Photodynamic therapy using intense pulsed light for treating actinic keratoses and photoaged skin of the dorsal hands: a randomized placebo-controlled study.

BACKGROUND: The efficacy of photodynamic therapy (PDT) with intense pulsed light (IPL) has been shown for treating actinic keratoses (AK) and improving photoaged skin on the face but not yet on the dorsal hands. OBJECTIVES: To evaluate the efficacy of PDT with IPL for treating AK of the dorsal hands, inducing neocollagenesis and improving photoaged skin. METHODS: In this prospective, randomized, placebo-controlled, monocentric, within-patient, observer-blinded trial, patients with one to four mild-to-moderate AK on the dorsal hands were randomly allocated to two different treatment groups: methyl aminolaevulinate (MAL) and IPL (λ ≥ 600 nm, 16·2 J cm-2 , three passes, Ellipse Flex PPT) (MAL-IPL) or placebo and IPL (λ ≥ 600 nm, 16·2 J cm-2 , three passes, Ellipse Flex PPT) (placebo-IPL). Patients received three treatments at 6-week intervals, and follow-up was 10 weeks after the last treatment. Thirty-seven patients aged 68·84 ± 9·28 years were randomized. The primary study end points were complete AK clearance per hand and neocollagenesis of subepidermal collagen 10 weeks after the last treatment. RESULTS: Ten weeks after the last treatment, complete AK clearance rates per hand were 54·5% after MAL-IPL and 3·0% after placebo-IPL (P < 0·0001); complete AK clearance rates per lesion were 69% and 15%, respectively (P < 0·001). The thickness of the subepidermal collagen band had increased by 290·6% (± 327·4%, P < 0·001) after MAL-IPL and by 215·5% (± 215·3%, P < 0·001) after placebo-IPL without any significant difference between the two groups. Ratings regarding mottled pigmentation and overall appearance by the blinded investigator were significantly higher for MAL-IPL than for placebo-IPL. Wrinkle size (MAL-IPL, -23·5%, P = 0·006; placebo-IPL, -17·7%, P = 0·010) and skin roughness (MAL-IPL, -18·3%, P < 0·001; placebo-IPL, -12·4%, P = 0·009) were significantly reduced in both groups without any significant difference between the two groups. CONCLUSIONS: On the dorsal hands, MAL-IPL reduced AK more efficaciously than placebo-IPL; both treatment modalities significantly improved photoaged skin.

Comparing cold-air analgesia, systemically administered analgesia and scalp nerve blocks for pain management during photodynamic therapy for actinic keratosis of the scalp presenting as field cancerization: a randomized controlled trial.

BACKGROUND: Photodynamic therapy (PDT) using methyl aminolaevulinate (MAL) is an effective treatment for extensive actinic keratosis (AK). However, pain is a major side-effect of this therapy. OBJECTIVES: To investigate whether scalp nerve blocks (group 1) provide adequate pain relief during MAL-PDT of the scalp and forehead in 32 men with baldness. METHODS: The patients received intravenous (IV) analgesia [piritramide 7.5 mg IV, plus oral metamizole (40 drops 30 min prior to PDT)] in combination with cold-air analgesia (group 2; IV analgesia) and cold-air analgesia alone (group 3). Maximum pain was evaluated by means of a visual analogue scale (VAS) during and up to 300 min after PDT. Pain during PDT was further analysed according to a pain perception scale. Furthermore, we measured haemodynamics and investigated stress hormone levels in blood samples at different time points. RESULTS: Maximum pain during PDT (primary end point) was significantly reduced in the treatment group receiving scalp nerve blocks (VAS 2.1 ± 1.3) compared with the treatment groups receiving IV analgesia (VAS 7.3 ± 1.1) and cold-air analgesia (VAS 8.4 ± 2.0; P < 0.05). No significant difference was found between groups 2 and 3 with regard to pain relief (P = 0.32). The increase in systolic blood pressure during the first 3 min of PDT was significantly lower for group 1 than for groups 2 and 3 (P < 0.001). No correlation between stress hormone levels and pain were found. CONCLUSIONS: Scalp nerve blocks provide an effective method for pain management during PDT for patients with extensive AK.

Fractional carbon dioxide laser resurfacing of rhytides and photoageing: a prospective study using profilometric analysis.

BACKGROUND: Results of profilometric skin analyses after fractional ablative skin resurfacing are not only important for evaluating the efficacy of this therapy but are also relevant for physicians practising laser and aesthetic skin therapy. Currently, objective measurements of wrinkle reduction after fractional CO2 laser resurfacing are scarce, and it remains unclear whether the various facial areas respond differently to this therapy. OBJECTIVES: To measure wrinkle parameters, the homogeneity of melanin distribution and skin roughness in four facial areas (periorbital, perioral, forehead, cheeks) before and after three fractional CO2 laser treatments. METHODS: Twenty-five women were analysed with regard to wrinkle parameters and mottled pigmentation on the face. We measured wrinkle size, depth and width and the homogeneity of melanin distribution and skin roughness in four facial areas before and after three fractional CO2 laser treatments. Additionally, the investigators rated clinical improvement using five-point grading scales. RESULTS: Wrinkles were significantly reduced in all facial areas, and the best results for wrinkle size and depth were found for the cheeks (-58·3%, P = 0·018 and -51·3%, P = 0·018) and the periorbital area (-35·1%, P < 0·001 and -31·1%, P = 0·001, respectively). The percentage improvements of rhytides evaluated by the investigators were mostly similar to those found from in vivo measurements. The homogeneity of melanin distribution in the skin was improved by 21·4% on the cheeks (P = 0·012) and by 24·0% in the periorbital area (P < 0·001). Clinical investigators rated the improvement of mottled pigmentation considerably higher (51-75%). CONCLUSIONS: After a serial treatment with the fractional CO2 laser, we measured considerably varying wrinkle reduction depending on the area of the face, and the best results were found for the cheeks.

Indocyanine green-augmented diode laser therapy vs. long-pulsed Nd:YAG (1064 nm) laser treatment of telangiectatic leg veins: a randomized controlled trial.

BACKGROUND: Telangiectatic leg veins (TLV) represent a common cosmetic problem. Near infrared lasers have been widely used in treatment because of their deeper penetration into the dermis, but with varying degrees of success, particularly because of different vessel diameters. Indocyanine green (ICG)-augmented diode laser treatment (ICG+DL) may present an alternative treatment option. OBJECTIVES: This trial evaluates the efficacy of ICG+DL in the treatment of TLV and compares the safety and efficacy of therapy with the standard treatment, the long-pulsed neodymium-doped yttrium aluminium garnet (Nd:YAG) laser. METHODS: In a prospective randomized controlled clinical trial, 29 study participants with TLV were treated with a Nd:YAG laser (λem = 1064 nm, 160-240 J cm(-2) , 65-ms pulse duration, 5-mm spot size) and ICG+DL (λem = 810 nm, 60-110 J cm(-2) , 48-87-ms pulse duration, 6-mm spot size; total ICG dose 4 mg kg(-1) ) in a side-by-side comparison in one single treatment setting that included histological examination in four participants. Two blinded investigators and the participants assessed clearance rate, cosmetic appearance and adverse events up to 3 months after treatment. RESULTS: According to both the investigators' and participants' assessment, clearance rates were significantly better after ICG+DL therapy than after Nd:YAG laser treatment (P < 0·05). On a 10-point scale indicating pain during treatment, participants rated ICG+DL therapy to be more painful (6·1 ± 2·0) than Nd:YAG laser (5·4 ± 2·0). CONCLUSIONS: ICG+DL therapy represents a new and promising treatment modality for TLV, with high clearance rates and a very good cosmetic outcome after one single treatment session.

[Erythema scarlatiniforme desquamativum generalisatum]. / Erythema scarlatiniforme desquamativum generalisatum.

Erythema scarlatiniforme desquamativum generalisatum (Féréol-Besnier disease) is a rare skin disease characterized by generalized erythematous rash with subsequent desquamation. An 86-year-old woman presented with generalized erythema followed by an extensive, scarlatiniform peeling especially of the hands and feet. This generalized episode may be followed by erythema scarlatiniforme desquamativum localisatum recidivans, which is a recurring variant of the disease, localized to the hands and feet.

An arrayed RNA interference genome-wide screen identifies candidate genes involved in the MicroRNA 21 biogenesis pathway.

MicroRNAs (miRNAs) are evolutionary conserved noncoding molecules that regulate gene expression. They influence a number of diverse biological functions, such as development and differentiation. However, their dysregulation has been shown to be associated with disease states, such as cancer. Genes and pathways regulating their biogenesis remain unknown and are highly sought after. For this purpose, we have validated a multiplexed high-content assay strategy to screen for such modulators. Here, we describe its implementation that makes use of a cell-based gain-of-function reporter assay monitoring enhanced green fluorescent protein expression under the control of miRNA 21 (miR-21); combined with measures of both cell metabolic activities through the use of Alamar Blue and cell death through imaged Hoechst-stained nuclei. The strategy was validated using a panel of known genes and enabled us to successfully progress to and complete an arrayed genome-wide short interfering RNA (siRNA) screen against the Ambion Silencer Select v4.0 library containing 64,755 siRNA duplexes covering 21,565 genes. We applied a high-stringency hit analysis method, referred to as the Bhinder-Djaballah analysis method, leading to the nomination of 1,273 genes as candidate inhibitors of the miR-21 biogenesis pathway; after several iterations eliminating those genes with only one active duplex and those enriched in seed sequence mediated off-target effects. Biological classifications revealed four major control junctions among them vesicular transport via clathrin-mediated endocytosis. Altogether, our screen has uncovered a number of novel candidate regulators that are potentially good druggable targets allowing for the discovery and development of small molecules for regulating miRNA function.

[New developments in laser therapy]. / Neue Entwicklungen in der Lasertherapie.

Based on the theory of stimulated emission of radiation that was proposed by Albert Einstein in 1916, the first lasers were developed in the 1960s. The first clinical use of laser technology in a German university took place in 1978 in the Department of Dermatology of the Ludwig-Maximilian-University in Munich under the guidance of the former director, Prof. Dr. med. Dr. h.c. mult. Otto Braun-Falco. In the following years, laser technology developed rapidly. Today laser technology is a widely used interdisciplinary therapeutic procedure that has deep clinical and scientific roots in dermatology. There are many conditions in both classic and aesthetic dermatology that are routinely - and sometimes exclusively - treated with lasers. Here we review recent developments in laser medicine. There seems to be a trend to combination procedures. To enhance efficacy, different laser systems are together or lasers are combined with specific topical medications.

Indocyanine green-augmented diode laser treatment of port-wine stains: clinical and histological evidence for a new treatment option from a randomized controlled trial.

BACKGROUND: Complete clearance of port-wine stains (PWS) is difficult to achieve, mainly because of the resistance of small blood vessels to laser irradiation. Indocyanine green (ICG)-augmented diode laser treatment (ICG+DL) may overcome this problem. OBJECTIVES: To evaluate the feasibility of ICG+DL therapy of PWS and to compare the safety and efficacy of ICG+DL with the standard treatment, flashlamp-pumped pulsed dye laser (FPDL). METHODS: In a prospective randomized controlled clinical study, 31 patients with PWS were treated with FPDL (λ(em)=585 nm, 6 J cm(-2) , 0.45 ms pulse duration) and ICG+DL (λ(em)=810 nm, 20-50 J cm(-2) , 10-25 ms pulse duration, ICG-concentration: 2 mg kg(-1) body weight) in a split-face modus in one single treatment setting that included histological examination (haematoxylin and eosin, CD34). Two blinded investigators and the patients assessed clearance rate, cosmetic appearance and side-effects up to 3 months after treatment. RESULTS: ICG+DL therapy induced photocoagulation of medium and large blood vessels (>20 µm diameter) but not of small blood vessels. According to the investigators' assessment, clearance rates and cosmetic appearance were better after ICG+DL therapy than after FPDL treatment (P=0.114, P=0.291, respectively), although not up to a statistically significant level, whereas patients considered these parameters superior (P=0.003, P=0.006, respectively). On a 10-point scale indicating pain during treatment, patients rated ICG+DL to be more painful (5.81 ± 2.12) than FPDL treatment (1.61 ± 1.84). CONCLUSION: ICG+DL represents a new and promising treatment modality for PWS, but laser parameters and ICG concentration need to be further optimized.

Off-label use of fumarate therapy for granulomatous and inflammatory skin diseases other than psoriasis vulgaris: a retrospective study.

BACKGROUND: Fumarates are approved for the systemic treatment of moderate and severe psoriasis vulgaris in Germany. However, a number of studies and case reports indicate their efficacy in the treatment of further inflammatory skin disorders or granulomatous skin diseases. OBJECTIVES: To examine the efficacy and safety of fumarates for the treatment of granulomatous and inflammatory skin diseases other than psoriasis vulgaris. PATIENTS AND METHODS: The therapeutic efficacy and side-effects of fumarate therapy were analysed retrospectively in patients with granuloma annulare (GA, n = 4), cutaneous sarcoidosis (SA, n = 1), lichen planus (LP, n = 3), pityriasis rubra pilaris (PRP, n = 1) or chronic discoid lupus erythematosus (CDLE, n = 1). RESULTS: Six patients (GA: 3/4; LP: 2/3; PRP: 1/1) showed complete clearance and two patients (GA: 1/3; SA: 1/1) had a partial response, and the CDLE patient showed stable disease under a combination therapy with hydroxychloroquine. Side-effects associated with fumarate therapy were seen in seven of ten patients and resolved spontaneously upon dose reduction or discontinuation of the therapy. CONCLUSION: According to this data, fumarates may represent a new approach in the treatment of granulomatous and inflammatory skin diseases other than psoriasis vulgaris. For the first time, the successful treatment of LP and CDLE with fumarates is reported. Side-effects are not limiting in most cases, but can hamper a dose escalation.

Development of a targeted risk-group model for skin cancer screening based on more than 100,000 total skin examinations.

BACKGROUND: Skin cancer screening aims to detect potentially metastasizing skin cancers at an early and surgically curable stage. This may take the form of mass screening, as currently occurs in Germany, or of targeted screening of those at greatest risk. OBJECTIVE: To develop a model to identify patients at high risk of developing skin cancer who would benefit from regular skin cancer screening. METHODS: This was an open prospective point-prevalence study of consecutive patients presenting to dermatologists for a total skin check. Demographic and skin cancer risk factors were recorded and, for the first time, histology of skin lesions was documented. Results were analysed by univariate and multivariate analyses and, after logistic regression with stepwise forward selection, a risk-group model was developed. RESULTS: The results of 108,281 total skin examinations were available for analysis. 142 definite melanomas, 108 severely dysplastic naevi/cannot-exclude-melanoma, 491 basal cell carcinomas (BCC) and 93 squamous cell carcinomas (SCC) were excised. A risk model was developed for melanoma and SCC based on mathematical e-functions. The model had >92% sensitivity for melanoma and SCC and an overall 67.24% specificity for melanoma, SCC and BCC. This targeted risk model identified one-third of the study population as being at risk for the development of melanoma and SCC. CONCLUSIONS: Using the risk calculator developed from this study, targeted screening of the identified at-risk population reduces the numbers needed to be screened regularly by 50%, yet has better sensitivity for melanoma and similar sensitivity for SCC compared to the current mass screening programme in Germany.

FGFR3, PIK3CA and RAS mutations in benign lichenoid keratosis.

BACKGROUND: Benign lichenoid keratoses (BLKs) are solitary skin lesions which have been proposed to represent a regressive form of pre-existent epidermal tumours such as solar lentigo or seborrhoeic keratosis. However, the genetic basis of BLK is unknown. OBJECTIVES: FGFR3, PIK3CA and RAS mutations have been shown to be involved in the pathogenesis of seborrhoeic keratosis and solar lentigo. We thus investigated whether these mutations are also present in BLK. METHODS: After manual microdissection and DNA isolation, 52 BLKs were screened for FGFR3, PIK3CA and RAS hotspot mutations using SNaPshot(®) multiplex assays. RESULTS: We identified 6/52 (12%) FGFR3 mutations, 10/52 (19%) PIK3CA mutations, 6/52 (12%) HRAS mutations and 2/52 (4%) KRAS mutations. FGFR3 and RAS mutations were mutually exclusive. One BLK showed a simultaneous PIK3CA and HRAS mutation. In nine BLKs with a mutation, nonlesional control tissue from the epidermal margin and the dermal lymphocytic infiltrate were wild-type, indicating that these mutations are somatic. To demonstrate that these findings are specific, 10 samples of lichen planus were analysed without evidence for FGFR3, PIK3CA or RAS mutations. CONCLUSIONS: Our results indicate that FGFR3, PIK3CA and RAS mutations are present in approximately 50% of BLKs. These findings support the concept on the molecular genetic level that at least a proportion of BLKs represents regressive variants resulting from former benign epidermal tumours such as seborrhoeic keratosis and solar lentigo.

Absence of BRAF and HRAS mutations in eruptive Spitz naevi.

BACKGROUND: Eruptive Spitz naevi have been reported rarely in the literature. In solitary Spitz naevi, BRAF and HRAS mutations, as well as increased copy numbers of chromosome 11p have been identified. OBJECTIVES: To investigate the genetic changes underlying eruptive Spitz naevi. METHODS: We report on a 16-year-old boy who developed multiple disseminated eruptive Spitz naevi within a few months. We analysed BRAF, HRAS, KRAS and NRAS genes in 39 naevi from this patient for hotspot mutations. Furthermore, comparative genomic hybridization analysis was performed in three lesions. RESULTS: None of the Spitz naevi displayed a mutation in the analysed genes, and no chromosomal imbalances were observed. Conclusions Our results indicate that the typical genetic alterations described in solitary Spitz naevi appear to be absent in eruptive Spitz naevi. Yet unknown alternative genetic alterations must account for this rare syndrome.

[Graft-versus-host disease (GvHD) - an update. Part 2: prognosis and therapy of GvHD]. / Graft-versus-Host-Disease (GvHD) - ein Update. Teil 2: Prognose und Therapie der GvHD.

Graft-versus-host disease (GvHD) remains one of the major complications after allogeneic stem cell transplantation (SCT) and is responsible for morbidity, mortality and decrease in quality of life of patients after SCT. The most important preventive approach is the selection of a donor with best possible HLA compatibility between donor and recipient. Basic prophylaxis of acute GvHD begins already prior to transplantation and usually consists of cyclosporine with or without methotrexate. In the past few years, many new therapies have been introduced for the treatment of acute and chronic GvHD. Extracorporeal photopheresis (ECP), for example, represents a promising treatment option for acute and chronic GvHD with very few side effects. For chronic GvHD mTOR inhibitors (sirolimus, everolimus) may replace calcineurin-inhibitors with the advantage of not inducing malignant skin tumors. Guidelines are available ort he management of acute and chronic GvHD. While pathophysiology, classification and skin manifestations of GvHD have been already presented in the first part of this article, this second part covers the prognosis, prevention and treatment of GvHD.

[Graft-versus-Host Disease (GvHD) - an update : Part 1: Pathophysiology, clinical features and classification of GvHD]. / Graft-versus-Host-Disease (GvHD) - ein Update : Teil 1: Pathophysiologie, Klinik und Stadieneinteilung der GvHD.

GvHD remains associated with significant morbidity and mortality despite new techniques for allogeneic stem cell transplantation (SCT), such as optimized conditioning regimens. Within the past ten years, the incidence of acute GvHD has remained unchanged and the incidence of chronic GvHD has even increased. The traditional classification of GvHD according to the time of clinical manifestation is now out-dated. Acute GvHD symptoms may even occur after 100 days; vice versa, primary chronic GvHD may already be observed one month after stem cell transplantation. The current classification introduced by the National Institutes of Health includes classic acute GvHD (up to 100 days), late-onset acute GvHD (after 100 days), as well as an overlap syndrome showing features of acute and chronic GvHD and classic chronic GvHD without any time limit. Diagnosis of GvHD of the skin remains difficult because of histological similarities to drug eruptions and viral exanthems. In this first part of the article the pathophysiology, classification, skin manifestations of acute and chronic GvHD and the histopathology will be presented. In a second part the prognosis, prophylaxis and therapy of GvHD will be discussed.

Skin ageing.

Similar to the entire organism, skin is subject to an unpreventable intrinsic ageing process. Additionally, skin ageing is also influenced by exogenous factors. Ultraviolet radiation in particular results in premature skin ageing, also referred to as extrinsic skin ageing or photoageing, which is the main cause of the changes associated with the ageing process in sun-exposed areas. Despite their morphological and pathophysiological differences, intrinsic and extrinsic ageing share several molecular similarities. The formation of reactive oxygen species and the induction of matrix metalloproteinases reflect the central aspects of skin ageing. Accumulation of fragmented collagen fibrils prevents neocollagenesis and accounts for the further degradation of the extracellular matrix by means of positive feedback regulation. The importance of extrinsic factors in skin ageing and the detection of its mechanisms have furthered the development of various therapeutic and preventive strategies.

A randomized clinical trial in psoriasis: synchronous balneophototherapy with bathing in Dead Sea salt solution plus narrowband UVB vs. narrowband UVB alone (TOMESA-study group).

BACKGROUND: Synchronous balneophototherapy (sBPT) simulates treatment conditions at the Dead Sea for outpatient use. In the past, sBPT proved to be an effective treatment for psoriasis. However, there is a lack of sufficiently large randomized controlled clinical trials evaluating the additional benefit of sBPT compared with ultraviolet B (UVB) monotherapy. OBJECTIVES: The purpose of this study was to compare the effectiveness and safety of sBPT with UVB phototherapy (PT) alone in a randomized controlled effectiveness study. METHODS: In this phase III, multicentre effectiveness study, 367 patients with moderate to severe psoriasis were randomly allocated in a 1 : 1 ratio to receive either sBPT consisting of narrowband UVB PT with 311 nm and synchronous bathing in 10% Dead Sea salt solution or PT with 311 nm alone. Primary endpoint, analysed on an intention-to-treat basis (n = 356), was the relative improvement of the Psoriasis Area and Severity Index (PASI) from baseline to end of treatment (35 sessions or clearance). Sample size calculation aimed at the detection of superiority of at least 10%. RESULTS: Median PASI values were comparable at baseline (sBPT: 15.1, interquartile range: 10.9-24.3; PT: 15.3, interquartile range: 10.0-23.7). A clinically relevant and statistically significant difference of 49.5% between sBPT and PT could be proven at the end of the therapy phase (P < 0.001; Wilcoxon-Mann-Whitney test). Exploratory testing showed a statistically significant superiority of sBPT after 6 months. CONCLUSIONS: In routine clinical practice, sBPT is superior to PT alone after 35 treatment sessions and a follow-up of 6 months. Both treatments demonstrated to be safe.