Photodynamic therapy in dermatology: established and new indications.

Photodynamic therapy (PDT) is internationally established as an approved treatment option for in situ forms of keratinocytic skin cancer (actinic keratoses, Bowen's disease, basal cell carcinoma). For these indications, there are standardized treatment protocols using narrow-spectrum light sources or (artificial) daylight, the use of which is associated with successful healing, a low rate of lesion recurrence, and a very good cosmetic result. Daylight PDT is superior to conventional PDT in terms of significantly less pain and associated higher patient acceptance. Newer indications, for which no approval has yet been granted, but which nevertheless have sufficient evidence of efficacy according to the study situation, are inflammatory (lichen sclerosus, acne) and infectious dermatoses (viral warts, cutaneous leishmaniasis, atypical mycobacteriosis). In addition, PDT is increasingly being used in aesthetic dermatology with the aim of skin rejuvenation.

S2k guideline: Rosacea.

This updated and upgraded S2k guideline deals with the diagnosis and treatment of rosacea, which is a common, chronic inflammatory skin disease mostly affecting the face. Initially, rosacea is characterized by recurrent erythema, telangiectasia and flushing. Later, the inflammatory component predominates, with persistent erythema with follicular papules, papulopustules and pustules. The development of phyma, which usually occurs on the acral localizations, is the most severe manifestation. For the treatment of rosacea, the interdisciplinary guideline committee, with representatives of the German Dermatological Society (DDG), the Professional Association of German Dermatologists (BVDD), the German Opthalmological Society (DOG), the Society for Dermopharmacy (GD), the Swiss Society for Dermatology and Venereology (SGDV) and the German Rosacea Aid e. V., recommends the avoidance of trigger factors and topical applications of metronidazole, azelaic acid or ivermectin. For symptomatic treatment of persistent centrofacial erythema, the topical vasoconstrictors brimonidine or oxymetazoline can also be used. Systemic therapy is recommended for therapy-resistant and severe forms of rosacea papulopustulosa. The drug of choice is low-dose doxycycline. Alternatively, low-dose isotretinoin can be recommended. Ocular rosacea should be treated with lid margin hygiene. For topical treatment, ciclosporin eye drops, azithromycin, ivermectin or metronidazole are suggested.

Computer-aided clinical image analysis for non-invasive assessment of tumor thickness in cutaneous melanoma.

OBJECTIVE: Computerized clinical image analysis is shown to improve diagnostic accuracy for cutaneous melanoma but its effectiveness in preoperative assessment of melanoma thickness has not been studied. The aim of this study, is to explore how melanoma thickness correlates with computer-assisted objectively obtained color and geometric variables. All patients diagnosed with cutaneous melanoma with available clinical images prior to tumor excision were included in the study. All images underwent digital processing with an automated non-commercial software. The software provided measurements for geometrical variables, i.e., overall lesion surface, maximum diameter, perimeter, circularity, eccentricity, mean radius, as well as for color variables, i.e., range, standard deviation, coefficient of variation and skewness in the red, green, and blue color space. RESULTS: One hundred fifty-six lesions were included in the final analysis. The mean tumor thickness was 1.84 mm (range 0.2-25). Melanoma thickness was strongly correlated with overall surface area, maximum diameter, perimeter and mean lesion radius. Thickness was moderately correlated with eccentricity, green color and blue color. We conclude that geometrical and color parameters, as objectively extracted by computer-aided clinical image processing, may correlate with tumor thickness in patients with cutaneous melanoma. However, these correlations are not strong enough to reliably predict tumor thickness.

Patterns of care and follow-up care of patients with uveal melanoma in German-speaking countries: a multinational survey of the German Dermatologic Cooperative Oncology Group (DeCOG).

PURPOSE: Uveal melanoma (UM) is an orphan cancer of high unmet medical need. Current patterns of care and surveillance remain unclear as they are situated in an interdisciplinary setting. METHODS: A questionnaire addressing the patterns of care and surveillance in the management of patients with uveal melanoma was distributed to 70 skin cancer centers in Austria, Germany and Switzerland. Frequency distributions of responses for each item of the questionnaire were calculated. RESULTS: 44 of 70 (62.9%) skin cancer centers completed the questionnaire. Thirty-nine hospitals were located in Germany (88.6%), three in Switzerland (6.8%) and two in Austria (4.5%). The majority (68.2%) represented university hospitals. Most patients with metastatic disease were treated in certified skin cancer centers (70.7%, 29/41). Besides, the majority of patients with UM were referred to the respective skin cancer center by ophthalmologists (87.2%, 34/39). Treatment and organization of follow-up of patients varied across the different centers. 35.1% (14/37) of the centers stated to not perform any screening measures. CONCLUSION: Treatment patterns of patients with uveal melanoma in Germany, Austria and Switzerland remain extremely heterogeneous. A guideline for the treatment and surveillance is urgently needed.

Solar urticaria: Clinic, diagnostic, course and therapy management in 27 patients.

BACKGROUND AND OBJECTIVES: Solar urticaria is a rare photodermatosis, the diagnosis and therapy of which have not yet been standardized. The aim of this research was to use innovative radiation sources for diagnostics with defined and reproducible emission spectra and doses. A uniform therapy step scheme was to be created. PATIENTS AND METHODS: In a longitudinal study, 27 patients with solar urticaria were examined over 13 years. With a characteristic anamnesis, the diagnosis was confirmed with phototesting (photoprovocation) from various radiation sources (UVB, UVB311nm, UVA, UVA-1, green light, red light) and a therapy step scheme was designed consisting of light protection, antihistamines, rush hardening with UVA-1, and administration of omalizumab. RESULTS: Action spectrum: UVB 44 %, UVA 70 %, UVA-1 89 %, green light 37 % and red light 22 %. Rush hardening with subsequent maintenance therapy was performed on 20 patients, 17 of whom were hereby adequately protected. In three further patients, omalizumab was additionally administered. CONCLUSIONS: Phototesting with UVB, UVB311nm, UVA, UVA-1, and visible light with innovative radiation sources is uniformly possible in every major skin clinic. With the help of the therapy step scheme the patients can be adjusted well. Rush hardening with UVA-1 is a safe method to help the patients during the sunny season. Omalizumab as the last therapy option is effective, but currently only possible in off-label use.

Lichturtikaria: Klinik, Diagnostik, Verlauf und Therapiemanagement bei 27 Patienten.

BACKGROUND AND OBJECTIVES: Solar urticaria is a rare photodermatosis, yet lacking standardization in diagnosis and therapy. The aim of this research was to use innovative radiation sources for diagnostics with defines and reproducible emission spectrum and doses. A uniform therapy step scheme was to be created. PATIENTS AND METHODS: In a longitudinal study, 27 patients were examined with solar urticaria over 13 years. With a characteristic anamnesis, the diagnosis was confirmed with phototesting from various radiation sources (UVB, UVB311nm, UVA, UVA1, green light, red light) and a therapy step scheme consisting of light protection, antihistamines, rush hardening with UVA-1 and the treatment with omalizumab. RESULTS: Action spectrum: UVB 44 %, UVA 70 %, UVA1 89 %, green light 37 % and red light 22 %. Rush hardening was performed on 20 patients, 17 of whom were adequately protected. In three further patients, omalizumab was additionally treated in off-label use. CONCLUSIONS: Photoprovocation with UVB, UVB311nm, UVA, UVA-1 and visible light with innovative radiation sources is uniformly possible in every major skin clinic. With the help of the therapy step scheme the patients can be adjusted well, a Rush Hardening with UVA-1 is a safe method to help the patients during the sunny season. Omalizumab as the last therapy option is effective, but currently only possible in off-label use.

Final Analysis of DeCOG-SLT Trial: No Survival Benefit for Complete Lymph Node Dissection in Patients With Melanoma With Positive Sentinel Node.

PURPOSE: We have previously reported on the 3-year results of the phase III German Dermatologic Cooperative Oncology Group trial (DeCOG; ClinicalTrials.gov identifier: NCT02434107) comparing distant metastasis-free survival (DMFS), recurrence-free survival (RFS), and overall survival (OS) in patients with positive sentinel lymph-node biopsy who were randomly assigned to complete lymph node dissection (CLND) or observation. Here, we report the final analysis with 72 months of median follow up. PATIENTS AND METHODS: The multicenter randomized phase III trial included patients with cutaneous melanoma of the trunk and extremities who were randomly assigned (1:1) to undergo CLND or observation. DMFS was analyzed as the primary end point, and RFS, OS, and recurrences in the regional lymph node basin were secondary end points. The analysis was by intention to treat. Disease and survival information were collected quarterly. RESULTS: From January 2006 to December 2014, 5,547 patients were screened to identify 1,256 with metastases in the sentinel lymph node (SLN). Of these, 483 (39%) were included: 241 in the observation arm and 242 in the CLND arm. In the final analysis, median follow up was 72 months (interquartile range, 67-77 months). No significant treatment-related difference was seen in the 5-year DMFS between the observation and CLND arms (67.6% v 64.9%, respectively; hazard ratio [HR], 1.08; P = .87). The 5-year RFS and OS also showed no difference (HR, 1.01 and 0.99, respectively). Grade 3 and 4 adverse effects occurred in 32 patients (13%) in the CLND arm; lymphedema (n = 20) and delayed wound healing (n = 5) were most common and no serious adverse events were reported. CONCLUSION: The final results of the German Dermatologic Cooperative Oncology Group trial with a median follow up of 72 months showed higher event rates, but similar HRs compared with those at the 3-year analysis. These results confirm that immediate CLND in SLN-positive patients is not superior to observation in terms of DMFS, RFS, or OS and support not recommending CLND in patients with SLN metastasis.

Physikalische Methoden zur Behandlung der Rosazea.

Die Rosazea ist durch vielfältige vaskuläre Veränderungen gekennzeichnet. Neben Teleangiektasien und Erythemen treten häufig auch sogenannte "Flushings" auf. Haupteinsatzgebiete von Licht- und Lasersystemen sind diese vaskulären Veränderungen, wie Erytheme und Teleangiektasien. Neben dem KTP-Laser, dem Farbstofflaser (PDL) und dem Nd:YAG-Laser kommen auch Blitzlampen (IPL) zum Einsatz. Neben der Rückbildung der vaskulären Komponente, ist auch eine Verbesserung der papulopustulösen Komponente beschrieben. Während der KTP-Laser sehr gute Ergebnisse bei Teleangiektasien zeigt, werden der Farbstofflaser und die Blitzlampen bevorzugt bei flächigen Erythemen eingesetzt. Der ND:YAG-Laser kann bei Teleangiektasien und Erythemen eingesetzt werden, birgt aber von allen Systemen das nicht einschätzbare Narbenbildungsrisiko in sich. Die Bildung von Phymen stellt eine klinische Ausprägung der Rosazea dar. Das am häufigsten vorkommende ist das Rhinophym. Bei moderaten und schweren Formen steht die Abtragung im Vordergrund. Die klassische chirurgische Abtragung stellt eine Möglichkeit zur Behandlung dar, häufig kommt es hierbei jedoch intraoperativ zu stärkeren Blutungen. Alternativmethode ist die Elektrochirurgie und die Dermabrasion, wobei bei beiden Methoden Narbenbildungen auftreten können. Neuere Methoden wie die CO2 -Laserabtragung, eventuell in Kombination mit der Erbium:YAG-Abtragung, stellen sichere und komplikationsärmere Varianten dar.

Physical modalities for the treatment of rosacea.

Rosacea is characterised by a wide variety of vascular changes. Apart from telangiectasia and erythema, often so-called flushing occurs. These vascular abnormalities can be targeted with specific light and laser devices. In addition to KTP laser, pulsed dye laser (PDL) and Nd:YAG laser, also intense pulsed light devices (IPLs) are used. The described therapeutic effects include the reduction of vascular abnormalities and even improvement of papulopustular changes. While the KTP laser shows very good results in telangiectasia, the dye laser and IPL devices are used preferably in erythema. The Nd:YAG laser is also a possibility for patients with telangiectasia and erythema. However, compared to the other laser and light devices the Nd:YAG laser carries the highest risk of unpredictable scarring. Phymatous changes are another clinical manifestation of rosacea, mostly affecting the nose (rhinophyma). Moderate and severe cases are commonly treated with ablation modalities. Traditional surgery is a treatment option, but is often associated with major intraoperative bleeding. Alternative methods include electrosurgery and dermabrasion, although both methods can cause scarring. Newer methods such as CO2 laser ablation, possibly in combination with the erbium:YAG laser, are safe alternatives with a lower risk of complications.

S1-Guidelines on UV phototherapy and photochemotherapy.

Known in part since antiquity, the salutary effects of sunlight again garnered increasing attention in the second half of the 19(th) century. The development of a device for ultraviolet irradiation of cutaneous tuberculosis by Finnsen at the onset of the twentieth century truly marked the beginning of modern phototherapy. In dermatology, treatment methods almost exclusively use wavelengths below the visible light range (ultraviolet light). Since the early 1970s, increasingly powerful artificial light sources have become available for UVB and UVA therapy as well as the combination of UVA and photosensitizers (photochemotherapy). High structural and procedural quality standards are an essential prerequisite for the implementation of effective as well as safe phototherapy. The following guidelines outline the current consensus of leading experts in the field of phototherapy with respect to indications, contraindications, and side effects of various treatment options available. Particular focus is also on adequate UV doses at the beginning and over the further course of treatment as well as on management of side effects.

Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial.

BACKGROUND: Complete lymph node dissection is recommended in patients with positive sentinel lymph node biopsy results. To date, the effect of complete lymph node dissection on prognosis is controversial. In the DeCOG-SLT trial, we assessed whether complete lymph node dissection resulted in increased survival compared with observation. METHODS: In this multicentre, randomised, phase 3 trial, we enrolled patients with cutaneous melanoma of the torso, arms, or legs from 41 German skin cancer centres. Patients with positive sentinel lymph node biopsy results were eligible. Patients were randomly assigned (1:1) to undergo complete lymph node dissection or observation with permuted blocks of variable size and stratified by primary tumour thickness, ulceration of primary tumour, and intended adjuvant interferon therapy. Treatment assignment was not masked. The primary endpoint was distant metastasis-free survival and analysed by intention to treat. All patients in the intention-to-treat population of the complete lymph node dissection group were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02434107. Follow-up is ongoing, but the trial no longer recruiting patients. FINDINGS: Between Jan 1, 2006, and Dec 1, 2014, 5547 patients were screened with sentinel lymph node biopsy and 1269 (23%) patients were positive for micrometastasis. Of these, 483 (39%) agreed to randomisation into the clinical trial; due to difficulties enrolling and a low event rate the trial closed early on Dec 1, 2014. 241 patients were randomly assigned to the observation group and 242 to the complete lymph node dissection group. Ten patients did not meet the inclusion criteria, so 233 patients were analysed in the observation group and 240 patients were analysed in the complete lymph node dissection group, as the intention-to-treat population. 311 (66%) patients (158 in the observation group and 153 in the dissection group) had sentinel lymph node metastases of 1 mm or less. Median follow-up was 35 months (IQR 20-54). Distant metastasis-free survival at 3 years was 77·0% (90% CI 71·9-82·1; 55 events) in the observation group and 74·9% (69·5-80·3; 54 events) in the complete lymph node dissection group. In the complete lymph node dissection group, grade 3 and 4 events occurred in 15 patients (6%) and 19 patients (8%) patients, respectively. Adverse events included lymph oedema (grade 3 in seven patients, grade 4 in 13 patients), lymph fistula (grade 3 in one patient, grade 4 in two patients), seroma (grade 3 in three patients, no grade 4), infection (grade 3 in three patients, no grade 4), and delayed wound healing (grade 3 in one patient, grade 4 in four patients); no serious adverse events were reported. INTERPRETATION: Although we did not achieve the required number of events, leading to the trial being underpowered, our results showed no difference in survival in patients treated with complete lymph node dissection compared with observation only. Consequently, complete lymph node dissection should not be recommended in patients with melanoma with lymph node micrometastases of at least a diameter of 1 mm or smaller. FUNDING: German Cancer Aid.

European Dermatology Forum Guidelines on topical photodynamic therapy.

Topical photodynamic therapy (PDT) is a widely approved therapy for actinic keratoses, squamous cell carcinoma in-situ, superficial and certain thin basal cell carcinomas. Recurrence rates are typically equivalent to existing therapies, although inferior to surgery for nodular basal cell carcinoma. PDT can be used both as a lesional or as a field therapy and has the potential to delay/reduce the development of new lesions. PDT has also been studied for its place in the treatment of, as well as its potential to prevent, superficial skin cancers in immune-suppressed patients, although sustained clearance rates are lower than for immunocompetent individuals. Many additional indications have been evaluated, including photo-rejuvenation and inflammatory and infective dermatoses. This S2 guideline considers all current and emerging indications for the use of topical photodynamic therapy in Dermatology, prepared by the PDT subgroup of the European Dermatology Forum guidelines committee. It presents consensual expert recommendations reflecting current published evidence. An unabridged version of this guideline is available online at: http://www.euroderm.org/edf/index.php/edf-guidelines.

Electrochemotherapy in advanced skin tumors and cutaneous metastases - a retrospective multicenter analysis.

BACKGROUND AND OBJECTIVES: Once classic treatments such as chemotherapy or radiation therapy have been exhausted, only few therapeutic options remain for extensive skin tumors or cutaneous metastases. In such cases, electrochemotherapy may be considered as alternative therapy. PATIENTS AND METHODS: In this retrospective study, clinical features, treatment response, and adverse effects were evaluated in 56 patients treated with electrochemotherapy at six German dermatology departments. RESULTS: The mean age of the patient cohort (14 men, 42 women) was 69.3 years. Included were 20 patients with skin metastasis of advanced malignant melanoma, 13 patients with breast cancer metastases, 15 patients with primary squamous cell carcinoma of the skin or cutaneous metastases of other carcinoma types, and 8 patients with cutaneous lymphoma or sarcoma. The overall response rate was 44.6% (10.7% complete response; 33.9% partial response). By contrast, 31 (55.4%) patients did not respond (12.5% had stable disease; 42.9%, tumor progression). Patients with melanoma and cutaneous lymphoma or sarcoma responded significantly better than those with carcinoma. Roughly one quarter of patients showed an improvement in tumor-related exudation, fetor, and chronic bleeding. CONCLUSION: Showing only few adverse effects, electrochemotherapy was effective in about one half of the patients with advanced tumors. Treatment response appears to depend on the tumor entity.

Progressive nodular histiocytosis.

Progressive nodular histiocytosis (PNH) represents a very rare type of non-Langerhans cell histiocytosis (NLCH). It can be distinguished from other types by the occurrence of yellow to red-brown papules and nodules measuring a few centimeters in size. Histologically the nodules represent spindle-cell xanthogranulomas. We report on two new cases of PNH with novel clinical symptoms. In the first case, the patient had microcytic anemia due to massive iron deposition in the nodules and a progressively worsening limp due to involvement of the soles. The complex therapeutic challenge was effectively managed by successive surgical ablation of all visible lesions. The second patient had epibulbar infiltrates. The clinical variability of PNH leads to considerable overlap with other forms of NLCH.