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Background: Oral finasteride and topical minoxidil are the current standard of care for male androgenetic alopecia and a combination of the two treatments can be considered for greater efficacy. Clinical trials of topical finasteride have also yielded promising results, but routine care data are lacking., Aims: To examine patient-reported outcomes of men with androgenetic alopecia who received topical finasteride admixed with minoxidil compared to the current standard of care (oral finasteride)., Methods: Retrospective, cross-sectional study with data from a German direct-to-consumer teledermatology platform between December 2021 and January 2023. Patient-reported outcomes were collected through voluntary follow-up questionnaires provided after 6 weeks on topical finasteride/minoxidil or oral finasteride treatment., Results: A total of 1545 patients who received topical finasteride/minoxidil treatment were included; 238 (15.4%) participated in the follow-up questionnaire. At week six, 62.2% (148/238) reported positive changes in their hair appearance, and 44.1% (105/238) reported an improvement of self-esteem. Treatment-related adverse events were reported in 11.8% (28/238). Full treatment adherence was observed in 74.4% (177/238). Comparing the topical treatment group to those receiving oral finasteride, lower treatment adherence was reported, along with higher rates of local adverse events; no difference was found in the incidence of sexual adverse events., Conclusion: Based on patient-reported outcomes, topical finasteride/minoxidil seems to be effective and well tolerated, but not superior to oral finasteride. Lower treatment adherence for topical usage must be considered when considering treatment options. Additional real-world data are needed to further evaluate the efficacy and safety of topical finasteride/minoxidil., (© 2024 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Background: Skin diseases in patients with skin of colour (Fitzpatrick skin types IV to VI) are underrepresented in dermatology training, which may lead to lower quality of care for these patients. To address this underrepresentation in medical education, a newly developed seminar on skin type diversity using an interactive teaching method was implemented in an undergraduate medical curriculum. This study examined the effects of a seminar on the self-assessed competence of medical students in managing skin conditions in patients with skin of colour., Methods: A questionnaire survey was conducted among fourth-year undergraduate medical students at the University of Hamburg (Germany) between October 2023 and February 2024. Students' self-assessed competence was compared before and after the obligatory seminar (pre- and post-design)., Results: In total, 158 students participated in the survey. After the seminar, knowledge of the presentation of skin diseases in patients with skin of colour and the associated psychological burden, differences in the incidence of skin diseases in different skin types, and the ability to diagnose skin diseases in darker skin types increased. Most participants stated that they wanted to attend more courses on this topic., Discussion: Appropriate courses for medical students can improve their competence in managing different skin diseases in patients with skin of colour. In the future, more attention should be paid to teaching the diversity of skin types in dermatology education., (© 2024. The Author(s).)

Mogamulizumab, a monoclonal antibody directed against CC chemokine receptor 4, is approved as a second-line treatment of mycosis fungoides and Sézary syndrome. One of the most common side effects is mogamulizumab-associated rash (MAR), which can present in a variety of clinical and histological types. Clinically, it can be difficult to differentiate between MAR and progression of the underlying disease, so histological examination is crucial for clinicopathological correlation. Current data analyses suggest that MAR is more common in patients with Sézary syndrome and is associated with a significantly better response to treatment, making the distinction from disease progression particularly important. The management of MAR depends on its severity, and therapy may need to be paused. This article presents three cases from our clinic and reviews the current literature on MAR. It emphasizes the importance of understanding MAR in the management of patients with cutaneous lymphomas., (© 2024 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by Wiley‐VCH GmbH on behalf of Deutsche Dermatologische Gesellschaft.)

Background: The treatment of melanoma has been revolutionized by the use of immune checkpoint inhibition (ICI), but many patients do not benefit. Furthermore, immune-related adverse events may occur during therapy. A predictive biomarker is needed to reliably identify patients benefitting. In lung, renal cell and bladder cancer early C-reactive protein (CRP) kinetics were shown to be a predictive biomarker for ICI., Objective: Here, we investigate early CRP kinetics as predictive biomarker for ICI in melanoma patients., Methods: Two independent prospectively collected cohorts were analysed: Cohort 1 (n = 87) with advanced and Cohort 2 (n = 99) with completely resected melanoma. Patients were stratified by in the dynamics of CRP after ICI initiation: A doubling of baseline CRP within 30 days followed by at least a 30% drop within 3 months was classified as a CRP flare. If no doubling of CRP was reported, but a 30% drop within 3 months, patients were classified as CRP responders and all others as CRP non-responders. Analysed factors included clinical characteristics like S100B and LDH. Median follow-up was 1.5 and 1.7 years for Cohorts 1 and 2., Results: In Cohort 1 CRP flare (n = 12), CRP responders (n = 43) and CRP non-responders (n = 32) with a progression-free survival (PFS) of 0.7, 0.6 and 0.2 years (p = 0.017) and an overall survival (OS) of 2.2, 1.5 and 1.0 years (p = 0.014), respectively. Multivariable Cox analysis showed an independent risk reduction of progression for CRP responders by 62% compared to CRP non-responders (p = 0.001). In Cohort 2 CRP flare (n = 13), CRP responders (n = 70) and CRP non-responders (n = 16) the log-rank analysis showed a significant difference between OS and recurrence-free survival (RFS) curves (p = 0.046 and p = 0.049)., Conclusion: Early CRP kinetics could indicate a response to ICI with improved OS and RFS/PFS. CRP flare and CRP response indicating significantly improved outcomes compared to CRP non-responders., (© 2024 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Circulating tumor DNA (ctDNA) is the cornerstone of liquid biopsy diagnostics, revealing clinically relevant genomic aberrations from blood of cancer patients. Genomic analysis of single circulating tumor cells (CTCs) could provide additional insights into intra-patient heterogeneity, but it requires whole-genome amplification (WGA) of DNA, which might introduce bias. Here, we describe a novel approach based on mass spectrometry for mutation detection from individual CTCs not requiring WGA and complex bioinformatics pipelines. After establishment of our protocol on tumor cell line-derived single cells, it was validated on CTCs of 33 metastatic melanoma patients and the mutations were compared to those obtained from tumor tissue and ctDNA. Although concordance with tumor tissue was superior for ctDNA over CTC analysis, a larger number of mutations were found within CTCs compared to ctDNA (p = 0.039), including mutations in melanoma driver genes, or those associated with resistance to therapy or metastasis. Thus, our results demonstrate proof-of-principle data that CTC analysis can provide clinically relevant genomic information that is not redundant to tumor tissue or ctDNA analysis., (© 2024. The Author(s).)

Background: Pulsed-dye lasers (PDL) are one of the standard therapies for rosacea, but alternatives are needed., Aims: To compare the efficacy and safety of the variable-sequenced, large-spot 532 nm KTP laser to the 595 nm PDL in treating rosacea., Materials and Methods: A prospective, controlled, evaluator-blinded study. Patients were treated with either a KTP or PDL with 1-3 sessions at intervals of 6-8 weeks. A follow-up visit was scheduled on Week 6 post-treatment. Clinical outcome was assessed by computer-assisted analysis and by patients and two blinded dermatologists. Pain intensity during treatment and adverse events were documented., Results: Forty-five patients (mean age 51 years) were allocated in a 2:1 ratio to either the KTP or PDL. Erythema in both treatment arms decreased significantly (p < 0.01). Clinical evaluation revealed high improvement. Mean pain intensity was significantly lower with the KTP (2.5/10) than with the PDL (4.1/10). Both lasers showed a good safety profile. Relevant purpura was only seen in the PDL group., Conclusions: Both the variable-sequenced, large-spot KTP and the PDL demonstrated comparable efficacy in treatment of rosacea. Regarding safety, the KTP exhibited fewer post-treatment reactions. The KTP might serve as a potential alternative to PDL in the treatment of rosacea., (© 2024 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Background: Adjuvant treatment of stage II-IV melanoma with PD-1-based immune checkpoint inhibitors (ICI) has improved relapse-free survival (RFS) and has therefore become a standard-of-care treatment option. Approximately 25%-30% of patients still recur within 1 year. Predictive biomarkers reflecting real-world data are desired. The predictive relevance of tumour tissue PD-L1 expression in the adjuvant setting remains inconclusive., Objectives: This retrospective, observational study was conducted to evaluate the value of PD-L1 expression scores in different tumour tissue locations in predicting response towards adjuvant immunotherapeutic treatment., Methods: Tumour tissue taken prior to anti-PD-1 adjuvant ICI in 243 stage II-IV melanoma patients was collected at University Skin Cancer Center Hamburg. PD-L1 expression was evaluated on immune cells (ICS), tumour cells (TPS) and combined (CPS). Scores were determined by independent pathological physician quantification and correlated with therapy outcome at different cut-off (CO) levels (relapse-free survival, RFS) for different tumour tissue locations (primary tumour, metastases)., Results: A total of 104 patients were eligible for analysis. Positivity of ICS, TPS and CPS showed no predictive RFS outcome association at different CO levels when analysed irrespective of tissue origin. In primary tumours, ICS at CO 1% showed a significantly improved RFS upon positivity (HR 0.22). In contrast, positivity to TPS (CO 1%) correlated significantly and independently with improved RFS when evaluated in metastatic tumour tissue specimens (HR 0.37)., Conclusions: PD-L1 tumour tissue expression may serve as a predictive biomarker for adjuvant ICI treatment response stratification in melanoma, but caution should be spent on the origin of tumour tissue analysed. The cell-type relevant for the predictive value of PD-L1 expression is tissue-specific with immune cells being important in primary tumours while tumour cells are key in metastases. The present results should be validated in a multicentre cohort., (© 2024 The Author(s). Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: Pulsed dye lasers (PDL) are currently the first-line treatment of port-wine birthmarks (PWB). Due to high maintenance costs and instable technology, alternative methods are needed., Objectives: To compare clinical outcomes of a variable-sequenced, long-pulsed 532-nm potassium titanyl-phosphate (KTP) laser and PDL on treating PWB., Methods: A prospective, randomized, split-side study. Patients were treated with a KTP laser and PDL with 1 to 5 sessions at intervals of 6-8 weeks. A follow-up visit was scheduled 6 weeks post-treatment. Efficacy was evaluated through colorimetric analysis, area reduction measurements and clinical evaluations by two blinded investigators based on photo documentation. Subjects provided rating of pain intensity during treatment, post-treatment reactions and satisfaction. Safety was measured by adverse events. Maintenance issues of the laser systems were documented., Results: A total of 35 patients (mean age 42.1 years) were enrolled. 63% were female. Patients received 2.4 (SD 1.4; 1-5) treatment sessions. Colorimetric analysis indicated a comparable clearance effect in PWB of both KTP laser and PDL. Independent investigators rated clinical appearance to be significantly improved compared to baseline. No significant difference was observed between both laser systems. Regarding post-treatment reactions, the KTP laser caused less swelling, purpura and crusts. 96% would recommend both treatment modalities. Patients were satisfied with both laser systems. During the study, PDL systems malfunctioned for 6.6 months in total. For the KTP laser, we did not observe any system failures., Conclusion: Our data indicate that the KTP laser of the latest generation with large-spot sizes, subpulse technology and cryogen cooling has a comparable efficacy to the PDL in treating PWB. In addition, KTP laser is associated with greater tolerability, fewer technical failures and lower repair costs. Further prospective studies are required to determine the true effectiveness of the KTP laser in PWB treatment. This study was preregistered in Clinicaltrials.gov (NCT05771298)., (© 2023 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: Immune checkpoint inhibition has revolutionized melanoma therapy, but many patients show primary or secondary resistance. Biomarkers are, therefore, urgently required to predict response prior to the initiation of therapy and to monitor disease progression., Methods: In this prospective study, we analyzed the serum C-C motif chemokine ligand 20 (CCL20) concentration using an enzyme-linked immunosorbent assay. Blood was obtained at baseline before the initiation of immunotherapy with anti-PD-1 monotherapy or Nivolumab and Ipilimumab in advanced melanoma patients (stages III and IV) enrolled at the University Medical Center Hamburg-Eppendorf. The CCL20 levels were correlated with clinico-pathological parameters and disease-related outcomes., Results: An increased C-C motif chemokine ligand 20 (CCL20) concentration (≥0.34 pg/mL) at baseline was associated with a significantly impaired progression-free survival (PFS) in the high-CCL20 group (3 months (95% CI: 2-6 months) vs. 11 months (95% CI: 6-26 months)) ( p = 0.0033) and could be identified as an independent negative prognostic factor for PFS in univariate (Hazard Ratio (HR): 1.98, 95% CI 1.25-3.12, p = 0.004) and multivariate (HR: 1.99, 95% CI 1.21-3.29, p = 0.007) Cox regression analysis, which was associated with a higher risk than S100 (HR: 1.74). Moreover, high CCL20 levels were associated with impaired overall survival (median OS not reached for low-CCL20 group, p = 0.042) with an HR of 1.85 (95% CI 1.02-3.37, p = 0.043) in univariate analysis similar to the established prognostic marker S100 (HR: 1.99, 95% CI: 1.02-3.88, p = 0.043)., Conclusions: CCL20 may represent a novel blood-based biomarker for the prediction of resistance to immunotherapy that can be used in combination with established strong clinical predictors (e.g., ECOG performance score) and laboratory markers (e.g., S100) in advanced melanoma patients. Future prospective randomized trials are needed to establish CCL20 as a liquid biopsy-based biomarker in advanced melanoma.

Background: One of the areas of care in dermatosurgery is the surgical treatment of diseases of the nail organ. Side effects and complications after nail surgery were investigated by telephone follow-up (TFU), and its suitability for postoperative monitoring and consultation was assessed., Patients and Methods: All patients who underwent nail surgery at the Department of Dermatology at the Ludwigshafen City Hospital from October 2019 to December 2021 in outpatient setting were contacted by telephone on the second to third postoperative day and questioned in a standardized manner about postoperative complaints and counselled if necessary., Results: A total of 100 cases were followed up. The most common procedures performed were phenol matricectomy (41%), nail avulsion (16%), and nail matrix biopsies (9%). 50% and 21% of patients reported pain on the day of the procedure and the day after surgery, respectively. After nail avulsion, pain was statistically significantly more frequently reported on the day following the procedure and pain medication was statistically significantly more frequently required (p  =  0.002). Serious adverse events did not occur after nail surgery. 10% of the respondents raised specific questions and needed counseling by TFU., Conclusions: All nail surgeries were well tolerated in the outpatient setting. Pain was the most common side effect, although only half of all patients reported pain on the day of surgery and only 21% on the day after the procedure. The TFU proved to be an effective and practical as well as easy to establish method for postoperative follow-up and consultation after outpatient nail surgery., (© 2024 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by Wiley‐VCH GmbH on behalf of Deutsche Dermatologische Gesellschaft.)

Laser-assisted drug delivery (LADD) is a treatment method to enhance the penetration of pharmaceuticals through the skin. The aim of the present study is to track hyaluronic acid (HA) and analyse its effect on human skin in vivo after ablative fractional laser (AFL) treatment. Healthy male and female subjects were recruited. Four areas were marked on their forearms of each volunteer, and each area was assigned to one of the following treatment options: AFL + HA, AFL only, HA only or untreated control. A carbon dioxide laser was used for the AFL treatment. Follow-up measurements were scheduled 30 min and 30 days after treatment using multiphoton tomography equipped with fluorescence lifetime imaging (MPT-FLIM). A total of 11 subjects completed the study. By detecting fluorescence lifetimes, the HA and the anaesthetic ointment were clearly distinguishable from surrounding tissue. After AFL treatment, HA could be visualized in all epidermal and upper dermal layers. In contrast, HA in intact skin was only detected in the superficial layers at distinctly lower levels. The applied HA gel seemed to have beneficial properties for the wound healing process after laser treatment. LADD has proven to be a fast and effective method to increase HA uptake into the skin, allowing for improved hydration and skin rejuvenation over time. Furthermore, LADD could be a beneficial treatment option in laser resurfacing. MPT-FLIM proved to be an appropriate diagnostic tool for drug delivery tracking and monitoring of treatment response for individualized therapy adjustment., (© 2023 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

Necrobiotic xanthogranuloma is a rare disease that is part of the non-Langerhans cell histiocytoses. It is characterized by yellowish skin lesions, which are typically periorbitally localized. Extracutaneous manifestations of all organs are possible and can cause potentially life-threatening complications. The disease also belongs to the facultative paraneoplasias and is often associated with paraproteinemia. These aspects should be considered regarding further diagnostics. Due to the rarity of the disease, there are no standardized guidelines for therapy so far. The combination of prednisolone and chlorambucil as well as intravenous immunoglobulins seem to be effective therapeutic options. We present four cases from our clinic as well as the current results of the literature in this mini-review and would like to highlight the therapeutic challenge as well as the need for the development of guidelines., (© 2023 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Objective: The use of direct-to-consumer (DTC) teledermatology platforms has increased, particularly for androgenetic alopecia (AGA). However, little is known about the efficacy and safety of these platforms. This study aimed to investigate the patient-reported treatment outcomes and safety of DTC teledermatology for the finasteride treatment of male AGA., Methods: This retrospective, cross-sectional study used data from a German DTC platform for finasteride treatment between December 2021 and January 2023. Patient-reported outcomes were collected through voluntary follow-up questionnaires provided to the patients six weeks after the first prescription to assess treatment outcomes and safety., Results: Data collection included 2269 patients. Of all patients who answered the follow-up questionnaire ( n  = 191), 79% (150 out of 191) self-reported positive changes in hair appearance, and 59% (113 out of 191) reported an improvement in self-esteem under treatment. Patients with self-reported positive changes in hair appearance were more likely to report improved self-esteem ( P  < 0.0001). Treatment-related adverse events occurred in 12% (22 out of 191) of the patients. Full treatment adherence was reported in 87% (167 out of 191) of patients., Conclusion: From the patient's perspective, DTC teledermatology has the potential to improve hair appearance and self-esteem. Our results suggest that it may be an effective and safe treatment option for men with AGA, justifying low-threshold access. However, treatment-related adverse events should be closely monitored during follow-up. Further studies are required to evaluate the long-term effects of the DTC teledermatology treatment. By collecting real-world data, teledermatology platforms could be useful beyond their primary focus and could play an important role in the context of future research., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JB, FS, and JV: Employees of Wellster Healthtech Group. JB: Member of the Medical Advisory Board of Wellster Healthtech Group. JB: Stock options. The other authors declare no conflicts of interest., (© The Author(s) 2023.)

Background: There is a high demand for dermatological care in Germany. As use of teledermatology has increased significantly, this study aimed to investigate the impact of teledermatology on patient care. Methods: This retrospective cross-sectional study used data from a direct-to-consumer teledermatology platform using store-and-forward technology available in Germany between July 2021 and April 2022. Additional patient characteristics were collected using a voluntary follow-up questionnaire, 28 days after teleconsultation. Results: Data of 1,999 enrolled patients were evaluated. Patients had a mean age of 36 years, and 61.2% (1,223/1,999) lived in a rural residence. The most common diagnoses included eczema (36.0%, 701/1,946), fungal diseases (15.4%, 299/1,946), and acne (12.5%, 243/1,946). The follow-up questionnaire was answered by 166 patients (8.3%, 166/1,999). In total, 42.8% (71/166) of patients had undergone no previous medical consultation. The most frequent reason for using teledermatology was the waiting time for a dermatology outpatient appointment (62.0%, 103/166). A total of 62.0% (103/166) participants rated the treatment success as good or very good, while 86.1% (143/166) rated the quality of telemedical care as equal or better to that of an outpatient visit. Conclusion: This study showed that patients often use teledermatology because of functional barriers (waiting times). In this cohort, the diagnoses strongly corresponded to reasons for outpatient presentation. Most patients rated the quality of teledermatology service as at least equivalent to that of outpatient physician visits and reported treatment success. Thus, teledermatology can relieve the burden of outpatient care while providing high benefits from the patient's perspective.

Background : Adherence to dermatological treatment is described as poor. Empathy and open communication in the physician-patient relationship has been proven to improve adherence. As direct-to-consumer teledermatology enables patients to access dermatological consultations without in-person interactions, we hypothesized treatment adherence in teledermatology to be low. Methods : The objective of the study was to examine treatment adherence in teledermatology. This retrospective cross-sectional study used data from patients treated through a German direct-to-consumer teledermatology platform between July 2021 and April 2022. Additional information was collected through voluntary follow-up questionnaires provided to patients to assess individual treatment success, treatment-related adverse events, and treatment adherence. Results : Data collection included 771 patients; 61.6% (475/771) were women (mean age 35 years). In 46% (355/771), skin disease had been present for <3 months before teleconsultation. Of all patients who answered the follow-up questionnaire ( n  = 228), 28.5% (65/228) reported treatment-related adverse events, with skin dryness being the most common (56.9%, 37/65). Adverse events resulting in treatment discontinuation were reported in 1.3% (3/228) of all cases. Improvement in skin condition on therapy was described by 75.4% (172/228). In 85.5% (195/228), full treatment adherence was reported. Conclusion : This is the first study worldwide to examine data on treatment adherence in direct-to-consumer-teledermatology. Despite the lack of doctor-patient interaction, the results of our study demonstrate that most patients show high treatment adherence. Possible drivers contributing to high compliance rates could be the high proportion of new-onset skin diseases, the high treatment success of the prescribed therapies, and the low rate of serious adverse events.

Cancer metastasis is a complex process. After their intravasation into the circulation, the cancer cells are exposed to a harsh environment of physical and biochemical hazards. Whether circulating tumor cells (CTCs) survive and escape from blood flow defines their ability to metastasize. CTCs sense their environment with surface-exposed receptors. The recognition of corresponding ligands, e.g., fibrinogen, by integrins can induce intracellular signaling processes driving CTCs' survival. Other receptors, such as tissue factor (TF), enable CTCs to induce coagulation. Cancer-associated thrombosis (CAT) is adversely connected to patients' outcome. However, cancer cells have also the ability to inhibit coagulation, e.g., through expressing thrombomodulin (TM) or heparan sulfate (HS), an activator of antithrombin (AT). To that extent, individual CTCs can interact with plasma proteins, and whether these interactions are connected to metastasis or clinical symptoms such as CAT is largely unknown. In the present review, we discuss the biological and clinical relevance of cancer-cell-expressed surface molecules and their interaction with plasma proteins. We aim to encourage future research to expand our knowledge of the CTC interactome, as this may not only yield new molecular markers improving liquid-biopsy-based diagnostics but also additional targets for better cancer therapies.

Background: The picosecond laser is one of the latest laser systems in dermatology and was originally developed to optimize tattoo removal. Advances in this technology has expanded the use of the picosecond laser to numerous other indications., Objectives: This article provides an overview of the technical background as well as the indications of the picosecond laser in dermatological laser medicine and elucidates the possibilities and limits of this laser system., Materials and Methods: The article is based on a review of the current literature as well as experience from clinical practice in a university laser department., Results: The picosecond laser enables a particularly gentle and effective treatment due to ultra-short pulses and the principle of laser-induced optical breakdown. Compared to Q‑switched lasers, the picosecond laser has fewer side effects and is associated with lower pain intensity and shorter downtime. In addition to the removal of tattoos and pigmentary disorders, it is also used in the treatment of scars and rejuvenation., Conclusions: The picosecond laser has a wide range of indications in dermatological laser medicine. The current data indicate that the laser is an effective method with few side effects. Further prospective studies have to be conducted to assess the efficacy, tolerability and patient satisfaction in an evidence-based manner., (© 2023. The Author(s).)

Background: An increased incidence of thrombotic complications associated with an increased mortality rate has been observed under immune checkpoint inhibition (ICI). Recent investigations on the coagulation pathways have highlighted the direct role of key coagulatory proteins and platelets in cancer initiation, angiogenesis and progression. The aim of this study was to evaluate the prognostic value of von Willebrand factor (vWF) and its regulatory enzyme a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), D-dimers and platelets in a cohort of patients with metastatic melanoma receiving ICI., Methods: In a prospective cohort of 83 patients with metastatic melanoma, we measured the systemic levels of vWF-antigen (vWF:Ag), ADAMTS13 activity, D-dimers and platelets, before the beginning of the treatment (baseline), and 6, 12 and 24 weeks after. In parallel, we collected standard biological parameters used in clinical routine to monitor melanoma response (lactate deshydrogenase (LDH), S100). The impact of neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) on overall survival (OS) in patients receiving ICI was assessed. Univariable and multivariable Cox proportional models were then used to investigate any potential association of these parameters to clinical progression (progression-free survival (PFS) and OS). Baseline values and variations over therapy course were compared between primary responders and resistant patients., Results: Patients with melanoma present with dysregulated levels of vWF:Ag, ADAMTS13 activity, D-dimers, LDH, S100 and CRP at the beginning of treatment. With a median clinical follow-up of 26 months, vWF:Ag interrogated as a continuous variable was significantly associated with PFS in univariate and multivariate analysis (HR=1.04; p=0.007). Lower values of vWF:Ag at baseline were observed in the primary responders group (median: 29.4 µg/mL vs 32.9 µg/mL; p=0.048) when compared with primary resistant patients. As for OS, we found an association with D-dimers and ADAMTS13 activity in univariate analysis and vWF:Ag in univariate and multivariate analysis including v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation and Eastern Cooperative Oncology Group (ECOG) performance status. Follow-up over the course of treatment depicts different evolution profiles for vWF:Ag between the primary response and resistance groups., Conclusions: In this prospective cohort, coagulatory parameters such as ADAMTS13 activity and D-dimers are associated with OS but baseline vWF:Ag levels appeared as the only parameter associated with response and OS to ICI. This highlights a potential role of vWF as a biomarker to monitor ICI response of patients with malignant melanoma., Competing Interests: Competing interests: J-CS, LK, ATB, CM, AA, SVS, MS, WH, CS, BD, ILH, RR, TH, JK, IH, GG, KP and SWS declare no competing interest. CG is a member of the advisory board and has received honoraria and travel expenses from Almirall, Amgen, Beiersdorf, BioNTech, Bristol-Myers Squibb, Immunocore, Janssen, MSD Sharp & Dohme, Novartis, Pierre-Fabre, Roche, Sanofi Genzyme, SUN Pharma, Sysmex/Inostics, outside the submitted work. CG holds shares of Dermagnostix., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In recent years, severe ocular complications after dermatological laser therapies have been reported. One hypothesis is thermal damage due to heating of the metal eye shields. The aim of the present study is to evaluate the safety of ocular metal eye shields during laser therapy of the periocular region. For the experimental study, porcine eyelids were exposed to continuously increasing laser energy and multiple pulses using a number of dermatologic laser systems. Temperature differences of the convex and concave surface of metal eye shields were constantly measured using a thermocouple. Maximum increase of the convex surface of shields was + 8.9 °C (± 0.1 °C) provided by the long-pulsed alexandrite laser (20-25-J/cm 2 energy, 15-mm spot size, 20-ms pulse duration, 1 Hz). Present data indicate that metal eye shields provide sufficient thermal protection when clinically used laser parameters are applied. Other safety precautions continue to be essential to protect both the patient and the laser operator. These include the use of nonreflective metal eye shields, precise knowledge of laser physics, and a clear understanding of how they interact with ocular and periocular anatomy., (© 2023. The Author(s).)

Crossing the blood-brain barrier is a crucial, rate-limiting step of brain metastasis. Understanding of the mechanisms of cancer cell extravasation from brain microcapillaries is limited as the underlying cellular and molecular processes cannot be adequately investigated using in vitro models and endpoint in vivo experiments. Using ultrastructural and functional imaging, we demonstrate that dynamic changes of activated brain microcapillaries promote the mandatory first steps of brain colonization. Successful extravasation of arrested cancer cells occurred when adjacent capillary endothelial cells (EC) entered into a distinct remodeling process. After extravasation, capillary loops were formed, which was characteristic of aggressive metastatic growth. Upon cancer cell arrest in brain microcapillaries, matrix-metalloprotease 9 (MMP9) was expressed. Inhibition of MMP2/9 and genetic perturbation of MMP9 in cancer cells, but not the host, reduced EC projections, extravasation, and brain metastasis outgrowth. These findings establish an active role of ECs in the process of cancer cell extravasation, facilitated by cross-talk between the two cell types. This extends our understanding of how host cells can contribute to brain metastasis formation and how to prevent it., Significance: Tracking single extravasating cancer cells using multimodal correlative microscopy uncovers a brain seeding mechanism involving endothelial remodeling driven by cancer cell-derived MMP9, which might enable the development of approaches to prevent brain metastasis. See related commentary by McCarty, p. 1167., (©2023 American Association for Cancer Research.)

Purpose: The number of online prescription platforms (OPPs) offering telemedical diagnosis and treatment, including finasteride, for androgenetic alopecia (AA) by using medical questionnaires (MQs) has increased. This type of care delivery differs completely from traditional forms. This study aimed to investigate a potential paradigm shift in AA treatment by measuring the extent of traffic generated by OPPs that exclusively treat AA and furthermore by characterizing sociodemographic features of men undergoing finasteride treatment from an OPP in Germany., Patients and Methods: Examination of three OPPs (Keeps, Shapiro MD, Myspring), offering finasteride treatment via MQ between Q1 2018 and Q1 2022 was performed by using SEMRush, a marketing software platform for traffic analysis. Further data regarding sociodemographic characteristics were collected from Myspring by recruiting men with AA who obtained finasteride prescriptions between March 2021 and January 2022., Results: A high number of unique quarterly visitors was recorded. The number of visitors increased on all platforms (Keeps 846%, Shapiro MD 109%, Myspring 427%). Most patients had accessed the platforms from mobile devices. Further data from Myspring included a total of 2904 men. Of all patients who answered the follow-up questionnaire (n = 177), 33.9% had been referred to the platform by television advertising. Of all respondents, 21.5% reported a monthly net income below 1000 euros. 45.2% of responding patients reported being single, while 15.3% considered themselves homosexual, and 4.5% bisexual. Convenience was the most common reason indicated for using an OPP (79.1%)., Conclusion: The tremendous increase in the number of visits to OPPs for AA suggests a paradigm shift in medical care, particularly regarding MQ-based finasteride treatment. Sociodemographic data and reasons for platform use suggest that the shift away from traditional care models may increase in the future. The broad use of these digital health services warrants further investigation, particularly regarding patient safety., Competing Interests: Finn Abeck certifies that all potential conflicts of interest, including specific interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript, are as follows: Florian Schröder and Johannes von Büren: employees of Wellster Healthtech Group. Johannes von Büren: Member of the medical advisory board of Wellster Healthtech Group and owns stock options from Wellster Healthtech Group. All other authors declare no conflicts of interest in this work., (© 2023 Abeck et al.)

Background and Objectives: Skin diseases are a common reason for consultations in pediatric practice. The present study aims to characterize the dermatological requests of resident pediatric specialists using teledermatology in Germany., Patients and Methods: This analysis of consultation requests, submitted by pediatricians to a designated pediatric dermatologist via a telemedical consultation system (PädExpert) using the store-and-forward technology, was performed between February 2021 and December 2021., Results: The study analysis included 504 telemedical consultation requests. The mean age of the patients was 6.5 ± 5.0 years with 45.5% of the patients being female. Telemedicine was useful in providing a definite diagnosis in 88.3%. The diagnoses were most frequently assigned to the group of infectious skin diseases (28.8%). Referral to a dermatologist was recommended in 11.5%. The requests were answered on the same day in 63.8% of the cases., Conclusions: The study data shows the great potential of teledermatology to improve access for children with skin diseases to specialized dermatological care. Another advantage is its function as a triage instrument. Since most cases could be managed by teledermatology only, it is possible to reduce the need for an in-person visit to the dermatologist, thus saving resources., (© 2023 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Human prepubertal testicular tissues are rare, but organ culture conditions to develop a system for human in vitro-spermatogenesis are an essential option for fertility preservation in prepubertal boys subjected to gonadotoxic therapy. To avoid animal testing in line with the 3Rs principle, organ culture conditions initially tested on human adult testis tissue were applied to prepubertal samples ( n = 3; patient ages 7, 9, and 12 years). Tissues were investigated by immunostaining and transmission electron microscopy (TEM), and the collected culture medium was profiled for steroid hormones by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Culture conditions proved suitable for prepubertal organ culture since SSCs and germ cell proliferation could be maintained until the end of the 3-week-culture. Leydig cells (LCs) were shown to be competent for steroid hormone production. Three additional testis tissues from boys of the same age were examined for the number of germ cells and undifferentiated spermatogonia (SPG). Using TEM micrographs, eight tissues from patients aged 1.5 to 13 years were examined, with respect to the sizes of mitochondria (MT) in undifferentiated SPG and compared with those from two adult testicular tissues. Mitochondrial sizes were shown to be comparable between adults and prepubertal boys from approximately 7 years of age, which suggests the transition of SSCs from normoxic to hypoxic metabolism at about or before this time period.

Introduction: The intravascular formation of neutrophil extracellular traps (NETs) is a trigger for coagulation and blood vessel occlusion. NETs are released from neutrophils as a response to strong inflammatory signals in the course of different diseases such as COVID-19, cancer or antiphospholipid syndrome. NETs are composed of large, chromosomal DNA fibers decorated with a variety of proteins such as histones. Previous research suggested a close mechanistic crosstalk between NETs and the coagulation system involving the coagulation factor XII (FXII), von Willebrand factor (VWF) and tissue factor. However, the direct impact of NET-related DNA fibers on blood flow and blood aggregation independent of the coagulation cascade has remained elusive., Methods: In the present study, we used different microfluidic setups in combination with fluorescence microscopy to investigate the influence of neutrophil-derived extracellular DNA fibers on blood rheology, intravascular occlusion and activation of the complement system., Results: We found that extended DNA fiber networks decelerate blood flow and promote intravascular occlusion of blood vessels independent of the plasmatic coagulation. Associated with the DNA dependent occlusion of the flow channel was the strong activation of the complement system characterized by the production of complement component 5a (C5a). Vice versa, we detected that the local activation of the complement system at the vascular wall was a trigger for NET release., Discussion: In conclusion, we found that DNA fibers as the principal component of NETs are sufficient to induce blood aggregation even in the absence of the coagulation system. Moreover, we discovered that complement activation at the endothelial surface promoted NET formation. Our data envisions DNA degradation and complement inhibition as potential therapeutic strategies in NET-induced coagulopathies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Burmeister, Vidal-y-Sy, Liu, Mess, Wang, Konwar, Tschongov, Häffner, Huck, Schneider and Gorzelanny.)

Background: Radiofrequency microneedling (RFMN) treatment is the latest generation of fractional skin rejuvenation methods., Objective: To evaluate the efficacy, safety, tolerability and patient satisfaction of RFMN treatment for skin rejuvenation of the lower face and neck area., Materials and Methods: A prospective, intraindividual, controlled study. Subjects were treated with a fractional insulated RFMN system with 1 to 3 sessions at intervals of 4 to 12 weeks. Follow-up visits were scheduled on Day 90 and 180 posttreatment. Outcome was assessed by volume analysis of standardized 3-dimensional imaging, and validated clinical scales were rated by the physician, a blinded investigator, and patients., Results: Thirty patients (mean age 55.5 years, Fitzpatrick skin type I-IV) were included. Mean submental volume difference was -4.72 cm3 (±10.07 cm3; range -26.65 cm3 to +16.01 cm3). Physician, blinded investigator, and subjects rated the clinical outcome as highly improved. Mean pain intensity was 5.61/10 on Numeric Rating Scale. Beside slight swelling and redness, no relevant downtime has been observed., Conclusion: Fractional RFMN treatment is a safe and effective technique for rejuvenation of the lower face, jawline, and neck region. Sufficient pain management should be provided. Data indicated low to no downtime and high patient satisfaction., (Copyright © 2022 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Immune checkpoint inhibition (ICI) has yielded remarkable results in prolonging survival of metastatic melanoma patients but only a subset of individuals treated respond to therapy. Success of ICI treatment appears to depend on the number of tumor-infiltrating effector T-cells, which are known to be influenced by activated eosinophils. To verify the co-occurrence of activated eosinophils and T-cells in melanoma, immunofluorescence was performed in 285 primary or metastatic tumor tissue specimens from 118 patients. Moreover, eosinophil counts and activity markers such as eosinophil cationic protein (ECP) and eosinophil peroxidase (EPX) were measured in the serum before therapy start and before the 4th infusion of ICI in 45 metastatic unresected melanoma patients. We observed a positive correlation between increased tumor-infiltrating eosinophils and T-cells associated with delayed melanoma progression. High baseline levels of eosinophil count, serum ECP and EPX were linked to prolonged progression-free survival in metastatic melanoma. Our data provide first indications that activated eosinophils are related to the T-cell-inflamed tumor microenvironment and could be considered as potential future prognostic biomarkers in melanoma.

Ingenol mebutate (IM) is highly effective in the treatment of human papillomavirus (HPV)-induced anogenital warts (AGW) leading to fast ablation within hours. However, the exact mode of action is still largely unknown. We performed dermoscopy, in vivo confocal microscopy (CLM), histology, immunohistochemistry, and immunofluorescence to gain insights in mechanisms of IM treatment in AGW. In addition, we used in vitro assays (ELISA, HPV-transfection models) to further investigate in vivo findings. IM treatment leads to a strong recruitment of neutrophils with thrombosis of small skin vessels within 8 h, in a sense of immunothrombosis. In vivo and in vitro analyses showed that IM supports a prothrombotic environment by endothelial cell activation and von Willebrand factor (VWF) secretion, in addition to induction of neutrophil extracellular traps (NETosis). IM superinduces CXCL8/IL-8 expression in HPV-E6/E7 transfected HaCaT cells when compared to non-infected keratinocytes. Rapid ablation of warts after IM treatment can be well explained by the observed immunothrombosis. This new mechanism has so far only been observed in HPV-induced lesions and is completely different from the mechanisms we see in the treatment of transformed keratinocytes in actinic keratosis. Our initial findings indicate an HPV-specific effect, which could be also of interest for the treatment of other HPV-induced lesions. Larger studies are now needed to further investigate the potential of IM in different HPV tumors.

With increased popularity of decorative tattoos, awareness of tattoo-based dermatological complications has been raised. Health issues include a broad spectrum dominated by allergies and infections. To examine the etiopathology and prognose the outcome of an appropriate therapy, a non-invasive intravital diagnostic approach is indicated. The present pilot study introduces multiphoton tomography equipped with fluorescence lifetime imaging as a diagnostic technique to examine the morphological and metabolic status of tattooed human skin at patient's bedside. The distributing course of tattoo particles can be visualised over time. By providing optical biopsies, inflammation-based alterations in freshly tattooed skin and tattoo complications can be analysed. The study concludes that multiphoton tomography combined with fluorescence lifetime imaging is a suitable technique for in vivo visualisation of tattoo pigments as well as for the assessment of quantitative and qualitative skin changes after injection of tattoo ink into human skin., (© 2022 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

The microenvironment of malignant melanomas defines the properties of tumor blood vessels and regulates infiltration and vascular dissemination of immune and cancer cells, respectively. Previous research in other cancer entities suggested the complement system as an essential part of the tumor microenvironment. Here, we confirm activation of the complement system in samples of melanoma patients and murine melanomas. We identified the tumor endothelium as the starting point of the complement cascade. Generation of complement-derived C5a promoted the recruitment of neutrophils. Upon contact with the vascular endothelium, neutrophils were further activated by complement membrane attack complexes (MACs). MAC-activated neutrophils release neutrophil extracellular traps (NETs). Close to the blood vessel wall, NETs opened the endothelial barrier as indicated by an enhanced vascular leakage. This facilitated the entrance of melanoma cells into the circulation and their systemic spread. Depletion of neutrophils or lack of MAC formation in complement component 6 (C6)-deficient animals protected the vascular endothelium and prevented vascular intravasation of melanoma cells. Our data suggest that inhibition of MAC-mediated neutrophil activation is a potent strategy to abolish hematogenous dissemination in melanoma.

Heparan sulfate (HS), a highly negatively charged glycosaminoglycan, is ubiquitously present in all tissues and also exposed on the surface of mammalian cells. A plethora of molecules such as growth factors, cytokines or coagulation factors bear HS binding sites. Accordingly, HS controls the communication of cells with their environment and therefore numerous physiological and pathophysiological processes such as cell adhesion, migration, and cancer cell metastasis. In the present work, we found that HS exposed by blood circulating melanoma cells recruited considerable amounts of plasmatic von Willebrand factor (vWF) to the cellular surface. Analyses assisted by super-resolution microscopy indicated that HS and vWF formed a tight molecular complex. Enzymatic removal of HS or genetic engineering of the HS biosynthesis showed that a reduced length of the HS chains or complete lack of HS was associated with significantly reduced vWF encapsulation. In microfluidic experiments, mimicking a tumor-activated vascular system, we found that vWF-HS complexes prevented vascular adhesion. In line with this, single molecular force spectroscopy suggested that the vWF-HS complex promoted the repulsion of circulating cancer cells from the blood vessel wall to counteract metastasis. Experiments in wild type and vWF knockout mice confirmed that the HS-vWF complex at the melanoma cell surface attenuated hematogenous metastasis, whereas melanoma cells lacking HS evade the anti-metastatic recognition by vWF. Analysis of tissue samples obtained from melanoma patients validated that metastatic melanoma cells produce less HS. Transcriptome data further suggest that attenuated expression of HS-related genes correlate with metastases and reduced patients' survival. In conclusion, we showed that HS-mediated binding of plasmatic vWF to the cellular surface can reduce the hematogenous spread of melanoma. Cancer cells with low HS levels evade vWF recognition and are thus prone to form metastases. Therefore, therapeutic expansion of the cancer cell exposed HS may prevent tumor progression., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing financial interests., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Chronic pruritus (CP) is a symptom of dermatologic, neurologic, systemic and psychosomatic diseases. CP has a prevalence of ~20% in the general population and is therefore a significant burden on society, but the transition from acute pruritus to CP is not well understood. It probably involves interactions between biological and psychosocial factors and pruritus-specific risk factors as well as mechanisms shared with other persistent somatic symptoms addressed in other projects of the SOMACROSS Research Unit (RU). Here we aim to identify psychosocial and biological factors and their interactions which might be associated with the persistence of CP with and without immunologic/inflammatory origin, that is, atopic dermatitis and pruritus on non-inflamed skin. We expect that psychosocial factors relevant to the persistence of symptoms such as fatigue and pain may also show associations to CP., Methods and Analysis: In this prospective, exploratory observational study situated in Germany, three cohorts of 40 patients each with acute exacerbation of atopic dermatitis and chronic atopic dermatitis and 40 CP patients with unaffected skin will be recruited for a comprehensive translational investigation including pruritus-specific and the shared psychosocial assessments of the RU SOMACROSS. Pruritus-specific measures will include questionnaires, quantitative sensory testing, cutaneous nerve fibre morphology, skin barrier morphology, epidermal metabolism and pruritogen blood levels. Within 1 year, patients and 80 age-matched and sex-matched healthy controls will be examined at three time points, allowing cross-sectional comparison and a longitudinal investigation of predictive outcome factors in patients under treatment according to existing guidelines., Ethics and Dissemination: The study has been approved by the ethics committees of Hamburg (2020-10200-BO-ff) and Münster (2020-676 f-S), Germany. All participants are required to provide written informed consent. Findings will be disseminated through peer-reviewed publications, scientific conferences and involvement of relevant stakeholders, patients and the lay public., Trial Registration Number: DRKS00026646., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cutaneous angiosarcoma (CAS) is a highly aggressive cancer with a poor prognosis. Primary, spontaneous CAS (pCAS) and secondary, post-irradiation- or lymphedema-associated CAS (sCAS) are clinically, but also molecularly distinct. Myc amplification/overexpression is a characteristic, although not exclusive feature of sCAS, while loss of TP53 selectively occurs in pCAS. Detailed molecular analyses with modern multi-omics approaches have revealed that both pCAS and sCAS exhibit considerable molecular heterogeneity. Affected genes and their molecular regulators including a plethora of microRNAs may serve as future drug targets. Furthermore, pCAS could be subdivided into clusters with high tumor mutational burden and/or high tumor inflammation signatures providing a rationale for the stratification of pCAS patients in future immunotherapeutic clinical studies. Development of novel treatment regimens guided by these molecular alterations, however, cannot fully keep up with the pace of their discovery due to the low incidence of the disease. Nevertheless, beyond conventional surgery and chemoradiotherapy, clinical trials investigating novel treatment options have been initiated including targeted therapies against VEGF and VEGFR1-3 such as bevacizumab and pazopanib, and β-adrenoreceptor blockers such as propranolol. Finally, immunotherapies are being developed including immune checkpoint inhibitors pembrolizumab and nivolumab as well as anti-RANKL antibody denosumab., (© 2022 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Das kutane Angiosarkom (CAS) ist ein hochaggressiver maligner Tumor mit schlechter Prognose. Das primäre, spontane CAS (pCAS) und das sekundäre, mit einer Bestrahlung oder einem Lymphödem assoziierte CAS (sCAS) unterscheiden sich klinisch sowie molekular. Die Amplifikation/Überexpression von Myc ist ein charakteristisches, wenn auch nicht ausschließliches Merkmal von sCAS, während der Verlust von TP53 selektiv bei pCAS vorkommt. Detaillierte molekulare Analysen mit modernen Multi-Omics-Ansätzen haben gezeigt, dass sowohl pCAS als auch sCAS eine erhebliche molekulare Heterogenität aufweisen. Die betroffenen Gene und ihre molekularen Regulatoren sind mögliche therapeutische Zielstrukturen. Darüber hinaus kann das pCAS in Cluster mit hoher Mutationsrate und/oder ausgeprägten Entzündungssignaturen eingeteilt werden, die als Grundlage für die künftige Stratifizierung von pCAS-Patienten in immuntherapeutischen klinischen Studien dienen können. Während die Aufklärung der der Erkrankung zugrunde liegenden molekularen Veränderungen zügig voranschreitet, verläuft die Entwicklung daraus abgeleiteter neuer Therapien für das CAS jedoch bisher eher langsam. Dennoch wurden einige über die Standardtherapien wie Operation und Radiochemotherapie hinausgehende klinische Studien zu neuen Behandlungsmöglichkeiten initiiert. Dazu gehören zielgerichtete Therapien gegen VEGF und VEGFR1-3 wie Bevacizumab und Pazopanib, sowie β-Adrenozeptorenblocker wie Propranolol. Derzeit werden auch Immuntherapien entwickelt, unter anderem unter Verwendung der Immuncheckpoint-Inhibitoren Pembrolizumab und Nivolumab sowie des Anti-RANKL-Antikörper Denosumab., (© 2022 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)