Practical approach to the use of daylight photodynamic therapy with topical methyl aminolevulinate for actinic keratosis: a European consensus.

INTRODUCTION: Daylight-mediated photodynamic therapy has been shown to be an effective therapy for actinic keratoses (AKs) and a simple and tolerable treatment procedure in three randomized Scandinavian studies and two recent Phase III randomized controlled studies in Australia and Europe. OBJECTIVES: To establish consensus recommendations for the use of daylight photodynamic therapy (DL-PDT) using topical methyl aminolaevulinate (MAL) in European patients with AKs. METHODS: The DL-PDT consensus recommendations were developed on behalf of the European Society for Photodynamic Therapy in Dermatology and comprised of 10 dermatologists from different European countries with experience in how to treat AK patients with PDT. Consensus was developed based on literature review and experience of the experts in the treatment of AK using DL-PDT. RESULTS: The recommendations arising from this panel of experts provide general guidance on the use of DL-PDT as a dermatological procedure with specific guidance regarding patient selection, therapeutic indications, when to treat, pre-treatment skin preparation, MAL application and daylight exposure for patients with AK in different countries of Europe. CONCLUSIONS: This consensus recommendation provides a framework for physicians to perform DL-PDT with MAL cream while ensuring efficiency and safety in the treatment of patients with AK in different European countries.

[Acute generalized exanthematous pustulosis]. / Akute generalisierte exanthematische Pustulose.

CLINICAL FEATURES: Acute generalized exanthematous pustulosis (AGEP) is a reaction pattern mostly caused by drugs. It is characterized by the rapid occurrence of dozens to thousands pinhead-sized, non-follicular, sterile pustules on a slightly edematous erythematous base, commonly with accentuation in the major flexures and usually accompanied by a facial edema, fever and leukocytosis. Histology reveals spongiform subcorneal and/or intraepidermal pustules, an inflammatory infiltrate consisting of neutrophils and often eosinophils and frequently a marked edema of the papillary dermis. TRIGGERS: Even if in single case reports a large number of drugs has been described as triggers for AGEP, larger studies have revealed a list with an elevated risk to cause the reaction which includes antibacterial agents like ampicillin/amoxicillin, quinolones, pristinamycin, anti-infective sulfonamides, the antimycotic drug terbinafine, (hydroxy)chloroquine, and diltiazem. In some cases infections have been reported as triggers. CLINICAL COURSE, PROGNOSIS AND TREATMENT: AGEP is an acute and--especially in patients with concomitant diseases--sometimes severe reaction. Withdrawal of the causative agent usually leads to a rapid and complete resolution--even without further specific therapy.

Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study.

BACKGROUND: Cases of severe drug hypersensitivity, demonstrating a variable spectrum of cutaneous and systemic involvement, are reported under various names, especially drug reaction with eosinophilia and systemic symptoms (DRESS). Case definition and overlap with other severe cutaneous adverse reactions (SCAR) are debated. OBJECTIVES: To analyse the spectrum of signs and symptoms of DRESS and distribution of causative drugs in a large multicentre series. PATIENTS AND METHODS: RegiSCAR, a multinational registry of SCAR, prospectively enrolled 201 potential cases from 2003 to mid-2009. Using a standardized scoring system, 117 cases were validated as showing probable or definite DRESS. RESULTS: The male/female ratio was 0.80; females were borderline significantly younger than males. Next to the ubiquitous exanthema, the main features were eosinophilia (95%), visceral involvement (91%), high fever (90%), atypical lymphocytes (67%), mild mucosal involvement (56%) and lymphadenopathy (54%). The reaction was protracted in all but two patients; two patients died during the acute phase. Drug causality was plausible in 88% of cases. Antiepileptic drugs were involved in 35%, allopurinol in 18%, antimicrobial sulfonamides and dapsone in 12% and other antibiotics in 11%. The median time interval after drug intake was 22 days (interquartile range 17-31) for all drugs with (very) probable causality, with differences between drugs. CONCLUSION: This prospective observational study supports the hypothesis that DRESS is an original phenotype among SCAR in terms of clinical and biological characteristics, causative drugs, and time relation. The diversity of causative drugs was rather limited, and mortality was lower than that suggested by prior publications.

European guidelines for topical photodynamic therapy part 2: emerging indications--field cancerization, photorejuvenation and inflammatory/infective dermatoses.

In addition to established indications in non-melanoma skin cancer in immunocompetent patients, photodynamic therapy (PDT) has been studied for the treatment, and possible prevention, of superficial skin cancers in immunosuppressed patients. As a topical photosensitizer can be applied over large areas, PDT is also increasingly used for field cancerization in photodamaged skin, with evidence of potential to delay the development of actinic keratoses and basal cell carcinoma, although direct evidence of prevention of invasive squamous cell carcinoma remains limited. PDT has been studied in patch/plaque-stage cutaneous T-cell lymphoma, with efficacy more likely in unilesional disease. Accumulating evidence supports the use of PDT in acne and several other inflammatory/infective dermatoses including cutaneous leishmaniasis, although protocols are still to be refined. Despite proven efficacy, PDT is not widely used in viral/genital warts, where pain during treatment can be intense. PDT is a therapeutic option for photorejuvenation, with improvement in fine wrinkles, mottled hyperpigmentation, roughness and sallowness reported.

European guidelines for topical photodynamic therapy part 1: treatment delivery and current indications - actinic keratoses, Bowen's disease, basal cell carcinoma.

Topical photodynamic therapy (PDT) is a widely used non-invasive treatment for certain non-melanoma skin cancers, permitting treatment of large and multiple lesions with excellent cosmesis. High efficacy is demonstrated for PDT using standardized protocols in non-hyperkeratotic actinic keratoses, Bowen's disease, superficial basal cell carcinomas (BCC) and in certain thin nodular BCC, with superiority of cosmetic outcome over conventional therapies. Recurrence rates following PDT are typically equivalent to existing therapies, although higher than surgery for nodular BCC. PDT is not recommended for invasive squamous cell carcinoma. Treatment is generally well tolerated, but tingling discomfort or pain is common during PDT. New studies identify patients most likely to experience discomfort and permit earlier adoption of pain-minimization strategies. Reduced discomfort has been observed with novel protocols including shorter photosensitizer application times and in daylight PDT for actinic keratoses.

Photodynamic therapy for skin field cancerization: an international consensus. International Society for Photodynamic Therapy in Dermatology.

Field cancerization is a term that describes the presence of genetic abnormalities in a tissue chronically exposed to a carcinogen. These abnormalities are responsible for the presence of multilocular clinical and sub-clinical cancerous lesions that explains the increased risks of multiple cancers in this area. With respect to the skin, this term is used to define the presence of multiple non-melanoma skin cancer, its precursors, actinic keratoses and dysplastic keratinocytes in sun exposed areas. The multiplicity of the lesions and the extent of the area influence the treatment decision. Providing at least equivalent efficacy and tolerability, field directed therapies are therefore often more worthwhile than lesion targeted approaches. Photodynamic therapy (PDT) with its selective sensitization and destruction of diseased tissue is one ideal form of therapy for this indication. In the following paper the use of PDT for the treatment of field cancerized skin is reviewed and recommendations are given for its use.

Daylight photodynamic therapy for actinic keratosis: an international consensus: International Society for Photodynamic Therapy in Dermatology.

Photodynamic therapy (PDT) is an attractive therapy for non-melanoma skin cancers including actinic keratoses (AKs) because it allows treatment of large areas; it has a high response rate and results in an excellent cosmesis. However, conventional PDT for AKs is associated with inconveniently long clinic visits and discomfort during therapy. In this article, we critically review daylight-mediated PDT, which is a simpler and more tolerable treatment procedure for PDT. We review the effective light dose, efficacy and safety, the need for prior application of sunscreen, and potential clinical scope of daylight-PDT. Three randomized controlled studies have shown that daylight-mediated PDT is an effective treatment of thin AKs. Daylight-mediated PDT is nearly pain-free and more convenient for both the clinics and patients. Daylight-mediated PDT is especially suited for patients with large field-cancerized areas, which can easily be exposed to daylight. Further investigations are necessary to determine at which time of the year and in which weather conditions daylight-mediated PDT will be possible in different geographical locations.

Taking treatment decisions in non-melanoma skin cancer--the place for topical photodynamic therapy (PDT).

BACKGROUND: Epithelial non-melanoma skin cancer (NMSC) like actinic keratosis (AK), Bowen's disease (BD) and basal cell carcinoma (BCC) represent the most common malignancies in the fair skinned population. Epidemiological data reveal high incidences, especially for actinic keratoses, which are basically non-invasive squamous cell carcinomas, but fortunately bear a low risk of mortality for a single lesion. Nevertheless these lesions should be generally treated if other factors such as the state of the patient indicate that this is appropriate. The appearance of new treatment modalities like immuno-modulating topical agents, topical diclofenac, and photodynamic therapy in addition to a long list of already established treatments (curettage, surgery, cryotherapy, topical 5-fluorouracil, and many others) have led to the fact that patients and treating physicians have a large spectrum of therapeutic options to choose from. The same--with some variations--holds true for Bowen's disease and BCC. METHODS: Aim of this article is to offer an overview over NMSCs and their treatment options with emphasis on photodynamic therapy (PDT) as classical indications for PDT, to provide resources for guidelines for the treatment of these diseases, and to position PDT in this context by helping selecting patients that would profit most from topical PDT. RESULTS: Sufficient evidence is available to regard PDT as a standard treatment modality for NMSC. In addition to randomized controlled trials, long-term experience helps to find out the most appropriate treatment modality in a given patient. CONCLUSION: Physicians treating NMSC should have access to PDT and be trained and experienced in its use.

An application of propensity score methods to estimate the treatment effect of corticosteroids in patients with severe cutaneous adverse reactions.

PURPOSE: To investigate whether propensity score (ps) methods could reasonably be applied to estimate the treatment effect on mortality, based on a comparatively small sample of patients with severe cutaneous adverse reactions (SCAR) and who come from different countries where physicians prefer different treatment schemes. METHODS: Ps methods were applied to cope with confounding due to non-randomized treatment assignment for the analysis of the treatment data obtained in the case-control study EuroSCAR. For the study's purpose, the analysis focused on the comparison of the treatments: corticosteroids (STER) and supportive care only (SUPP). RESULTS: 206 French and German patients were treated either with SUPP or STER. Imbalances between treatment groups as well as between the countries were recognized. Concerning the balance between the treatment groups no ps model for the full cohort was satisfying. In addition, the inclusion of a variable for patient's country led to a separation of the patients by country. Thus, we developed ps models for each country separately and estimated the treatment effects (France: odds ratio (OR) 0.52, 95% confidence interval (CI) 0.09-3.10, Germany: OR 0.23, CI 0.06-0.92, Overall: OR 0.33 CI 0.11-1.04). CONCLUSIONS: The application of the ps methods was successful and provided valuable information. We could confirm the findings of the original analysis which was based on standard logistic regression, especially concerning the necessity of a country-specific analysis. The observed country differences in the estimated treatment effects were less pronounced and thus seemed to be more reasonable than those of the past analysis.

Pharmacovigilance of drug allergy and hypersensitivity using the ENDA-DAHD database and the GALEN platform. The Galenda project.

Nonallergic hypersensitivity and allergic reactions are part of the many different types of adverse drug reactions (ADRs). Databases exist for the collection of ADRs. Spontaneous reporting makes up the core data-generating system of pharmacovigilance, but there is a large under-estimation of allergy/hypersensitivity drug reactions. A specific database is therefore required for drug allergy and hypersensitivity using standard operating procedures (SOPs), as the diagnosis of drug allergy/hypersensitivity is difficult and current pharmacovigilance algorithms are insufficient. Although difficult, the diagnosis of drug allergy/hypersensitivity has been standardized by the European Network for Drug Allergy (ENDA) under the aegis of the European Academy of Allergology and Clinical Immunology and SOPs have been published. Based on ENDA and Global Allergy and Asthma European Network (GA(2)LEN, EU Framework Programme 6) SOPs, a Drug Allergy and Hypersensitivity Database (DAHD((R))) has been established under FileMaker((R)) Pro 9. It is already available online in many different languages and can be accessed using a personal login. GA(2)LEN is a European network of 27 partners (16 countries) and 59 collaborating centres (26 countries), which can coordinate and implement the DAHD across Europe. The GA(2)LEN-ENDA-DAHD platform interacting with a pharmacovigilance network appears to be of great interest for the reporting of allergy/hypersensitivity ADRs in conjunction with other pharmacovigilance instruments.

[Epidemiology of cutaneous vascular neoplasms and malformations in childhood]. / Epidemiologie kutaner vaskulärer Neu- und Fehlbildungen im Kindesalter.

PURPOSE: A representative compilation of data on the incidence and prevalence of benign cutaneous vascular neoplasms and malformations in childhood has been made. PATIENTS, MATERIALS AND METHODS: A review of the literature has been made and basic data from an own epidemiological survey in the province of Tyrol (Austria) in 6-year-old children are evaluated. RESULTS: For capillary malformations with spontaneous regression (salmon patches), the reported numbers usually vary between 20 and 30% of the newborns, while true, persisting capillary malformations (port-wine stains) can be found in about 1%. Strawberry angiomas are found in about 3% of mature newborns but in up to 12.5% of preterm children. Complex vascular malformations or severe cases of vascular tumours are very rare. CONCLUSION: All in all, vascular lesions are very common findings in childhood, but in most cases harmless and transient in nature. The number of lesions that may require adequate but usually uncomplicated treatment amounts to about one percent of children (strawberry angiomas and port-wine stains). Complex and/or life-threatening severe vascular tumours and malformations that represent a considerable therapeutic challenge are extremely rare events.

Risk factors for acute generalized exanthematous pustulosis (AGEP)-results of a multinational case-control study (EuroSCAR).

BACKGROUND: Acute generalized exanthematous pustulosis (AGEP) is a disease characterized by the rapid occurrence of many sterile, nonfollicular pustules usually arising on an oedematous erythema often accompanied by leucocytosis and fever. It is usually attributed to drugs. OBJECTIVES: To evaluate the risk for different drugs of causing AGEP. PATIENTS AND METHODS: A multinational case-control study (EuroSCAR) conducted to evaluate the risk for different drugs of causing severe cutaneous adverse reactions; the study included 97 validated community cases of AGEP and 1009 controls. Results Strongly associated drugs, i.e. drugs with a lower bound of the 95% confidence interval (CI) of the odds ratio (OR) > 5 were pristinamycin (CI 26-infinity), ampicillin/amoxicillin (CI 10-infinity), quinolones (CI 8.5-infinity), (hydroxy)chloroquine (CI 8-infinity), anti-infective sulphonamides (CI 7.1-infinity), terbinafine (CI 7.1-infinity) and diltiazem (CI 5.0-infinity). No significant risk was found for infections and a personal or family history of psoriasis (CI 0.7-2.2). CONCLUSIONS: Medications associated with AGEP differ from those associated with Stevens-Johnson syndrome or toxic epidermal necrolysis. Different timing patterns from drug intake to reaction onset were observed for different drugs. Infections, although possible triggers, played no prominent role in causing AGEP and there was no evidence that AGEP is a variant of pustular psoriasis.

[Photodynamic therapy of cutaneous epithelial malignancies. An evidence-based review]. / Photodynamische Therapie bei epithelialen Hauttumoren. Evidenzbasierte Datenlage.

During the last years photodynamic therapy (PDT) has progressively established itself as a standard treatment for non-melanoma skin cancer. A number of clinical studies have demonstrated its efficacy--also compared to other treatment modalities--as well as good acceptance by patients and outstanding cosmetic results. For Bowen disease and superficial basal cell carcinoma, PDT can be regarded as the first-line non-invasive treatment. In the treatment of actinic keratoses PDT should be considered when cosmesis is crucial or in cases of field cancerization. In nodular basal cell carcinoma, effectiveness for lesions up to a thickness of 2 mm is well documented. In summary the evidence level seems sufficient to regard PDT as valuable treatment modality of which patients should not be deprived.

Photodynamic therapy using topical methyl 5-aminolevulinate compared with cryotherapy for actinic keratosis: A prospective, randomized study.

BACKGROUND: Actinic keratoses (AKs) are the most common premalignant tumors. Without treatment, a significant number of patients with AK will experience squamous cell carcinoma. Photodynamic therapy (PDT) using the new highly selective photosensitizer methyl 5-aminolevulinate is a promising new treatment modality for AK. OBJECTIVE: We investigated the complete response rates, cosmetic outcome, and patient satisfaction after photodynamic therapy (PDT) using methyl 5-aminolevulinate (Metvix) versus cryotherapy in the treatment of AKs. METHODS: Patients were randomized to receive either cryotherapy with liquid nitrogen spray or PDT using methyl 5-aminolevulinate cream 160 mg/g, 3 hours application time, and red light (75 J/cm(2)). RESULTS: Efficacy results from 193 patients with 699 lesions (92% face/scalp and 93% thin/moderately thick) were analyzed. Overall complete response rates after 3 months were 69% for PDT and 75% for cryotherapy. Both treatments gave higher response rates in thin lesions (PDT 75%, cryotherapy 80%). PDT gave better cosmetic results and higher patient satisfaction than cryotherapy. CONCLUSION: PDT using methyl 5-aminolevulinate is an attractive treatment option for patients with AK, with a response rate similar to that of cryotherapy, but with superior cosmetic results and high patient satisfaction.

Reduced number of CD1a+ cells in cutaneous B-cell lymphoma.

Cutaneous B-cell lymphoma is difficult to distinguish from pseudolymphoma. The histologic pattern and monoclonal restriction (immunohistochemical analysis and molecular biology) are the criteria used for differentiating these entities. CD1a+ dendritic cells have been observed in the infiltrates of T-cell lymphoma, but the presence of these CD1a+ cells has not been compared in B-cell lymphoma and pseudolymphoma. We studied the presence of CD1a+ cells on frozen sections of 23 B-cell lymphomas, 13 pseudolymphomas, and 17 T-cell lymphomas by immunohistochemical analysis. We found abundant CD1a+ dendritic cells in only 1 (4%) of 23 B-cell lymphomas, whereas in 8 (62%) of 13 pseudolymphomas and 17 (100%) of 17 T-cell lymphomas, strong CD1a staining was present. Our study demonstrates a distinct pattern of CD1a staining in the infiltrates of B-cell lymphoma and pseudolymphoma that may be of value in the differential diagnosis of these skin disorders.

Acute generalized exanthematous pustulosis (AGEP)--a clinical reaction pattern.

BACKGROUND: A wide range of diseases or reactions can cause pustular eruptions of the skin. In this spectrum there seems to be a subgroup with characteristic clinical features and a typical course which is mostly caused by drugs for which the term acute generalized exanthematous pustulosis (AGEP) has been established. OBJECTIVE: To describe the clinical features of AGEP. METHODS: The authors' experience from a multinational epidemiological study on severe cutaneous adverse reactions and a comprehensive review of the literature were used to provide an overview of the disease and it's possible causes. An algorithm for validating cases which was established for this study is also presented. RESULTS: AGEP typically presents with at least dozens of non follicular sterile pustules occurring on a diffuse, edematous erythema predominantly in the folds and/or on the face. Fever and elevated blood neutrophils are common. Histopathology typically shows spongiform subcorneal and/or intraepidermal pustules, a marked edema of the papillary dermis, and eventually vasculitis, eosinophils and/or focal necrosis of keratinocytes. Onset is acute, most often following drug intake, but viral infections can also trigger the disease. Pustules resolve spontaneously in less than 15 days. CONCLUSION: The diagnosis AGEP should be considered in cases of acute pustular rashes and detection of the causative drug should be strived for. Knowledge of the clinical features and usual course of this disease can often prevent unnecessary therapeutical measures.

Combined dermatofibroma: co-existence of two or more variant patterns in a single lesion.

AIMS: Based on a series of 25 cases, we define and characterize combined dermatofibroma, a tumour comprising two or more variant patterns of dermatofibroma in a single lesion. METHOD AND RESULTS: Dermatofibroma may present with a wide variety of architectural, cellular or stromal peculiarities. Architectural peculiarities include deep penetration, atrophy, collarette formation, fascicular to plexiform architecture, massive haemorrhage, prominent haemangiopericytoma-like vascularity and palisading; cellular peculiarities the presence of epithelioid cells, clear cells, granular cells, prominent myofibroblastic differentiation and atypical giant cells ('monster cells'); or stromal peculiarities such as prominent sclerosis, mucin, haemosiderin and cholesterotic deposits. In combined dermatofibromas two or more of these features are seen in complex or inhomogenous combination such as the silhouette of a deep penetrating dermatofibroma with an 'ordinary' storiform pattern in the upper and granular cell differentiation in the lower part of the lesion; or a dermatofibroma with ordinary features in the upper, prominent sclerosis in the middle and clear cells in the lower portion of the lesion; or the characteristic epidermal collarette and cells of epithelial cell histiocytoma with a plexiform ('neurothekeoma-like') architecture surrounded by a myxoid stroma with spindle-shaped to stellate cells. Clinically, these lesions preferentially occur on the lower extremities of young to middle-aged females, frequently with the diagnosis of a fibrohistiocytic lesion. Apart from one recurrence follow-up was uneventful in all other cases. Immunohistochemically, lesions are consistently positive with KiM1p, variably positive for factor XIIIa, smooth muscle specific actin and with KP1 (CD68), NK1C3 and E9. CONCLUSION: Recognition of combined dermatofibroma allows the histopathologist to apply a confident benign label to unusual lesions which might otherwise elude diagnosis, or tempt description of 'new' entities and to avoid a misdiagnosis of malignancy.

Drug-induced Stevens-Johnson syndrome/toxic epidermal necrolysis.

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a rare (occurring in approximately 2 to 3 people/million population/year in Europe and the US), life-threatening, intolerance reaction of the skin. It is most often caused by drugs (most commonly sulfonamides, nonsteroidal anti-inflammatory drugs, antimalarials, anticonvulsants, and allopurinol). SJS/TEN is characterized by a macular exanthema ('atypical targets') which focusses on the face, neck, and the central trunk regions. Lesions show rapid confluence, a positive Nikolsky's sign, and quickly result in widespread detachment of the epidermis and erosions. Mucosal, conjunctival, and anogenital mucous membranes are prominently involved. Histopathology shows satellite cell necrosis in the early stages progressing to full thickness necrosis of the epidermis, contrasting with rather inconspicuous inflammatory infiltrates of the dermis. Damage to the skin is thought to be mediated by cytotoxic T lymphocytes and mononuclear cells which induce apoptosis in keratinocytes expressing drug-derived antigens at their surfaces. No guidelines for the treatment of SJS/TEN exist since no controlled clinical trials have ever been performed. The controversy over whether systemic corticosteroids should be used to curtail progression is still unresolved; while many authors agree that corticosteroids do in fact suppress progression, it is obvious that they also greatly enhance the risk of infection, the complication which most frequently leads to a fatal outcome. It appears reasonable to only administer corticosteroids in the phase of progression and to withdraw them as soon as possible, and to add antibacterials for prophylaxis. Recently, in a small series of patients, intravenous immunoglobulins were presumed to be effective by the blockade of lytic Fas ligand-mediated apoptosis in SJS/TEN. However, these results have to be confirmed by large clinical trials. Supportive treatment and monitoring of vital functions is of utmost importance in SJS/TEN, and out-patient treatment is unacceptable. Recovery is usually slow, depending on the extent and severity and the presence of complications, and may take 3 to 6 weeks. Skin lesions heal without scars as a rule, but scarring of mucosal sites is a frequent late complication, potentially leading to blindness, obliteration of the fornices and anogenital strictures. There is no reliable laboratory test to determine the offending drug; diagnosis rests on the patient's history and the empirical risk of drugs to elicit skin SJS/TEN. Provocation tests are not indicated since re-exposure is likely to elicit a new episode of SJS/TEN of increased severity.