[Clinical, pathology-associated and molecular biomarkers of hidradenitis suppurativa/acne inversa]. / Klinische, pathologische und molekulare Biomarker der Hidradenitis suppurativa/Acne inversa.

Hidradenitis suppurativa/acne inversa is a scarring disease of the intertrigines that is now intensively researched. Improved pathogenetic understanding has led to the introduction of tumor necrosis factor alpha (TNF­α) inhibition, which represents a major advance over traditional broad immunosuppression and antibiotic administration. In addition, a wide range of newer and promising treatments is or is about to be clinically evaluated. These include various specific antibodies against cytokines and the complement system and small molecules. Successful use of the individual drugs depends on the stratification of suitable patient groups with the help of clinically relevant biomarkers. While molecular investigations have shown a number of possible biomarkers and/or therapeutic target molecules, the detection of robust predictive biomarkers is still in its initial phase. In summary, the therapeutic options for hidradenitis suppurativa/acne inversa are improving through the introduction of new drugs, possibly in combination with surgical interventions, whereby the possibilities for predictive therapeutic decisions through the discovery of biomarkers would revolutionize the chances of therapeutic success.

Loss of Concurrent Regulation of the Expression of BIF-1, BAX, and Beclin-1 in Primary and Metastatic Melanoma.

Melanoma is one of the most aggressive and drug-resistant cancers. Despite novel promising therapeutic strategies, the prognosis of metastatic melanoma patients remains poor and it is often associated with high relapse rates. Endophilin B1, also known as BIF-1, is a multifunctional protein involved in several biological processes such as autophagy and apoptosis. BIF-1 promotes apoptosis through binding to BAX and its translocation to the mitochondrial outer membrane. On the other hand, BIF-1 can interact with Beclin-1 through UVRAG to promote autophagy. Several reports suggest an ambiguous role of BIF-1 in cancer development and progression. For example, it has been demonstrated that the expression of BIF-1 is reduced in both primary and metastatic melanoma and that the reduction of BIF-1 expression is associated with reduced overall survival of melanoma patients. Here we show that the expression of Beclin-1 and active form of BAX are also reduced in the melanoma patients. However, while we observed strong positive correlations between the expression of BIF-1 and Beclin-1 as well as between BIF-1 and BAX in benign nevi, these correlations were lost in the primary and metastatic melanoma cells. These data indicate disruption in the proximal molecular mechanisms which regulate expression of BIF-1, Beclin-1, and BAX in the primary and metastatic melanoma.

[Checkpoint inhibitors-indications and application in melanoma patients]. / Checkpoint-Inhibitoren ­ Indikation und Verwendung bei Melanompatienten.

Since its introduction in 2011 the checkpoint inhibitor ipilimumab, has revolutionized the whole of oncology. After this first major step more checkpoint inhibitors, such as the PD­1 antibodies nivolumab and pembrolizumab have been developed. The results are groundbreaking, especially in advanced malignant melanoma, which only a few years ago led to certain death in most cases after only a few months. Currently, the application of checkpoint inhibitors has been extended to many more tumor entities, with very promising results.

European Dermatology Forum guidelines on topical photodynamic therapy 2019 Part 2: emerging indications - field cancerization, photorejuvenation and inflammatory/infective dermatoses.

In addition to approved indications in non-melanoma skin cancer in immunocompetent patients, topical photodynamic therapy (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 immune-competent individuals. PDT using a nanoemulsion of ALA in a daylight or conventional PDT protocol has been approved for use in field cancerization, although evidence of the potential of the treatment to prevent new SCC remained limited. High-quality evidence supports a strong recommendation for the use of topical PDT in photorejuvenation as well as for acne, refractory warts, cutaneous leishmaniasis and in onychomycosis, although these indications currently lack approvals for use and protocols remain to be optimized, with more comparative evidence with established therapies required to establish its place in practice. Adverse events across all indications for PDT can be minimized through the use of modified and low-irradiance regimens, with a low risk of contact allergy to photosensitizer prodrugs, and no other significant documented longer-term risks with no current evidence of cumulative toxicity or photocarcinogenic risk. The literature on the pharmacoeconomics for using PDT is also reviewed, although accurate comparisons are difficult to establish in different healthcare settings, comparing hospital/office-based therapies of PDT and surgery with topical ointments, requiring inclusion of number of visits, real-world efficacy as well as considering the value to be placed on cosmetic outcome and patient preference. This guideline, published over two parts, considers all current approved 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.

Melanoma of the nail apparatus: a systematic review and meta-analysis of current challenges and prognosis.

Nail apparatus melanoma (NAM) is a rare dermatologic malignancy. Its prognosis is poor because it is often diagnosed late. However, progression and survival of NAM patients have only been studied among small populations. Early biopsy could help to identify suspicious lesions at a less invasive stage. While surgery is generally seen as the treatment of choice, the extent of excision margins and the use of sentinel biopsy remain debated. This systematic review aims to summarize the treatment procedures and observed prognosis in the literature during the last two decades and present pooled survival and progression rates of NAM by using meta-analysis. A systematic review on studies assessing pathology, treatment and prognosis of NAM was carried out up to end of 2018. After evaluation of eligible studies, the main emerging topics were outlined and pooled survival outcomes estimated. A total of 30 articles out of 624 identified records were included for systematic review. Finally, meta-analysis of pooled mortality rates including 18 studies was 4.6 × 100 patient-years (95% CI: 2.7, 6.8) equivalent to 5-year cumulative survival of 77.0%. Additionally, the pooled progression rate based on 17 studies was 6.3 × 100 patient-years (95% CI: 4.1, 8.9) with estimated 5-year cumulative progression-free survival of 68.5%. While the optimal extent of surgical treatment remains debated, prompt biopsy could help to identify early lesions. This is the first study to present pooled survival and progression rates by meta-analysis.

European Dermatology Forum guidelines on topical photodynamic therapy 2019 Part 1: treatment delivery and established indications - actinic keratoses, Bowen's disease and basal cell carcinomas.

Topical photodynamic therapy (PDT) is a widely approved therapy for actinic keratoses, Bowen's disease (squamous cell carcinoma in situ), superficial and certain thin basal cell carcinomas. Recurrence rates when standard treatment protocols are used are typically equivalent to existing therapies, although inferior to surgery for nodular basal cell carcinoma. PDT can be used both as lesional and field therapies and has the potential to delay/reduce the development of new lesions. A protocol using daylight to treat actinic keratoses is widely practised, with conventional PDT using a red light after typically a 3-h period of occlusion employed for other superficial skin cancer indications as well as for actinic keratoses when daylight therapy is not feasible. PDT is a well-tolerated therapy although discomfort associated with conventional protocol may require pain-reduction measures. PDT using daylight is associated with no or minimal pain and preferred by patient. There is an emerging literature on enhancing conventional PDT protocols or combined PDT with another treatment to increase response rates. This guideline, published over two parts, considers all current approved and emerging indications for the use of topical PDT in dermatology, prepared by the PDT subgroup of the European Dermatology Forum guidelines committee. It presents consensual expert recommendations reflecting current published evidence.

Patient and physician satisfaction in an observational study with methyl aminolevulinate daylight photodynamic therapy in the treatment of multiple actinic keratoses of the face and scalp in six European countries.

BACKGROUND: Guidelines recommend treating actinic keratoses (AKs) as they are recognized as precursors of invasive squamous cell carcinoma. OBJECTIVE: The objective of this study was to collect real-world clinical data on the use of methyl aminolevulinate daylight photodynamic therapy (MAL DL-PDT) for the treatment of face and scalp AK in Europe. METHODS: A prospective, multicenter, non-interventional study was conducted in six European countries in patients receiving a single treatment of MAL DL-PDT for face and/or scalp AK. Patient-reported outcomes were assessed by patient questionnaires at baseline and at 3 months after treatment, efficacy was assessed at 3 months using a 6-point global improvement scale, and adverse events (AE) were recorded at each visit. RESULTS: Overall, 325 patients were enrolled from 52 investigational centres, 314 of whom attended the 3-month visit. Most patients had multiple lesions (58.4% had >10 lesions) with lesions mainly located on the scalp (60.0%) and/or forehead (54.2%). AKs were predominantly grade I (39.4%) or grade II (33.2%), and 10.5% of patients had grade III lesions. The proportions of patients and physicians that were overall satisfied to very satisfied with the MAL DL-PDT treatment were 80.4% and 90.3%, respectively. The vast majority of patients (90.0%) would consider using MAL DL-PDT again if needed. Physician-assessed efficacy at 3 months was at least much improved in 83.5% of patients, with 45.9% of patients requiring no retreatment. Related AEs were reported in 15% of patients. CONCLUSION: Use of MAL DL-PDT for multiple face and/or scalp AKs resulted in high levels of patient and physician satisfaction in clinical practice in Europe, reflecting the good efficacy and high tolerability of this convenient procedure.

Increased expression of the interleukin-36 cytokines in lesions of hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a recalcitrant chronic skin disease with poorly understood immunopathogenic mechanisms. Previous studies reported that the interleukin-36 (IL-36) cytokines [IL-36α, IL-36ß, IL-36γ and IL-36 receptor antagonists (IL-36RA)] are important players in the pathogenesis of psoriasis (PS). OBJECTIVE: We aim to determine whether the IL-36 cytokines are upregulated in patients with HS. For this purpose, we analysed local expression and systemic levels of the IL-36 cytokines in patients with HS and compared the results to healthy donors and patients with PS. METHODS: Skin biopsies from healthy donors and HS and PS patients were analysed for expression of the IL-36 cytokines by immunohistochemistry and semiquantitative real-time PCR. The enzyme-linked immunosorbent assay (ELISA) was used to measure systemic levels of the IL-36 cytokines in the serum of the three donor groups. RESULTS: The agonists IL-36α, IL-36ß and IL-36γ were found to be upregulated in HS both systemically and lesionally, while the IL-36RA was not differently regulated in comparison to healthy donors. CONCLUSION: Our findings suggest that the agonistic IL-36 isoforms are upregulated in HS. The relevance of the enhanced production of IL-36 cytokines in HS pathogenesis remains to be determined.

Interleukin-32 is highly expressed in lesions of hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease. Its immunopathogenic mechanisms are still poorly understood. Previous studies demonstrated that the proinflammatory cytokine interleukin (IL)-32 is implicated in the pathogenesis of other inflammatory diseases. OBJECTIVES: To investigate the tissue expression and systemic levels of IL-32, as well as its cellular sources, in patients with HS in comparison with healthy donors and patients with two other inflammatory skin diseases: psoriasis and atopic dermatitis (AD). METHODS: Tissue samples were obtained from healthy skin and lesional HS, psoriatic and AD skin to analyse the expression of IL-32 by immunohistochemistry and semiquantitative real-time polymerase chain reaction. The cellular source of the cytokine was determined by double immunofluorescence staining. Serum from the four donor groups was used to measure systemic levels of IL-32 by enzyme-linked immunosorbent assay. RESULTS: IL-32 was upregulated in patients with HS in both lesional skin and serum when compared with healthy donors and patients with AD or psoriasis. In HS, IL-32 was found to be expressed by natural killer cells, T cells, macrophages and dendritic cells in highly infiltrated areas of the dermis. High IL32 mRNA levels in lesional HS skin coincided with high amounts of T cells and macrophages. Additionally, IL32 mRNA levels in lesional HS skin correlate positively with interferon-γ and IL-17A and negatively with IL-13. CONCLUSIONS: Our findings suggest that IL-32 is overexpressed in HS. Targeting IL-32 may therefore represent a new therapeutic option for the treatment of this recalcitrant disease.

Bowen disease of the nail unit: a retrospective study of 12 cases and their association with human papillomaviruses.

BACKGROUND: Bowen disease is the most frequent nail malignancy, usually seen as a verrucous plaque of the nail in men. OBJECTIVE: To characterize the affected patient population, the clinical manifestations, the diagnostic delay and diagnostic steps, and presence of human papilloma virus (HPV) infection. METHODS: We retrospectively evaluated all cases of Bowen disease of the nail unit over a period of 9 years. Data were obtained from our electronic database. Human papilloma virus genotype was assessed in biopsy specimens by polymerase chain reaction (PCR) sequencing. RESULTS: We identified 12 cases of Bowen disease of the nail unit in 10 patients. Mean age at onset was 52 years, with a male predominance of 90%. The thumb and middle finger were the most frequently affected (66%). Fifty percent of the lesions presented as periungual and subungual verrucous tumours. Patients sought medical evaluation after a mean delay of 5.7 years; histopathological diagnosis was made after a mean delay of 3.2 years. HPV infection was identified in 75% of the cases. CONCLUSIONS: Any recently appeared verrucous lesion of the nail unit in men above the age of 40 years should raise the suspicion of Bowen disease and lead to further histopathological diagnostic procedures.

In vivo confocal microscopy efficacy assessment of daylight photodynamic therapy in actinic keratosis patients.

BACKGROUND: Reflectance confocal microscopy (RCM) is a noninvasive diagnostic technique with an acceptable sensitivity and specificity for actinic keratosis (AK). OBJECTIVES: We evaluated efficacy of daylight photodynamic therapy (DL-PDT) in patients with AK using a new RCM atypia scoring system. MATERIALS AND METHODS: All patients with AK lesions (Grade I-II) were included in our study (2012-15). Baseline clinical, dermoscopy and RCM evaluations were followed by DL-PDT. In the first follow-up, clinical examination, dermoscopy and RCM imaging of the treated area were carried out. Atypia scoring and cell size measurements were used to compare before and after RCM images. RESULTS: From 40 lesions (20 patients with mean age of 75·5 years), complete resolution and partial response of the actinic damage was detected in 80% and 17·5% of lesions, respectively. No cellular atypia was seen in the follow-up RCM images of 57·5% of lesions (n = 23), while in 40% of lesions (n = 16) minimal changes to the honeycomb pattern of the epidermis were seen in the follow-up RCM images (atypia score 1). Only one lesion showed minimal or no clinical response, and a persistent moderate amount of atypia in RCM. Furthermore, atypia score and mean cell size decreased significantly in the follow-up DL-PDT RCM images (P < 0·001, P = 0·001, respectively). CONCLUSIONS: RCM features of actinic damage at cellular level have been shown to correlate well with the results of a clinical assessment of AK lesions. This study confirms that in vivo RCM technology might be an additional technique to monitor the efficacy of DL-PDT for AK.

European S1 guideline for the treatment of hidradenitis suppurativa/acne inversa.

Hidradenitis suppurativa/acne inversa (HS) is a chronic, inflammatory, recurrent, debilitating skin disease of the hair follicle that usually presents after puberty with painful, deep-seated, inflamed lesions in the apocrine gland-bearing areas of the body, most commonly the axillae, inguinal and anogenital regions. A mean disease incidence of 6.0 per 100,000 person-years and an average prevalence of 1% has been reported in Europe. HS has the highest impact on patients' quality of life among all assessed dermatological diseases. HS is associated with a variety of concomitant and secondary diseases, such as obesity, metabolic syndrome, inflammatory bowel disease, e.g. Crohn's disease, spondyloarthropathy, follicular occlusion syndrome and other hyperergic diseases. The central pathogenic event in HS is believed to be the occlusion of the upper part of the hair follicle leading to a perifollicular lympho-histiocytic inflammation. A highly significant association between the prevalence of HS and current smoking (Odds ratio 12.55) and overweight (Odds ratio 1.1 for each body mass index unit) has been documented. The European S1 HS guideline suggests that the disease should be treated based on its individual subjective impact and objective severity. Locally recurring lesions can be treated by classical surgery or LASER techniques, whereas medical treatment either as monotherapy or in combination with radical surgery is more appropriate for widely spread lesions. Medical therapy may include antibiotics (clindamycin plus rifampicine, tetracyclines), acitretin and biologics (adalimumab, infliximab). A Hurley severity grade-relevant treatment of HS is recommended by the expert group following a treatment algorithm. Adjuvant measurements, such as pain management, treatment of superinfections, weight loss and tobacco abstinence have to be considered.

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.