A randomized, multinational, noninferiority, phase III trial to evaluate the safety and efficacy of BF-200 aminolaevulinic acid gel vs. methyl aminolaevulinate cream in the treatment of nonaggressive basal cell carcinoma with photodynamic therapy.

BACKGROUND: Basal cell carcinoma (BCC) represents the most common nonmelanoma skin cancer worldwide, affecting mainly adult, fair-skinned individuals. The World Health Organization distinguishes aggressive and nonaggressive forms, of which prototypical variants of the latter are primary nodular and superficial BCC. OBJECTIVES: To demonstrate noninferiority of BF-200 ALA (a nanoemulsion gel containing 5-aminolaevulinic acid) compared with MAL (a cream containing methyl aminolaevulinate) in the treatment of nonaggressive BCC with photodynamic therapy (PDT). Noninferiority of the primary efficacy variable (overall patient complete response 12 weeks after last PDT) would be declared if the mean response for BF-200 ALA was no worse than that for MAL, within a statistical margin of Δ = -15%. METHODS: The study was a randomized, phase III trial performed in Germany and the U.K. with ongoing 5-year follow-up. Of 281 randomized patients, 138 were treated with BF-200 ALA and 143 with MAL. Patients received two PDT sessions 1 week apart. Remaining lesions 12 weeks after the second PDT were retreated. Illumination was performed with a red light source (635 nm, 37 J cm-2 ). The results shown include clinical end points and patients' reassessment 12 months after the last PDT. The study was registered with EudraCT (number 2013-003241-42). RESULTS: Of the BF-200 ALA-treated patients, 93·4% were complete responders compared with 91·8% in the MAL group. The difference of means was 1·6, with a one-sided 97·5% confidence interval of -6·5, establishing noninferiority (P < 0·0001). The results for secondary efficacy parameters were in line with the primary outcome. Recurrence rates 12 months after the last treatment were ≤ 10%. CONCLUSIONS: Treatment of nonaggressive BCC with BF-200 ALA-PDT is highly effective and well tolerated with proven noninferiority to MAL-PDT. It demonstrates low recurrence rates after 1 year of follow-up.

UVB 308-nm excimer light and bath PUVA: combination therapy is very effective in the treatment of prurigo nodularis.

BACKGROUND: Prurigo nodularis (PN) is a chronic inflammatory skin disease with nodular itching lesions. UV therapy--both PUVA and NUVB--are known to clear up PN temporarily due to the antipruritic effect of UV light. However, relapse after treatment is common in PN, which means that either long-term therapy is necessary or the treatment protocols have to be optimized to minimize side-effects. OBJECTIVE: The aim of this study was to evaluate the effect that combining bath PUVA and targeted UVB 308 nm excimer radiation has on recalcitrant nodular prurigo. METHODS: In a prospective trial, 22 patients with PN were treated with either PUVA alone or with a combination of PUVA and excimer UVB. The end point was complete or almost complete remission of PN. RESULTS: Adding a 308-nm excimer UVB to the treatment of the pruritic nodules sped up the healing process; 30% less PUVA radiation was needed. CONCLUSION: The combination of PUVA and excimer UVB in PN appears to be very efficacious. Reducing psoralen UVA doses by 30% offered long-term benefits in phototherapy of chronic recalcitrant diseases like PN.

[Psoriasis. Natural versus artificial balneophototherapy]. / Psoriasistherapie. Künstliche versus natürliche Photosole.

Artificial balneophototherapy is an imitation of the natural balneophototherapy (Dead Sea climatotherapy; DSC) using highly concentrated salt solutions (25%) and UVB radiation. In 2008 the artificial balneophototherapy was included in the German healthcare system as an effective, evidence-based therapy for patients with moderate-severe psoriasis. In contrast, natural DSC is still considered a "non-standard and off-label therapy". Therefore we analyzed all studies published in the past two decades on both artificial and natural balneophototherapy comparing them in effectiveness, length of remission and practicability. Evidence-based studies on DSC showed good clinical results and long remission periods in psoriatic patients; the two methods seem comparable in effectiveness. Patients with chronic, therapy-resistant psoriasis should have access to DSC if they fail routine measures.

[New approach to photoepilation. Diode laser with SHR (Super Hair Removal) compared to alexandrite laser]. / Ein neuer Ansatz in der Laser-Haarreduktion. Diodenlaser mit SHR ("Super Hair Removal") im Vergleich mit dem Alexandritlaser.

BACKGROUND: Photoepilation has been an essential field of application of dermatologic laser therapy for many years. The present article evaluates whether the use of a new operation mode of a long-pulsed diode laser can be effective, nearly painless, with few side effects and independent of the skin type. To this aim, its use has been compared to an established method of photoepilation. MATERIAL AND METHODS: In a controlled prospective study with 18 (♀=12, ♂=6) patients aged between 22 and 58 years, the effects of photoepilation with the long-pulsed alexandrite laser and the long-pulsed diode laser, operated in the Super Hair Removal mode (SHR), were compared. RESULTS: The alexandrite laser is slightly more effective with fair skin types; the SHR mode is clearly more effective with dark skin types. Regarding painfulness, the SHR mode is clearly superior. In terms of speed, the two systems are comparable. The alexandrite laser is more user-friendly because of its light and small handpiece. CONCLUSION: The major advantages of the SHR mode are its effectiveness in dark skin types and its lack of pain. The alexandrite laser is slightly more effective with fair skin types, slightly faster and its handling is considerably more comfortable. None of the two systems has yet brought about a breakthrough with fair hair.

[Targeted UVB-308 nm (NUVB) therapy with excimer laser in the treatment of atopic dermatitis and other inflammatory dermatoses]. / UVB-308-nm- (NUVB-)Therapie mittels Excimer-Laser bei atopischer Dermatitis und weiteren inflammatorischen Dermatosen.

UVB 311 nm phototherapy (NUVB) is used successfully in the treatment of psoriasis or atopic dermatitis and is often chosen as "first-line" therapy. In a prospective study we investigated the efficacy of the targeted UVB 308 phototherapy by excimer laser in the treatment of 57 patients with localized, mild therapy-resistant atopic dermatitis. We achieved a complete remission (CR) in nearly 85% and a partial remission (PR) in 15% after 10 treatments during 6-8 weeks in all patients. A mean reduction in patient-reported pruritus was one hallmark after 3-4 treatments. 48 other patients with lichen simplex chronicus Vidal, nodular prurigo, granuloma anulare, alopezia areata (AA) and lichen ruber planus were also treated by targeted NUVB. We found higher rates of CR and PR only in patients with AA and in patients with oral Lichen ruber mucosae. These results and the systematically reviewing of the current medical literature shows that targeted NUVB by excimer laser cannot be successfully transferred for all inflammatory skin diseases. In particular, Excimer UVB treatment expands the therapeutic options in patients with localized and therapy-resistant atopic dermatitis enormously.

[Laser treatment of warts]. / Laser in der Therapie der Warzen.

Human papilloma viruses (HPV) lead to common warts in 5% of the population and genital warts in 1% of sexually-active individuals. Although about 50% of HPV infections regress spontaneously, the course is uncertain. Expectant waiting often leads to progression and dissemination. Plantar warts may cause pain on walking, while palmar and genital warts may impair social contacts. There are many treatments for warts, including a variety of laser systems. The CO(2) laser is the best ablative approach, producing cure rates of up to 75% for therapy-resistant common warts in cohort and case-control studies. Side effects such as bleeding, pain and reduced function over weeks must be weighed against the likelihood of success. Considering non-ablative approaches, pulsed dye lasers can be used for a selective, non-bloody destruction of extragenital and genital warts and may become the treatment of choice. In prospective randomized studies, they produced cure rates of up to 82% for therapy-resistant warts with few side effects.

[Treating papillomatous intradermal nevi: lasers - yes or no? A prospective study]. / Management papillomatöser intradermaler Nävi: Laser ja oder nein? Eine Prospektivstudie.

BACKGROUND: Papillomatous intradermal nevi are common acquired melanocytic nevi. Although harmless, they can be - especially on the face - cosmetically disturbing. At selected sites on the trunk, they may be traumatized by clothing, so that patients often wish to have them removed with a low likelihood of recurrence. MATERIAL AND METHODS: In a prospective study with 90 (female symbol=77, male symbol=13) patients aged between 13 and 67 years, 130 intradermal nevi (female symbol=114, male symbol=16) were removed using a combined therapy with CO(2), erbium: YAG and ruby lasers. RESULTS: After therapy, 2.3% of intradermal nevi recurred as a pigmented macule, while 6.9% reappeared as a papule or nodule (volume recurrence). 88% of the patients were very satisfied with the result; 11%, satisfied; and 1%, not satisfied. 99% would undergo the therapy again. CONCLUSION: The combined laser method (CO(2), erbium: YAG and ruby lasers) for the treatment of intradermal nevi produces excellent cosmetic results, is easily performed, leads to high patient satisfaction and is safe if correctly applied.

German evidence-based guidelines for the treatment of Psoriasis vulgaris (short version).

Psoriasis vulgaris is a common and chronic inflammatory skin disease which has the potential to significantly reduce the quality of life in severely affected patients. The incidence of psoriasis in Western industrialized countries ranges from 1.5 to 2%. Despite the large variety of treatment options available, patient surveys have revealed insufficient satisfaction with the efficacy of available treatments and a high rate of medication non-compliance. To optimize the treatment of psoriasis in Germany, the Deutsche Dermatologische Gesellschaft and the Berufsverband Deutscher Dermatologen (BVDD) have initiated a project to develop evidence-based guidelines for the management of psoriasis. The guidelines focus on induction therapy in cases of mild, moderate, and severe plaque-type psoriasis in adults. The short version of the guidelines reported here consist of a series of therapeutic recommendations that are based on a systematic literature search and subsequent discussion with experts in the field; they have been approved by a team of dermatology experts. In addition to the therapeutic recommendations provided in this short version, the full version of the guidelines includes information on contraindications, adverse events, drug interactions, practicality, and costs as well as detailed information on how best to apply the treatments described (for full version, please see Nast et al., JDDG, Suppl 2:S1-S126, 2006; or http://www.psoriasis-leitlinie.de ).

Ras gene mutations: a rare event in nonmetastatic primary malignant melanoma.

Ras gene mutations have been implicated in the pathogenesis of a variety of human tumors. Mutated ras genes have been isolated from human melanoma cell lines, but subsequent studies indicated that ras gene mutations may be a rare event in melanocytic lesions. Recently, a study reported a high frequency of ras mutations correlated with increasing invasion level. To address this inconsistency in the published data, we analyzed 50 primary melanomas to correlate invasion level, tumor thickness, histologic typing, and body localization with point mutations around codons 12/13/61 of the three ras genes. After micro-dissection of paraffin-embedded tumor tissue, ras gene mutations were analyzed by direct sequencing of tumor DNA amplified by polymerase chain reaction. Only two melanomas exhibited ras gene mutations, one sample containing a transition from A to G at position 2 of N-ras codon 61 and the other exhibiting a transversion from C to A at position 1 and a transition from A to G at position 2 of N-ras codon 61. Both tumors were classified as Clark level IV, with a tumor thickness of 2.5 and 1.2 mm, respectively. Both were typed as superficial spreading melanoma and localized to intermittently sun-exposed body sites. The low frequency of ras mutations in malignant melanoma and the lack of ras mutations in melanoma samples from constantly sun-exposed body sites argue against the hypothesis of ras mutations as a marker of progression in malignant melanoma and the suggestion that ras mutations occur predominantly in melanomas from constantly sun-exposed body sites.

Differential expression of tissue inhibitor of metalloproteinases-2 by cutaneous squamous and basal cell carcinomas.

Tumor cell invasion and metastasis are considered to represent a multistep process leading to the degradation of the extracellular matrix by proteolytic enzymes. The functional activity of matrix metalloproteinases (MMPs) is controlled by tissue inhibitor of metalloproteinases-2 (TIMP-2), which has been shown to inhibit tumor cell invasion and metastasis in vitro and in vivo. To assess the role of TIMP-2 in skin-derived epithelial tumors, we have analyzed the expression of TIMP-2 mRNA in primary tissue samples from human cutaneous basal (BCC) and squamous cell carcinoma (SCC) for a correlation with their different invasive and metastatic potential. Comparative quantitative analysis of TIMP-2 mRNA levels by Northern blot hybridization demonstrated significantly higher TIMP-2 tissue levels in BCC than in SCC, indicating an inverse correlation between TIMP-2 expression and the metastatic capacity of these tumors in vivo. By in situ hybridization, tumor stromal cells were identified as the principal source of TIMP-2 mRNA in both BCC and SCC. A comparable distribution has been reported previously for several matrix metalloproteinases in cutaneous BCC and SCC, indicating co-localization of metalloproteinases with their respective inhibitor. These results may suggest that TIMP-2 substantially contributes to the biological behavior of epithelium-derived skin tumors by significantly inhibiting tumor cell metastasis.

Inhibition of T cell cAMP formation by cyclosporin A and FK506.

The influence of the immunosuppressants, cyclosporin A (CsA) and FK506, on cAMP formation was studied in T cells from healthy controls and patients with psoriasis. While basal cAMP levels were not affected, CsA (1 microM) and FK506 (2 nM) prevented the isoprenaline (0.1 microM)-induced increase in cAMP formation. Half-maximal inhibition by FK506 and CsA was observed at about 0.2 nM and 20 nM, respectively. In addition, both agents significantly reduced (by about 50%) the forskolin (8 microM)-stimulated cAMP formation. No differences were noted in cAMP responses (basal, stimulation by isoprenaline, inhibition by CsA and FK506) of T cells from healthy controls and psoriatic patients. We conclude that CsA and FK506 potently and efficiently interfere with the stimulatory adenylyl cyclase pathway in T cells and that regulation of T cell cAMP formation is apparently not altered in psoriasis.

Cyclosporin A, FK506 and dithranol after tyrosine-specific protein phosphorylation in HaCaT keratinocytes.

Protein tyrosine kinases (PTKs) are closely related to cell growth, proliferation and differentiation. In keratinocytes, various growth factor receptors and cytosolic proteins, including the EGF and IGF receptors, the proteins of the src family and others, exhibit PTK activity. In psoriatic epidermis an increased level of EGF receptors and their ligand TGF-alpha has been found, and this is thought to be one reason for the pathological hyperproliferation of keratinocytes in this disease. Oral treatment with cyclosporin A (CsA) and FK506 or topical treatment with dithranol lead to an improvement in psoriasis. In the present study we examined the effect of these three drugs on the cellular content of phosphorylated tyrosines in highly proliferative HaCaT keratinocytes. HaCaT keratinocytes can be used as a model for highly proliferative epidermis, e.g. psoriatic epidermis. CsA had no effect whereas FK506 and dithranol reduced the phosphorylation of tyrosine residues in HaCaT keratinocytes. The activation of serine/threonine protein kinase C (PKC) is known to downregulate PTKs. Therefore we incubated keratinocytes with the selective PKC inhibitor Ro 31-8220 in addition to the other drugs. Only after the addition of Ro 31-8220 to FK506-treated keratinocytes was the phosphotyrosine (p-tyr) level elevated, but this was only one-third of the increase measured without additional therapeutic drugs. We assume that an induction of PKC alone is not responsible for the reduced p-tyr level after treatment with dithranol and FK506.(ABSTRACT TRUNCATED AT 250 WORDS)

Lithium and psoriasis: cytokine modulation of cultured lymphocytes and psoriatic keratinocytes by lithium.

The predominant cutaneous side effect of lithium is the exacerbation or aggravation of psoriasis, but the pathogenesis is still unclear. The hyperproliferation of keratinocytes and a dense lesional infiltrate of mononuclear cells are the hallmarks of psoriatic skin lesions. Interactions between keratinocytes and T cells are thought to be one reason for an increased secretion of proinflammatory cytokines and growth factors. To investigate whether lithium influences cytokines of the "psoriatic cytokine network', we established a coculture model with keratinocytes from psoriatic patients and from healthy controls cultured with HUT 78 lymphocytes and measured the cytokine levels of Il-2, Il-6, Il-8, IFN gamma and TGF alpha in the culture supernatants after treatment with lithium. Il-6 levels were slightly elevated in the supernatants obtained from psoriatic and control keratinocyte cultures after lithium treatment, but IFN gamma and Il-2 levels were elevated only in the lithium-treated cocultures with psoriatic keratinocytes. In contrast, these two cytokines were not affected by lithium in HUT 78 monocultures or in cocultures with normal epidermal cells. We also found slightly elevated TGF alpha levels in lithium-treated psoriatic cocultures but not in control cultures. We therefore demonstrated that lithium influences the cell communication of psoriatic keratinocytes with HUT 78 lymphocytes by triggering the secretion of TGF alpha, Il-2 and, massively, IFN gamma. It seems possible that lithium also influences similar parts of the psoriatic cytokine network in vivo.

Surgical excision of pseudotumorous pretibial myxedema.

Pretibial myxedema is a well-known clinical feature of autoimmune thyroid malfunction and is classically associated with Graves' disease. Its clinical course is frequently not related to the clinical control of the underlying thyroid disease. Treatment is primarily medical, consisting of oral and topical corticosteroids. We present a case of successful local excision of a pseudotumorous manifestation at the dorsum of the foot recalcitrant to multimodal medical and dermatological therapy.

German S3-guidelines on the treatment of psoriasis vulgaris (short version).

Psoriasis vulgaris is a common and often chronic inflammatory skin disease. The incidence of psoriasis in Western industrialized countries ranges from 1.5 to 2%. Patients afflicted with severe psoriasis vulgaris may experience a significant reduction in quality of life. Despite the large variety of treatment options available, patient surveys have revealed insufficient satisfaction with the efficacy of available treatments and a high rate of medication non-compliance (Richards et al. in J Am Acad Dermatol 41(4):581-583, 1999). To optimize the treatment of psoriasis in Germany, the Deutsche Dermatologische Gesellschaft (DDG) and the Berufsverband Deutscher Dermatologen (BVDD) have initiated a project to develop evidence-based guidelines for the management of psoriasis first published in 2006 and now updated in 2011. The Guidelines focus on induction therapy in cases of mild, moderate, and severe plaque-type psoriasis in adults. This short version of the guidelines presents the resulting series of therapeutic recommendations, which were based on a systematic literature search and discussed and approved by a team of dermatology experts. In addition to the therapeutic recommendations provided in this short version, the full version of the guidelines includes information on contraindications, adverse events, drug interactions, practicality, and costs, as well as detailed information on how best to apply the treatments described (for full version please see Nast et al. in JDDG Suppl 2:S1-S104, 2011 or http://www.psoriasis-leitlinie.de ).

[Unilateral acral necrosis as a minor form of hand-foot syndrome. Patient with unilateral acral necrosis secondary to capecitabine therapy for metastatic breast cancer]. / Unilaterale akrale Nekrosen als Abortivform einer palmoplantaren Erythrodysästhesie. Patientin mit unilateralen akralen Nekrosen unter Capecitabine-Therapie bei metastasiertem Mammakarzinom.

Hand-foot syndrome is a common toxic side-effect, particularly during chemotherapy, with an incidence of 6-64% overall and 10-24% for capecitabine (Xeloda) monotherapy. Consequently, differential diagnostic considerations should include hand-foot syndrome when acral skin lesions appear, particularly during capecitabine monotherapy. The dosage should be reduced or therapeutic regimen changed. We present a unique patient who while on capecitabine developed unilateral acral necrosis which should be classified as a minor form of hand-foot syndrome.

[Venous lakes. Treatment with a combination of diode laser (910 nm) and radio frequency]. / Lippenrandangiome. Behandlung mit einer Kombination aus Diodenlaser (910 nm) und Radiofrequenzenergie.

BACKGROUND: Venous lakes of the lip are a cosmetic problem for many patients due to their exposed location, nodularity, fragility and blue color. We sought an effective and well tolerated therapy method. PATIENTS AND METHODS: Over one year, we treated 20 patients with a combination of diode laser (910 nm) and radiofrequency. RESULTS: In all cases, there was complete regression of the venous lake (average: 1.4 treatment sessions). Side effects were transient pain that was assessed as mild by the patients, and transient swelling. Scarring or hypo-/hyperpigmentation did not occur. CONCLUSION: This combined approach is a recommended option at least equivalent to other therapy methods (argon laser, CO(2) laser, pulsed-dye-laser, and others), or even superior to them due to the low rates of side effects and low number of treatment sessions.

Does dye laser treatment with higher fluences in combination with cold air cooling improve the results of port-wine stains?

BACKGROUND AND OBJECTIVE: The use of cold air cooling (CAC) and cryogen spray cooling during dye laser treatment of port-wine stains (PWS) has become a standard in recent years. Still unsolved is the question of which fluences are necessary in combination with CAC in order to achieve an optimum clearance and the lowest possible rate of side-effects. STUDY DESIGN: In a prospective study, we treated 11 patients with PWS with pulsed dye laser (Photogenica V, Cynosure, lambda = 585 nm, iota(p) = 0.5 ms, spot size = 7 mm). Each PWS was partitioned into three areas: (area 1) 6 J/cm(2) without CAC, (area 2) 6 J/cm(2) with CAC (level 4), (area 3) 9 J/cm(2) with CAC (level 4). RESULTS: Area 3 (mean, 59%) showed a slightly better clearance than area 1 (mean, 57%); in area 2, we observed a reduced clearance (mean, 45%). Compared with area 1, we achieved a reduction of pain through CAC in areas 2 and 3. The healing periods as well as the rate of side-effects were comparable in all areas. CONCLUSION: We observed a slight but not statistically relevant increase in clearance with the use of higher fluences and CAC compared with lower fluences without CAC. Because pain is lowered significantly when using CAC, and because this makes the treatment more comfortable for the patients, we tend to recommend the use of higher fluences (9 J/cm(2)) with simultaneous CAC for treating PWS.

[Trigger factors for psoriasis]. / Triggermechanismen der Psoriasis.

Psoriasis is often defined as a disease in which there is a genetic predisposition but environmental stimuli ("trigger factors") are also necessary for clinical expression. Various endogenous and exogenous factors can either induce or exacerbate the clinical features. Knowledge of these factors is of primary importance in clinical practice. This review focuses on the most common environmental trigger factors (infection/superantigens, injury/Köbner phenomenon, stress/neuropeptides, smoking and alcohol) and evaluates the clinical and experimental concepts to explain "environmentally" triggered psoriasis.