparations in experimentally photo-induced PLE. METHOD: 30 patients with a history of PLE underwent photoprovocation after having had applied 3 different formulations with antioxidants and one formulation with the vehicle only to the extensor surface of their upper arms, representing the individual site of predilection, twice daily for 1 week prior to and during the consecutive week of photoprovocation. The antioxidants used were combinations of different concentrations of alpha-glycosylrutin, ferulic acid and tocopheryl acetate. RESULTS: Evaluation after the 4th photoprovocation revealed that the development and severity of PLE and concomitant pruritus were significantly reduced by the application of distinct combinations of antioxidants. CONCLUSION: The results offer a new insight into possible pathomechanisms of PLE and suggest a new approach for preventive and therapeutic measures.

Epidemiological features of Adamantiades-Behçet's disease in Germany and in Europe.

The German Registry of Adamantiades-Behçet's disease was founded in 1990 in Berlin and it provides current data on the epidemiology, the clinical manifestations and the course of the disease in Germany on a continuous basis. A total of 218 patients, including 89 German and 100 Turkish patients, had been reported to the German Registry until October 1997. One hundred and ninety-six patients fulfilled the criteria of the Behçet's disease classification tree. The prevalence of the disease evaluated in Berlin-West was 1.68/100,000 in 1989 and had risen to 2.26/100,000 by 1994. The median age of onset was 25 years (range 5 to 66 years; German-Turks, ns). Juvenile disease was recorded in 6.9% of patients. The complete clinical picture according to the criteria of the International Study Group of Behçet's Disease developed in 15.5 months. The interval between onset of the disease and diagnosis was 35 months, which was significantly longer than the duration of the development of the complete clinical picture (p < 0.0001). The disease was diagnosed later in German (48.5 months) than in Turkish patients (25.5 months, p = 0.003). While German patients presented an equal male-to-female ratio, a male predominance was shown in Turkish patients (M:F 2.1:1, p = 0.022). Familial occurrence was detected in 2.0% of German and 15.9% of Turkish patients (p = 0.013). The frequencies of major clinical manifestations were: oral ulcers 99%, skin lesions 76%, genital ulcers 75%, ocular manifestations 59%, arthritis 59%, and positive pathergy test 52%. Clinical differences between German and Turkish patients were only found in the frequency of ocular lesions (48% vs. 66%, p = 0.025). Oral ulcers were with 72% the most common onset symptom of the disease followed by erythema nodosum (9%), uveitis (7%), arthritis (7%), genital ulcers (3%), superficial thrombophlebitis (2%) and papules/sterile pustules (2%). Uveitis and erythema nodosum as onset symptoms shortened the median interval to diagnosis to 1.5 and 15 months, respectively, while arthritis delayed diagnosis (43.5 months; p = 0.029). A severe course developed in 25% of the patients; irreversible retinal vasculitis to blindness in 15%, sterile meningoencephalitis in 8%, severe arthritis in 5%, hemoptysis in 2%, lethal outcome in 2% and bowel perforation in 1%. The relative risk of HLA-B5 positive German natives developing the disease. HLA-B5 was confirmed as a marker of severe prognosis. Cardiolipin autoantibodies were associated with cutaneous vasculitis and superficial thrombophlebitis was correlated with systemic vessel involvement.

[Parry-Romberg syndrome. Summary and new knowledge based on an unusual case]. / Parry-Romberg-Syndrom. Zusammenfassung und neue Erkenntnisse anlässlich einer ungewöhnlichen Kasuistik.

A 52 year old female with Parry-Romberg syndrome presented with gradual atrophy of the subcutaneous fat and muscle on her chest and back. The disease process was limited to the C3 to T2 dermatomes on the right side. In addition, there was muscle atrophy of the right arm and extending down the back to T10, als well as right sided paralysis of the diaphragm. Sympathetic nerve blockage reduced pain and hyperesthesia; no progression was seen over several months using NMR to monitor the patient. The Parry-Romberg syndrome has been defined in many ways; in view of this unusual case, we review the literature, attempting to provide a more accurate case definition.

[Morbihan disease--chronic persistent erythema and edema of the face]. / Morbus Morbihan--Chronisch persistierendes Erythem und Odem des Gesichts.

Morbihan's disease was first reported as a distinct entity in 1957 by Degos, describing a chronic persistent erythema and oedema of the upper half of the face. Such conditions have been noted in the literature designated as chronic lymphoedema or solid persistent facial oedema in acne or rosacea. The characteristic features are a chronic course, a typical clinical picture, lack of specific laboratory and histological findings and refractoriness to therapeutic measures.