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Autoreactive CD8 T cells play a pivotal role in melanocyte destruction in autoimmune vitiligo. Immunotherapy for melanoma often leads to autoimmune side-effects, among which vitiligo-like depigmentation, indicating that targeting immune checkpoints can break peripheral tolerance against self-antigens in the skin. Therapeutically enhancing immune checkpoint signaling by immune cells or skin cells, making self-reactive T cells anergic, seems a promising therapeutic option for vitiligo. Here, we review the current knowledge on the PD-1/PD-L1 pathway in vitiligo as new therapeutic target for vitiligo therapy.

This study explores the efficacy of glibenclamide, a K ATP channel inhibitor, for treating Cantú syndrome (CS), a genetic disorder characterized by hypertrichosis and cardiovascular abnormalities. Treatment with glibenclamide for Cantú syndrome has only been reported in a single case report. In this study, we tested this repurposed drug in both a zebrafish model and an open-label trial with CS patients. CS zebrafish embryos, created using CRISPR/Cas9, were treated with glibenclamide. Their cardiac function was assessed using high-speed imaging. In the trial part of the study, four adults with CS used 2.5 mg glibenclamide daily for 8 months. Hypertrichosis, cardiac function, and edema were evaluated and glucose levels were monitored continuously. In the zebrafish model of CS glibenclamide reversed cardiac abnormalities. However, in the clinical trial, the effects on hypertrichosis were mixed, and there were no significant changes in cardiac phenotype or leg edema. One participant reported reduced facial erythema and puffiness, which relapsed post-trial. The treatment was generally safe, with multiple instances of level 1 hypoglycemia but no severe adverse events. In conclusion, glibenclamide can reverse cardiac abnormalities in a CS zebrafish model. Its effect on hypertrichosis and cardiovascular features in humans with CS are unclear and dosage increases are challenging due to hypoglycemia, which is important knowledge for treatment considerations in this rare genetic syndrome. Trial registration: EudraCT Number 2019-004651-36. Date of first registration 21/05/2021.

Non-melanoma skin cancers (NMSCs) occur frequently in the Caucasian population and are considered a burden for health care. Risk factors include ultraviolet (UV) radiation, ethnicity and immunosuppression. The incidence of NMSC is significantly higher in solid organ transplant recipients (SOTRs) than in immunocompetent individuals, due to immunosuppressive medication use by SOTRs. While the immunosuppressive agents, calcineurin inhibitors and purine analogues increase the incidence of NMSC in transplant recipients, mTOR inhibitors do not. This is most likely due to the different immunological pathways that are inhibited by each class of drug. This review will focus on what is currently known about the immune response against cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC), two of the main types of NMSC. Furthermore, we will describe the different classes of immunosuppressants given to SOTRs, which part of the immune system they target and how they can contribute to NMSC development. The risk of developing NMSC in SOTRs is the result of a combination of inhibiting immunological pathways involved in immunosurveillance against NMSC and the direct (pro/anti) tumor effects of immunosuppressants.

Background: Challenges remain for general practitioners (GPs) in diagnosing (pre)malignant and benign skin lesions. Teledermoscopy (TDsc) supports GPs in diagnosing these skin lesions guided by teledermatologists' (TDs) diagnosis and advice and prevents unnecessary referrals to dermatology care. However, the impact of the availability of TDsc on GPs’ self-reported referral decisions to dermatology care before and after the TDsc consultation is unknown. Objective: The objective of this study is to assess and compare the initial self-reported referral decisions of GPs before TDsc versus their final self-reported referral decisions after TDsc for skin lesions diagnosed by the TD as (pre)malignant or benign. Methods: TDsc consultations requested by GPs in daily practice between July 2015 and June 2020 with a TD assessment and diagnosis were extracted from a nationwide Dutch telemedicine database. Based on GP self-administered questions, the GPs’ referral decisions before and their final referral decision after TDsc consultation were assessed for (pre)malignant and benign TD diagnoses. Results: GP self-administered questions and TD diagnoses were evaluated for 6364 TDsc consultations (9.3% malignant, 8.8% premalignant, and 81.9% benign skin lesions). In half of the TDsc consultations, GPs adjusted their initial referral decision after TD advice and TD diagnosis. Initially, GPs did not have the intention to refer 67 (56.8%) of 118 patients with a malignant TD diagnosis and 26 (16.0%) of 162 patients with a premalignant TD diagnosis but then decided to refer these patients after the TDsc consultation. Furthermore, GPs adjusted their decision from referral to nonreferral for 2534 (74.9%) benign skin lesions (including 676 seborrheic keratosis and 131 vascular lesions). Conclusions: GPs adjusted their referral decision in 52% (n=3306) of the TDsc consultations after the TD assessment. The availability of TDsc is thus of added value and assists GPs in their (non)referral for patients with skin lesions to dermatology care. TDsc resulted in referrals of patients with (pre)malignant skin lesions that GPs would not have referred directly to the dermatologist. TDsc also led to a reduction of unnecessary referrals of patients with low complex benign skin lesions (eg, seborrheic keratosis and vascular lesions).

Background Vismodegib has been used for the treatment of locally advanced basal cell carcinoma (laBCC) and metastatic BCC (mBCC) since 2011. Most efficacy and safety data are provided by clinical trials. This study evaluates the effectiveness of vismodegib for the treatment of laBCC, mBCC and basal cell nevus syndrome (BCNS) patients, and the tumour characteristics associated with a higher probability of achieving a complete response in the Netherlands. Methods A retrospective cohort study that included all patients ≥18 years with histologically proven basal cell carcinoma that received ≥1 dose of vismodegib between July 2011 and September 2019 in the Netherlands. Results In total, 48 laBCC, 11 mBCC and 19 BCNS patients were included. Median progression-free survival was 10.3 months (95% confidence interval (CI), 7.5–22.6) for laBCC, 11.7 (95% CI, 5.2–17.5) for mBCC and 19.1 (95% CI, 7.4–20.2) for BCNS. Larger laBCCs were associated with a lower probability of complete response (hazard ratio (HR) 0.77 per increase in cm, p  = 0.02). Of all BCNS patients, 63% received ≥2 treatment sequences with vismodegib; all achieved partial responses. Conclusions Half of the aBCC patients progress within 1 year after the start of vismodegib treatment. More research is needed to investigate other treatment strategies after vismodegib progression and to evaluate long-term effects of repetitive vismodegib treatment.

Vitiligo patients may desire laser hair removal, skin rejuvenation, vascular treatments, and other laser or intense pulsed light (IPL) assisted treatments. However, there is a risk of inducing new depigmented patches (Koebner phenomenon). In absence of guidelines on the safe use of laser or IPL in vitiligo patients, dermatologists tend to be reluctant to administer these treatments. The aim of this survey study was to provide an estimation of the occurrence and related risk factors of laser/IPL-induced leukoderma or vitiligo. A cross-sectional survey study was performed among 15 vitiligo experts from 11 countries, with 14 questions about affected patients, involved laser/IPL treatments and the physicians’ approach. In a total of 11,300 vitiligo patients, laser/IPL-induced leukoderma or vitiligo was reported in 30 patients (0.27%). Of these, 12 (40%) patients had a medical history of vitiligo and seven (58%) of these patients had stable (> 12 months) vitiligo before the treatment. Most frequently reported were hair removal procedures and localization of the face and legs. Side effects like blistering, crusting, and erosions occurred in 56.7% of the cases. These vitiligo experts based their advice on the risk of the laser treatment on stability of the vitiligo (43%) and activity signs (50%), and 50% discuss the risks before starting a laser treatment. Relevant activity signs are the Koebner phenomenon (57.1%), confetti-like lesions (57.1%) and hypochromic borders (50%). Laser-induced leukoderma or vitiligo is an uncommon phenomenon. Remarkably, a minority had a medical history of vitiligo of which 58% were stable. Consequently, most cases could not have been prevented by not treating vitiligo patients. However, a majority had laser/IPL-induced skin damage. Therefore, caution is advised with aggressive settings and test-spots prior to the treatment are recommended. This study showed significant variation in the current recommendations and approach of vitiligo experts regarding laser/IPL-induced leukoderma or vitiligo.

Mycosis fungoides (MF) is a subtype of CTCL with a low incidence and high medical need for novel treatments. The objective of this randomized, placebo-controlled, double-blinded, first-in-human study was to evaluate safety, efficacy, cutaneous and systemic pharmacokinetics (PK) of topical bimiralisib in healthy volunteers (HVs) and MF patients. In this trial, a total of 6 HVs and 19 early-stage MF patients were treated with 2.0% bimiralisib gel and/or placebo. Drug efficacy was assessed by the Composite Assessment of Index Lesion Severity (CAILS) score, supported by objective measuring methods to quantify lesion severity. PK blood samples were collected frequently and cutaneous PK was investigated in skin punch biopsies on the last day of treatment. Local distribution of bimiralisib in HVs showed a mean exposure of 2.54 µg/g in the epidermis. A systemic concentration was observed after application of a target dose of 2 mg/cm2 on 400 cm2, with a mean Cavg of 0.96 ng/mL. Systemic exposure of bimiralisib was reached in all treated MF patients, and normalized plasma concentrations showed a 144% increased exposure compared to HVs, with an observed mean Cavg of 4.49 ng/mL and a mean cutaneous concentration of 5.3 µg/g. No difference in CAILS or objective lesion severity quantification upon 42 days of once-daily treatment was observed in the MF patient group. In general, the treatment was well tolerated in terms of local reactions as well as systemic adverse events. In conclusion, we showed that topical bimiralisib treatment leads to (i) meaningful cutaneous drug levels and (ii) well-tolerated systemic drug exposure in MF patients and (iii) a lack of clinical efficacy, in need of further exploration due to numerous unknown factors, before depreciation of topical bimiralisib as a novel therapeutic drug for CTCLs.

The authors wish to make the following corrections to this paper [...]

Background: Cutaneous lymphomas expressing CD56, a neural cell adhesion molecule, are characterised in most cases by a highly aggressive clinical course and a poor prognosis. However, prognostic subsets within the CD56+ group have been difficult to identify due to the lack of uniform clinicopathological and immunophenotypical criteria. Methods: A multicentre study was conducted by the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer to define prognostic parameters and establish diagnostic and therapeutic guidelines for CD56+ haematological neoplasms presenting primarily in the skin. Results: Four different subtypes of lymphoproliferations with CD56 expression were identified: (1) haematodermic neoplasm; (2) skin infiltration as the first manifestation of CD56+ acute myeloid leukaemia; (3) nasal-type extranodal natural killer/T-cell lymphoma; and (4) “classical” cases of cutaneous T-cell lymphoma (CTCL) with co-expression of the CD56 molecule. Patients in the first three groups had a poor outcome (93% died) with a median survival rate of 11 months (95% CI 2–72 months), whereas all patients with CD56+ CTCL were alive at the last follow-up. Conclusion: Results show that CD56+ cutaneous lymphoproliferative disorders, with the exception of CD56+ CTCL have a very poor prognosis. It is therefore clinically important to separate CD56+ CTCL from the remaining CD56+ haematological disorders.

Basal cell carcinoma (BCC) is the most common cancer diagnosed in white populations worldwide. The rising incidence of BCC is becoming a major worldwide public health problem. Therefore, there is a need for more efficient management. The aim of this research is to assess the efficacy and safety of a one-stop-shop (OSS) concept, using real-time in vivo reflectance confocal microscopy (RCM) (Vivascope 1500; Lucid Technologies, Henrietta, NY, USA) as a diagnostic tool, prior to surgical management of new primary BCCs. This is a prospective non-inferiority multi-center RCT designed to compare the \"OSS concept using RCM\" to current standards of care in diagnosing and treating clinically suspected BCC. Patients ≥ 18 years attending our outpatient clinic at the Department of Dermatology, Academic Medical Center, University of Amsterdam, and the Department of Dermatology, the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital (Amsterdam, The Netherlands) with a clinically suspected new primary BCC lesion will be considered for enrollment using predefined inclusion and exclusion criteria, and will be randomly allocated to the experimental or control group. The main outcome parameter is the assessment of incomplete surgical excision margins on the final pathology report of confirmed BCC lesions (either by punch biopsy or RCM imaging). Other outcome measures include diagnostic accuracy (sensitivity and specificity) of RCM for diagnosing BCC and dividing between subtypes, and throughput time. Patient satisfaction data will be collected postoperatively after 3 months during routine follow-up. This research is investigator-initiated and received ethics approval. Patient recruitment started in February 2015, and we expect all study-related activities to be completed by fall 2015. This RCT is the first to examine an OSS concept using RCM for diagnosing and treating clinically suspected BCC lesions. Results of this research are expected to have applications in evidence-based practice for the increasing number of patients suffering from BCC and possibly lead to a more efficient disease management strategy. ClinicalTrials.gov: NCT02285790; https://clinicaltrial.gov/ct2/show/NCT02285790 (Archived by WebCite at http://www.webcitation.org/6b2LfDKWu).