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.

Effects of dermatitis, stripping, and steroids on the morphology of corneocytes. A new bioassay.

This study was designed to investigate the effects of increased or decreased epidermal turnover on the morphology of human corneocytes. The desquamating portion of the stratum corneum was sampled with the detergent scrub technique using Triton X-100. The following parameters were measured: size (surface micron2), shape (regular, irregular), nuclear inclusions, trabeculae, and numerical counts. Specimens were obtained from adult males with allergic contact dermatitis (N=18); with tretinoin-induced dermatitis (N=11); after cellophane stripping (N=11); and after treatment of these conditions with topical steroids (N=40). Data from 250,000 cells were analyzed statistically. The reproducibility of the method is good (r=0.934). Corneocytes from skin of patients with allergic contact dermatitis differed from those of normal skin: they were 15% smaller and of irregular shape with asymmetrical trabeculae; 50% were nucleated and about 3 times as many cells were collected per cm2 skin surface. Tretinoin and stripping produced similar but more pronounced effects. Topical steroids significantly improved all parameters (p less 0.01). Betamethasone-17-dipropionate was more effective than the valerate. This bioassay permits sensitive measurements of corneocyte morphology in conditions with altered epidermal cellular kinetics. It provides a method to evaluate steroid effectiveness.

Polymorphous light eruption.

Polymorphous light eruption (PLE) is a common photodermatosis of unknown etiology. It afflicts mainly fair-skinned patients, with a preponderance of young females. There is, however, no absolute restriction as to age, sex, or race. Clinical variants include the papular, vesiculo-bullous, and hemorrhagic variety, as well as plaque, erythema multiforme-like, and insect bite (strophulus)-like types. Skin lesions appear only in certain exposed areas hours or a few days after intense sunshine, and are nearly always monomorphous in the same patient. The rash subsides spontaneously within several days without leaving scars. The histopathologic picture is characteristic and shows a perivascular lymphocytic infiltrate in the upper and middle corium with subepidermal edema, vacuolization of basal cells, and spongiosis in the lower epidermis. The most important differential diagnoses are solar urticaria, photosensitive erythema multiforme, and lupus erythematosus. The action spectrum of PLE is under debate. Reproduction of skin lesions has been reported with UVB, UVA, and, rarely, visible light, with UVA probably being the most effective part of the spectrum. More important than treatment of PLE is prophylaxis. UVA- and UVB-effective sunscreens are of some help. Phototherapy and especially photochemotherapy (psoralen + UVA; PUVA) offer effective ways to decrease light sensitivity. Systemic treatment with chloroquine or beta-carotene has been disappointing.

A new apparatus with high radiation energy between 320-460 nm: physical description and dermatological applications.

A new apparatus (UVASUN 5000) is presented with high radiation energy between 320-460 nm. The measurable energy below 320 nm was shown to be many orders of magnitude too low to produce erythema. The radiator is a specially developed source for high UV-A intensity, housing a quartz bulb with a mixture of argon, mercury and metal-halides. At a skin-target distance of 0.2 m the size of the irradiated area is 0.35 X 0.35 m, and the measured mean UV-A intensity is about 1400 W . m-2 (140 mW . cm-2). The UV-A energy in the range of 320-400 nm is about 84% of the total radiation energy. Effects of very high doses of UV-A on human skin were studied. Following single UV-A applications the minimal tanning dose UV-A (MTD) and the immediate pigment darkening (IPD) dose of UV-A were established. The calculated IPD threshold time was 1.8 min at 0.2 m. Repeated exposure to this UV-A delivering system yields long lasting dark brown skin pigmentation without any clinical or histological signs of "sunburn" (UV-B) damage, epidermal hyperplasia or thickening of the stratum corneum. The instrument was also successfully used for photo-patch testing and reproduction of skin lesions of polymorphous light eruption. Minimal therapeutic results were seen in the phototherapy of vitiligo and inflammatory acne.

The microbiology of the human axilla and its relationship to axillary odor.

The axillary microflora of 229 subjects was characterized quantitatively and the results correlated with whether the odor was pungent body odor or instead a faint "acid odor". The axillary flora was found to be a stable mixture of Micrococcaceae, aerobic diphtheroids and Propionibacteria. Significantly higher numbers of bacteria were recovered from the axilla of those with pungent axillary odor than in those with acid odor. Aerobic diphtheroids in high numbers were recovered in all subjects having typical body odor. These included lipophilic as well as large-colony diphtheroids. When droplets of apocrine sweat placed on the forearm were inoculated with various bacteria which reside in the axilla, only diphtheroids generated typical body odor. Cocci produced a sweaty odor attributable to isovaleric acid.

Protection against UV-B by UV-A-induced tan.

Suntan is known to be protective against sunburn resulting from medium-wavelength ultraviolet radiation. Protection against UV-B by UV-A-induced pigmentation was studied by the evaluation of the erythema produced and by histologic alterations in the epidermis, including sunburn cell counts. Six subjects were deeply tanned with UV-A (mean cumulative dose, 700 joules/sq cm). The minimal erythemal dose to UV-B (300 +/- 5 nm) was established for each subject in normal skin and in UV-A-tanned areas. The UV-A tan provided measurable protection against UV-B-induced erythema. Following UV-B irradiation, 36 to 93 sunburn cells were counted per 10 mm of epidermal surface length in histologic sections of untanned skin as compared with four to seven sunburn cells in UV-A-tanned skin.

Antimicrobial effects of an antiperspirant formulation containing aqueous aluminum chloride hexahydrate.

To document deodorant efficacy the antimicrobial activity of a gelatinous antiperspirant formulation of aqueous aluminum chloride hexahydrate was investigated. In vitro assays demonstrated highly bactericidal activity on microorganisms comprising the resident axillary skin flora, including micrococcaceae and aerobic diphtheroid bacteria. Gram-negative bacteria and yeast were partially inhibited. In vivo experiments utilizing occlusive patches on forearm skin and bacterial sampling of the axilla showed pronounced bacteriostasis and persistence of aluminum chloride on the skin. Inhibition of microbial growth lasted more than 3 days after a single treatment of the axilla. Following repeated open applications to the volar aspect of the forearm, the skin remained virtually sterile for 3 days.

PUVA-treatment for solar urticaria and persistent light reaction.

A technique is described to successfully treat patients with extreme sensitivity to UV electromagnetic wave lengths with photochemotherapy. Representative data from a patient with solar urticaria and two patients with persistent light reaction are given. Prior to treatment the threshold doses for UV-C, UV-B, and UV-A were determined. Photochemotherapy was performed with standard 8-methoxypsoralen-UV-A (PUVA) schedules. Initial treatments were very difficult because of the extreme UV-sensitivity in all patients. Once pigmentation was induced, PUVA-treatments were easy to perform. All patients became almost free of symptoms and were able, for the first time in years, to resume normal outdoor activities. Remission was long-lasting. Photochemotherapy is offered as a new effective means to alleviate the symptoms of disabling photodermatoses.

Extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma--the Düsseldorf and Munich experience.

Extracorporeal photopheresis (ECP) using UVA irradiation of enriched lymphocytes in the presence of 8-methoxypsoralen as a photoactivatable substrate was originally introduced as a therapeutic regimen for cutaneous T-cell lymphoma (CTCL). Whereas ECP has previously been reported to be useful primarily for erythrodermic lymphoma, our purpose was to obtain data on safety and efficacy of ECP in patients suffering from different stages of CTCL. We report on 17 patients, 3 with erythroderma and 14 with plaque or tumor stages. In contrast to other studies our patients were treated predominantly with ECP alone; only a few patients received concomitant therapy. These data have not been published previously, except for preliminary data on four patients. Of the 17 patients, 12 (70%) responded to ECP. In seven patients at least 50% of skin lesions disappeared (defined as partial response) and in five patients at least 25% of skin lesions disappeared (defined as minor response). In two patients the disease remained stable and in three patients the disease progressed under the ECP treatment. No complete remission was observed. Partial responses were achieved not only in patients with early CTCL (stage Ib) but also in those with far progressed tumours (stage IVa). After treatment for 6 months partial responders showed an increase in the number of NK cells in their peripheral blood (P < 0.01). We cannot confirm a relationship between this treatment and CD8 cell counts, as reported by others. Overall, our results indicate that ECP is a safe and effective regimen for the treatment of all stages of CTCL.

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.

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.

Pigmented lesions as a sign of photodamage.

Chronic exposure to ultraviolet (UV) radiation causes skin changes, known as photodamage. Apart from damage to the connective tissue of the dermis and to keratinocytes, pigmented lesions, known as 'age spots', occur. There are several types, but the most common lesions are the senile lentigines. The main differential diagnoses include reticular seborrhoeic keratosis and lentigo maligna, and histopathological examination is required for exact differentiation. Variants of lentigo senilis with acute onset after intense UV radiation are sunburn freckles. Psoralens- and UVA-induced freckles, and lentigines occur after phototherapy with artificial UV sources or use of sunbeds for cosmetic tanning. Ephelids are common genetically determined pigment spots appearing during childhood in a distinct photodistribution. Exposure to UV radiation also seems to play a role in the manifestation of acquired nevi. Since pigmented lesions in sun-damaged skin represent more than one entity, they differ in their response to treatment. This should be taken into account when the efficacy of topical therapy is evaluated.

[Physiopathologic aspects and clinical pictures in hyperhidrosis]. / Pathophysiologische Aspekte und klinische Erscheinungsbilder der Hyperhidrosis.

Fully developed eccrine glands distributed over the entire integument are found only in man. The secretory mechanism is based on the active transport of sodium ions; water diffuses passively following the osmotic gradient. The thermoregulatory center in the hypothalamic region receives impulses from external and internal thermoreceptors and is modified by levels of hormones, by emotions, physical activity and pyrogens. Heat loss is controlled by the blood flow through the skin and by activity of eccrine glands. Thermoregulatory sweating occurs mainly on head and trunk. Emotions trigger eccrine sweating predominantly in the axillae, on palms, and soles. Generalized hyperhidrosis is mostly due to metabolic or endocrinologic disorders; in the state of acclimatization or following menopause hyperhidrosis is conceived to be physiologic. In underlying neurologic disorders hyperhidrosis follows a segmental or irregular pattern. Functional or anatomic eccrine nevi have been described. Gustatory sweating elicited by certain foods is found to be idiopathic and occurs symmetrically on the face. Subsequent to neurologic lesions (e.g., Frey's syndrome) gustatory sweating in segmental distribution may be associated with salivation and can be triggered by any foodstuff. The idiopathic localized hyperhidrosis of axillae, palms, and soles poses a frequent therapeutic problem in the dermatologist's office. Frequently, a familial predisposition is found. To what extent the disorder may be part of a general imbalance of psychovegetative functions is not yet fully understood.

Long-term efficacy and side effects of tap water iontophoresis of palmoplantar hyperhidrosis--the usefulness of home therapy.

Treatment of palmoplantar hyperhidrosis was carried out with a conventional galvanic generator in 40 patients and with a newly developed iontophoresis apparatus, which is suited for home treatment, in 31 patients. The new apparatus is operated by a rechargeable energy source or by batteries and is disconnected from the electrical net during treatment. It conforms to most recent safety regulations as approved by Underwriter's Laboratory. Hyperhidrosis was completely controlled after 10-12 treatments as revealed by quantitative gravimetric measurements of sweat rates and semiquantitative estimation of starch iodine paper imprints. There was no apparent difference in efficacy between the two apparatuses. Not only hyperhidrosis was abolished, but associated symptoms, such as lividity of palms or soles, acral hypothermia and edema of fingers or toes, also subsided. Skin temperature on palms rose from 29.7 +/- 1.8 degrees C before treatment to 32.2 +/- 1.4 degrees C thereafter. Maintenance treatment was continued on an average for 14 months, in 4 patients for more than 3 years. No loss of efficacy was found during that period. Side effects were minimal and depended upon amperage used. Only slight discomfort during treatment and mild short-lasted skin irritation were observed. Long-term side effects did not occur.

[Photoallergic contact dermatitis by benzophenone containing sunscreening preparations]. / Photoallergische Kontaktdermatitis durch benzophenonhaltige Sonnenschutzpräparate.

The case of a 42-year-old woman with sunlight-provoked eczematous eruptions recurrent over several years is reported. Photopatch-testing with cosmetic products and sunscreen preparations used by the patient as well as the active ingredient of the sunscreen formulations revealed photosensitivity to the UV-blocking agent 2-hydroxy-4-methoxybenzophenone. The active wavelengths were shown to be in the UV-A range.