Basal cell carcinomas (BCCs) are the most common type of cancer diagnosed in the world, predominantly affecting the head and neck region. However, metastatic BCCs are exceptionally rare, with an estimated prevalence between 0.0028% and 0.55%. We present a case of a young patient that demonstrates the highly aggressive nature of morphoeic BCC and the challenges in achieving long-term disease control despite multimodal therapy. The case data have been collected from The Christie Hospital NHS Foundation Trust and St Mary’s Regional Genetics Centre, Manchester, UK.

The aim of this study was to describe physician-recorded disease characteristics, aetiological subtypes and treatment patterns in patients with moderate-to-severe chronic hand eczema (CHE) in real-world clinical practice in the UK. RWEAL was a multinational, retrospective physician chart review study, with data for the UK reported here. Dermatologists and general practitioners with a special focus on dermatology were eligible if they had ≥ 3 years of clinical experience and routinely diagnosed and treated CHE (≥ 15 patients in the last 12 months). Physicians completed a case report form for up to 10 patients treated with topical corticosteroids (TCS) over the past 12 months or for whom TCS were contraindicated. Information about the clinical characteristics and treatment of CHE was extracted from medical charts. In total 55 physicians were included and completed forms for 365 patients. Half of patients were female and the worst severity of CHE in the previous 12 months was moderate in 58% and severe in 42% of patients. Clinical judgement was the most frequent method for determining CHE severity (79% of patients), with 24% assessed using a scoring system. Erythema (64% of patients), pruritus (62%) and scaling (51%) were the most frequently reported clinical signs at the last visit. Palms were the most frequently affected area (59% of patients), followed by backs of hands (48%), wrists (45%), fingertips (44%) and interdigital spaces (34%). The most frequently reported aetiological CHE subtypes were irritant contact dermatitis (41%) and atopic dermatitis (40%); mixed aetiologies were frequent and only 28% of patients had atopic dermatitis aetiology alone. Among 183 patients treated by dermatologists, 11% received alitretinoin, 10% phototherapy, 10% methotrexate, 8% ciclosporin and 7% dupilumab during the past 12-month period. Overall, TCS were considered to have an inadequate response (or were medically inadvisable) in 43% of patients. Among these patients, 41% continued on TCS without escalation to other treatments. In conclusion, patients with CHE presented with a combination of different signs and symptoms and aetiological subtypes. Treatment with TCS was considered to have an inadequate response or was contraindicated in > 40% of patients, many of whom continued to receive TCS without treatment escalation. This indicates a need for new treatment options that address the heterogeneous and multifactorial nature of CHE. The absence of clear lines of treatment after TCS suggests a need for UK-specific guidelines for CHE.

BACKGROUND:Patients with Gorlin (basal cell naevus) syndrome (GS) have numerous phenotypic abnormalities due to overactivity of the hedgehog (HH) signalling pathway, most commonly caused by a heritable mutation in PTCH1, which encodes a major inhibitor of this pathway. Oral HH inhibitors (HHi) can reverse some of the manifestations, most prominent of which is the development of numerous cutaneous basal cell carcinomas (BCCs). In order to improve the benefit-risk ratio, we developed a gel containing a small cyclopamine-derived molecule that can be applied topically in expectation that this mode of delivery can reduce the burden of BCCs without producing the systemic adverse effects that cause patients to stop oral HHi treatment. OBJECTIVES:To determine whether or not patidegib topical gel 2% or 4% can accumulate in high enough concentrations to have local anti-BCC efficacy but not so high that systemic drug levels produce the adverse effects typical of oral HHi treatment. METHODS:We conducted a small randomized double-blinded phase IIA trial at two sites in the UK, to assess the clinical and molecular efficacy and adverse effects of 6 months of twice-daily application of patidegib topical gel to the entire face, as well as to treatment-targeted surgically eligible BCCs at other anatomical sites. RESULTS:Post hoc analyses suggested that patidegib topical gel reduced the number of new, surgically eligible BCCs and the level of HH signalling, with minimal adverse effects. CONCLUSIONS:Patidegib topical gel warrants further clinical development.

Melanoma is the fifth most common skin cancer in the UK, accounting for 4% of all new cancer cases, with a predicted 7% increase in incidence between 2014-35. In parallel, since the initial publication of the Melanoma NICE Guidelines in 2015, there has been a paradigm shift in the management of the disease, with the introduction of effective systemic therapies. These innovations have reshaped the management of melanoma throughout the patient journey, and improved clinical outcomes. Surgical management has evolved, with the role of sentinel node biopsy in staging and management of regional lymph nodes becoming clearly defined, and a reduction in the need and indications for morbid block dissections. In advanced disease, effective therapies have allowed a de-escalation of surgery, changing the role and sequencing of local therapies. Regional therapies for in-transit disease have expanded and are effective in controlling this pattern of disease as part of multidisciplinary care. These advances have undoubtedly improved the care for people with melanoma, but have also increased the complexity of management. In this context, this article seeks to summarizes the most relevant of the recent updates to the NICE guidelines.

Actinic keratosis (AK) is an intraepithelial condition characterized by the development of scaly, erythematous lesions after repeated exposure to ultraviolet radiation. Significant immunosuppression is a risk factor for the development of AK and subsequent lesion progression to squamous cell carcinoma. Immunocompromised patients (ICPs), particularly organ transplant recipients, often have more advanced or complex AK presentations and an increased risk of skin carcinomas versus non-ICPs with AK, making lesions more difficult to treat and resulting in worse treatment outcomes. The recent "Personalising Actinic Keratosis Treatment" (PAKT) consensus reported that delivering patient-centric care may play a role in supporting better clinical outcomes and patient satisfaction with treatments for chronic dermatologic conditions such as AK, which require repeated cycles of treatment. Additionally, currently published guidance and recommendations were considered by the PAKT panel to be overly broad for managing ICPs with their unique and complex needs. Therefore, the "Personalising Actinic Keratosis Treatment for Immunocompromised Patients" (IM-PAKT) panel was established to build upon general recommendations from the PAKT consensus. The panel identified current gaps in guidance for AK care in ICPs, offered practical care approaches based on typical ICP scenarios, and highlighted the need to adapt AK management to optimize care and improve treatment outcomes in ICPs. In particular, dermatologists should establish collaborative and transparent relationships with patients' multidisciplinary teams to enhance overall care for patients' comorbidities: given their increased risk of progression to malignancy, earlier assessments/interventions and frequent follow-ups are vital.The panel also developed a novel "triage" tool outlining effective treatment follow-up and disease surveillance plans tailored to patients' risk profiles, guided by current clinical presentation and relevant medical history. Additionally, we present the panel's expert opinion on three fictional ICP scenarios to explain their decision-making process for assessing and managing typical ICPs that they may encounter in clinical practice.

Background: The 31st European Academy of Dermatology and Venereology (EADV) Congress took place between 7th and 10th of September 2022 in Milan, Italy.Objectives: We report presented clinical data on the efficacy/effectiveness, safety and tolerability of tirbanibulin 1% ointment that has recently been licensed for actinic keratosis (AK) of the face or scalp in adults.Methods: Summary of presentations given at the EADV Congress.Results: Prof. Pellacani presented two post hoc analyses from two phase-III trials with AK patients (NCT03285477 [N = 351] and NCT03285490 [N = 351]): A descriptive analysis of medical history, concomitant medications, and safety results confirming a favourable profile for tirbanibulin showing that number of baseline AK lesions was not correlated to severity of local skin reactions. The latter analysis showed that cases of tirbanibulin application site pain or pruritus were few, and most were found to be mild. Prof. Kunstfeld reported six real-life clinical cases in Austria showing good tirbanibulin effectiveness, safety and tolerability for the treatment of new or recurring AK lesions. Results demonstrated that after 2- to 4-month follow-up, tirbanibulin was well tolerated and effective in AK patients. Presentations by Dr. Patel confirmed good outcomes and tolerability of tirbanibulin in Olsen grade 1-2 AK (N = 12) and porokeratosis patients (N = 4) treated once daily for 5 consecutive days in the United Kingdom. Furthermore, real-world experience in solid organ transplant recipients (N = 2) demonstrated effectiveness of tirbanibulin in skin field cancerization treatment. A symposium sponsored by Almirall was conducted during the congress in which Dr. Hadshiew and Dr. Lear brought together their clinical experience in Germany and the United Kingdom respectively. Interesting clinical cases of 5 consecutive days of tirbanibulin treatment compared to other treatments were discussed with attendees, as well as current treatment needs of AK patients.Conclusions: This article provides an overview of presentations and symposium discussions, summarizing key phase-III results and real-life clinical experience with tirbanibulin shared by dermatologists across Europe.

Metastatic basal cell carcinomas (mBCCs) are exceedingly rare, with an estimated variable prevalence rate between 0.003 and 0.55% among all basal cell carcinomas. Although there are hundreds of reported cases of mBCCs, a dearth of evidence exists of mBCCs in patients with Gorlin syndrome-an autosomal dominant genetic disorder. The purpose of this article was to present the first and largest case series of patients with mBCC in Gorlin. A literature review (LR) compares our data with the existing evidence base to underscore the importance of early surveillance, diagnosis and surgical intervention of suspicious lesions as distant metastases significantly reduce survival rates.

CONTEXT:Topical sirolimus is increasingly utilised off-license to manage various dermatological conditions whilst avoiding typical adverse effects associated with systemic sirolimus. However, widespread use is limited by a highly heterogeneous evidence base of mixed quality. OBJECTIVE:to evaluate the current evidence base for the indications, efficacy and safety profile for topical sirolimus in dermatology. DATA SOURCES:A literature search was conducted from 2005 to July 4th, 2023, of English language studies, with the following databases consulted: MEDLINE, PubMed, Embase, CENTRAL and EBSCO. Key words included 'topical', 'rapamycin', 'sirolimus' and 'dermatology'. DATA EXTRACTION:Data on drug efficacy, concentration, side effects, co-interventions and follow up were extracted. RESULTS:The search identified 202 studies; 71 studies met the inclusion criteria. Efficacy of topical sirolimus was demonstrated in facial angiofibromas (799 patients) compared to placebo across multiple randomised controlled trials with a predominant concentration of 0.1%. Evidence was mixed for sirolimus use in port-wine stains (61 patients), with evidence of effectiveness in combined sirolimus and pulsed-dye laser. Multiple case reports demonstrated clinical improvement with topical sirolimus use in cutaneous vascular abnormalities (33 patients) at a higher concentration of 1%. Other applications of topical sirolimus were predominantly case reports demonstrating generally favourable outcomes. Topical sirolimus was generally well tolerated - most reported adverse effects were localised irritation and pruritus. Ointment-based preparations and once-daily dosing appeared to confer a better side effect profile. CONCLUSION:Most high-quality data pertain to the efficacy of topical sirolimus in treating facial angiofibromas in tuberous sclerosis. Outcomes are generally promising in other indications and good tolerability, but data quality is mixed.

Non-melanoma skin cancer represents the most common form of cancer in humans. Cutaneous squamous cell carcinoma is second most common form behind basal cell carcinoma and is the most common type of cancer with significant metastatic potential. Immunosuppressed patients, including solid organ transplant recipients and those with human immunodeficiency virus infection, are at significantly elevated risk of cutaneous squamous cell carcinoma. This chapter discusses the incidence, presentation, diagnosis and management of non-melanoma skin cancer in patients with immunosuppression, with particular focus on the key areas of the management strategy that differ when compared to management of immunocompetent patients.

IntroductionSonidegib and vismodegib are currently the only US Food and Drug Administration and European Medicines Agency-approved small-molecule Hedgehog pathway inhibitors (HHIs)for treating adults with advanced or refractory basal cell carcinoma (BCC) that is not amenable to conventional surgery or radiotherapy. At this time, there are no head-to-head clinical trials comparing these two HHIs for efficacy and safety to assist clinicians with determining which HHI may be best suited for their patients.Areas coveredThis review briefly describes the pathogenesis of BCC, provides a detailed overview of the key pharmacokinetic profile differences between sonidegib and vismodegib, explains their pharmacodynamics, and highlights the therapeutic considerations when either HHI is used to treat special patient populations.Expert opinionAlthough both HHIs act at the same molecular target in the Hedgehog pathway, there are significant differences in their pharmacokinetic profiles that may play a potential role in their efficacy and safety. Evidence-based recommendations serve to inform clinicians until direct comparative clinical trials of sonidegib versus vismodegib are conducted to determine the clinical relevance of the reported differences in their pharmacokinetic properties.

Background Sonidegib is approved to treat locally advanced basal cell carcinoma (laBCC) in patients not amenable to surgery or radiation. The BOLT trial demonstrated durable efficacy of sonidegib in laBCC patients over 42 months. BCC is most common in the elderly, who often take chronic medications. Objectives We evaluated the efficacy of sonidegib (200 mg daily) in laBCC patients on select concomitant medications. Materials & Methods In the Phase II BOLT study, laBCC patients were randomized 1:2 to sonidegib 200 mg:800 mg daily. The primary endpoint was objective response rate (ORR) per central review. Post hoc assessments included ORR and duration of response (DOR) per investigator review for patients on concomitant medications. Results At 42 months, ORR for laBCC patients taking sonidegib 200 mg daily ( n =66) was 71.2% and DOR was 15.7 months according to investigator review. Patients on select concomitant medications ( n =37) had an ORR of 73.0%; DOR was not estimable. Conclusion Administration of sonidegib with concomitant medications, excluding strong cytochrome P450 3A4/5 inhibitors/inducers, does not appear to alter its efficacy in laBCC patients.

Introduction Hand eczema (HE) is one of the most common skin disorders and an important cause for morbidity and occupational disability. The 1-year prevalence of HE is estimated to be up to 10% and it is estimated that 5%–7% of those develop severe chronic HE. However, current clinical evidence is not compelling enough to guide clinical practice. In a survey among 194 UK dermatologists the most frequent first choice approaches were psoralen combined with ultraviolet A (UVA) treatment (PUVA), oral steroids and alitretinoin (AL). When asked which strategy was most efficient for long-term outcome 20% of clinicians indicated they did not know; 43% of clinicians reported AL and 30% reported PUVA. Methods and analysis ALPHA is a multicentre, open, prospective, two-arm parallel group, randomised controlled trial comparing PUVA and AL with a planned sample size re-estimation. Between 500 and 780 participants will be randomised on a 1:1 basis. The physician’s global assessment (PGA) will direct treatment after randomisation, non-responders will be treated according to usual clinical practice; providing valuable pilot data on second line therapeutic approaches to inform future trials. Assessments will be conducted up to 52 weeks post randomisation. The primary outcome measure is the Hand Eczema Severity Index at 12 weeks. Secondary outcome measures include modified Total Lesion Symptom Score, PGA, time to relapse, patient reported outcome measures and DNA extraction and assessment of genetic variants. A substudy on molecular inflammatory mediators will provide information on subgroup specific treatment responses. Photographs will be taken and HE severity assessed by a central review panel. Ethics and dissemination Ethics approval was obtained from Leeds West Research Ethics Committee (14/YH/1259).Trial results will be disseminated at relevant clinical conferences and societies, published in peer-reviewed journals and through relevant patient groups. Trial registration number ISRCTN80206075 .

Background: Bazex-Dupre-Christol syndrome (BDCS; MIM301845) is a rare X-linked dominant genodermatosis characterized by follicular atrophoderma, congenital hypotrichosis and multiple basal cell carcinomas (BCCs). Previous studies have linked BDCS to an 11.4 Mb interval on chromosome Xq25-27.1. However, the genetic mechanism of BDCS remains an open question. Methods: To investigate the genetic etiology of BDCS, we ascertained eight families with individuals affected with BDCS (F1-F8). Whole exome (F1 and F2) and genome sequencing (F3) were performed to identify putative disease-causing variants within the linkage region. Array-comparative genomic hybridization and quantitative PCR were used to explore copy number variations (CNV) in BDCS families, followed by long-range gap-PCR and Sanger sequencing to amplify duplication junction and define the precise head-tail junctions, respectively. Immunofluorescence was performed in hair follicles, BCCs and trichoepitheliomas from BDCS patients and sporadic BCCs to detect the expression of corresponding genes. The ACTRT1 variant (p.Met183Asnfs*17), previously proposed to cause BDCS, was evaluated with allele frequency calculator. Results: In eight BDCS families, we identified overlapping 18-135kb duplications (six inherited and two de novo) at Xq26.1, flanked by ARHGAP36 and IGSF1. We detected ARHGAP36 expression near the control hair follicular stem cells compartment, and found increased ARHGAP36 levels in hair follicles in telogen, BCCs and trichoepitheliomas from patients with BDCS. ARHGAP36 was also detected in sporadic BCCs from individuals without BDCS. Our modelling showed the predicted ACTRT1 variants maximum tolerated minor allele frequency in control populations to be orders of magnitude higher than expected for a high-penetrant ultra-rare disorder, suggesting loss-of-function of ACTRT1 is unlikely to cause BDCS. Conclusions: Our data support the pathogenicity of intergenic duplications at Xq26.1, most likely leading to dysregulation of ARHGAP36, establish BDCS as a genomic disorder, and provide a potential therapeutic target for both inherited and sporadic BCCs.

INTRODUCTION Contact dermatitis is an inflammatory skin disorder that can present as an acute, subacute or chronic condition. This review highlights the burden of allergic contact dermatitis for dental professionals as well as discussing its cellular mechanism, clinical features, common causative agents in dentistry and treatment options. FINDINGS There are two main types of contact dermatitis. Allergic contact dermatitis accounts for 20% of reported contact dermatitis cases while the remainder are due to irritant contact dermatitis. Allergic contact dermatitis is a type IV hypersensitivity reaction that affects 22-43% of dental professionals globally. There is limited literature on the impact of this condition on dental healthcare professionals. Moreover, with the increased and prolonged use of personal protective equipment (PPE) to prevent occupational transmission of SARS-CoV-2, more healthcare professionals are presenting with allergic contact dermatitis against their PPE. CONCLUSIONS Allergic contact dermatitis is a prevalent occupational skin condition that can affect all members of the dental team, especially with the increased use of PPE due to the COVID-19 pandemic. Dental professionals with signs and symptoms should seek relevant advice and reduce exposure to known allergens.

Background:Whilst there is international evidence around the high healthcare resource utilization (HRU) associated with atopic dermatitis (AD), there is a lack of published data from the United Kingdom (UK).Methods:A retrospective, descriptive, observational study was conducted to evaluate the burden of moderate-to-severe AD on the National Health Service (NHS) in an adult UK population treated with traditional standard of care prior to the introduction of biologics. Patients (n=59) were recruited from 6 UK NHS Hospital Trusts and observed over three years.Results:707 dermatology clinic visits were recorded over the observation period, amounting to 6.6 visits per patient-year, most commonly for routine check-ups most of which involved dermatology consultants (n=469, 66%). Physicians were the most consulted healthcare professional (n=652, 92%); emollients were the most common treatment (n=80 courses). 174 flares requiring additional medical advice were recorded in total (1.6 per patient-year).Discussion/Conclusions:Complex treatment pathways for adult patients in the UK with moderate-to-severe AD incur considerable HRU, particularly for those patients non-responsive to systemic therapies with broad immunosuppressant action. Recent advances in biologics-based AD management could possibly have a significant positive impact on HRU through significant reduction in the number of NHS touch points identified in this study.

Background The risk of cutaneous squamous cell carcinoma (cSCC) is significantly increased in organ transplant recipients (OTRs). Clearance of actinic keratoses (AKs) is generally regarded as a surrogate biomarker for cSCC prevention. OTR-cSCC chemoprevention with topical AK treatments has not been investigated in randomized controlled trials (RCTs), although there is evidence that 5% 5-fluorouracil (5-FU) may be chemoprotective in immunocompetent patients. Objectives To assess the feasibility, activity and evaluation outcomes relevant to the design of a future phase III RCT of topical cSCC chemoprevention in OTRs. Methods OTRs with 10 or more AKs in predefined areas were randomized 1 : 1 : 1 to topical 5-FU, 5% imiquimod (IMIQ) or sunscreen (sun-protective factor 30+) in a phase II, open-label RCT over 15 months. Feasibility outcomes included proportions of eligible OTRs randomized, completing treatment and willing to be re-treated. AK activity [AK clearance, new AK development, patient-centred outcomes (toxicity, health-related quality of life, HRQoL)] and evaluation methodology (clinical vs. photographic) were assessed. Results Forty OTRs with 903 AKs were randomized. All feasibility outcomes were met (56% of eligible OTRs were randomized; 89% completed treatment; 81% were willing to be re-treated). AK activity analyses found 5-FU and IMIQ were superior to sunscreen for AK clearance and prevention of new AKs. 5-FU was more effective than IMIQ in AK clearance and prevention in exploratory analyses. Although toxicity was greater with 5-FU, HRQoL outcomes were similar. Conclusions Trials of topical AK treatments in OTRs for cSCC chemoprevention are feasible and AK activity results support further investigation of 5-FU-based treatments in future phase III trials.

BACKGROUND:Individuals with a prior diagnosis of chronic lymphocytic leukaemia (CLL) have a higher risk of developing melanoma and exhibit poorer outcomes than patients without CLL. However, there are limited data reporting the clinicopathological features of melanoma diagnosed in patients with CLL.AIMS:To review clinicopathological characteristics of patients with coexisting diagnoses of melanoma and CLL.METHODS:A retrospective review was undertaken for patients with coexisting diagnoses of melanoma and CLL between 2005 and 2015 in 11 centres in the UK and Ireland.RESULTS:Overall, 46 cutaneous melanomas identified in 45 patients were included. In 28 (62.2%) patients, melanoma was diagnosed after an existing diagnosis of CLL. In this group, mean Breslow thickness was 2.7 mm (range 0.2-25 mm). Ten patients (35.7%) developed locoregional recurrence and 8 (28.6%) developed distant metastases. Melanoma-specific mortality was 5 of 28 (17.9%) and all-cause mortality was 13 of 28 (46.4%). In 17 patients, melanoma was diagnosed before CLL. In this group, mean BT was 2.9 mm (range 0.4-14 mm); five patients (29.4%) developed locoregional recurrence and three (17.6%) developed distant metastases. Melanoma-specific mortality was 1 of 17 (5.8%) and all-cause mortality was 5 of 17 (29.4%) in this group.CONCLUSIONS:To our knowledge, this is the first and largest cohort study to report clinicopathological data of coexisting melanoma and CLL in the UK and Ireland. Although the thickness of primary melanoma was not different before or after a CLL diagnosis, melanoma recurrence and melanoma-specific mortality appear to be more common in patients with a prior diagnosis of CLL.

Linked Comment: M.D. Moncrieff and J.P. Nobes. Br J Dermatol 2021; 185:877. Plain language summary available online

Abstract Purpose: Cancer susceptibility and mortality are higher in males, and the mutational and transcriptomic landscape of cancer differs by sex. The current assumption is that men are at higher risk of epithelial cancers as they expose more to carcinogens and accumulate more damage than women. We present data showing women present with less aggressive primary cutaneous squamous cell carcinoma (cSCC) and early strong immune activation. Experimental Design: We explored clinical and molecular sexual disparity in immunocompetent and immunosuppressed patients with primary cSCC (N = 738, N = 160), advanced-stage cSCC (N = 63, N = 20) and FVB/N mice exposed to equal doses of DMBA, as well as in human keratinocytes by whole-exome, bulk, and single-cell RNA sequencing. Results: We show cSCC is more aggressive in men, and immunocompetent women develop mild cSCC, later in life. To test whether sex drives disparity, we exposed male and female mice to equal doses of carcinogen, and found males present with more aggressive, metastatic cSCC than females. Critically, females activate cancer immune-related expression pathways and CD4 and CD8 T-cell infiltration independently of mutations, a response that is absent in prednisolone-treated animals. In contrast, males increase the rate of mitosis and proliferation in response to carcinogen. Women's skin and keratinocytes also activate immune-cancer fighting pathways and immune cells at UV radiation–damaged sites. Critically, a compromised immune system leads to high-risk, aggressive cSCC specifically in women. Conclusions: This work shows the immune response is sex biased in cSCC and highlights female immunity offers greater protection than male immunity.