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Basal cell carcinoma (BCC) is an increasingly common cancer. For high-risk BCCs, there are several treatment options, with similar efficacies. The current best practice in deciding upon a particular treatment is for a patient-centred approach. At present, there are few resources available for patients to assist their choice. This reduces patient autonomy and increases the burden on clinicians within clinic. Patient decision aids (PDAs) have been shown to increase patient autonomy and facilitate shared decision-making. Currently, there is no published PDA designed to facilitate the decision between surgical management or radiotherapy in high-risk BCCs. We developed a novel decision aid designed along the International Patient Decision Aid Standards to fill this clinical need, and evaluated its acceptance by both patients and clinicians. We describe the challenges faced at initial alpha and subsequent beta testing, and go on to validate our PDA with both the Decisional Conflict Scale and the nine-item Shared Decision Making Questionnaire (SDMQ9). We include an example of the PDA and encourage other units to modify the PDA for their own use.

Background The rate of growth of primary melanoma is a robust predictor of aggressiveness, but the mutational profile of fast-growing melanomas (FGMM) and the potential to stratify patients at high risk of death has not been comprehensively studied. Objective To investigate the epidemiologic, clinical, and mutational profile of primary cutaneous melanomas with a thickness ≥ 1 mm, stratified by rate of growth. Methods Observational prospective study. Deep-targeted sequencing of 40 melanoma driver genes on formalin fixed, paraffin-embedded primary melanoma samples. Comparison of FGMM (rate of growth > 0.5 mm/month) and nonFGMM (rate of growth ≤ 0.5 mm/month). Results Two hundred patients were enrolled, among wom 70 had FGMM. The relapse-free survival was lower in the FGMM group (P = .014). FGMM had a higher number of predicted deleterious mutations within the 40 genes than nonFGMM (P = .033). Ulceration (P = .032), thickness (P = .006), lower sun exposure (P = .049), and fibroblast growth factor receptor 2 (FGFR2) mutations (P = .037) were significantly associated with fast growth. Limitations Single-center study, cohort size, potential memory bias, number of investigated genes. Conclusion Fast growth is linked to specific tumor biology and environmental factors. Ulceration, thickness, and FGFR2 mutations are associated with fast growth. Screening for FGFR2 mutations might provide an additional tool to better identify FGMM, which are probably good candidates for adjuvant therapies.

Background: Skin self-examination (SSE) is widely promoted for the detection of suspicious pigmented lesions. However, determining screening accuracy is essential to appraising the usefulness of SSE. Objectives: The aim of this work was to pool estimates from studies of SSE diagnostic accuracy in the detection of suspicious pigmented lesions. Methods: This study was registered with PROSPERO (CRD42021246356) and conducted in accordance with PRISMA-DTA guidelines. A systematic search of Medline (PubMed) EMBASE, CINAHL, and The Cochrane Library was conducted to identify relevant studies. We included studies that examined the accuracy of SSE, either whole-body or site-specific, for detecting change in individual pigmented lesions or detecting an atypical naevus. A univariate random-effects model, based on logit-transformed data, was used to calculate a summary diagnostic odds ratio (DOR) as well as pooled sensitivity and specificity. Cochran’s Q test and the I2 statistic were calculated to assess heterogeneity. A proportional hazards model was used to calculate the area under the curve (AUC) and plot the summary receiver operator characteristic curve. We used the Quality Assessment of Diagnostic Accuracy Studies-2 tool to grade study quality. Results: We identified 757 studies, of which 3 met inclusion criteria for quantitative synthesis. The pooled sensitivity and specificity based on 553 included participants was 59 and 82%, respectively. The summary DOR was 5.88 and the AUC was 0.71. There were some concerns regarding risk of bias in all 3 studies. Conclusions: SSE can detect suspicious pigmented lesions with reasonable sensitivity and relatively high specificity, with the AUC suggesting acceptable discriminatory ability.

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.

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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 are more protected from aggressive cutaneous squamous cell carcinoma (cSCC) due to strong immune activation. Methods We explored clinical and molecular sexual disparity in immunocompetent and immunosuppressed patients (N= 738, N=160) with carcinoma cSCC, in FVB/N mice exposed to equal doses of DMBA, and in human keratinocytes by whole exome sequencing, 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 if sex drives disparity, we exposed male and female mice to equal doses of carcinogen, and found males present more aggressive, metastatic cSCC than females. Critically, females activate cancer immune-related expression pathways and CD4 and CD8 T cell infiltration independently of mutations. In contrast, males increase the rate of mitoses and proliferation in response to carcinogen. Human female skin and keratinocytes also activate immune-cancer fighting pathways and immune cells at ultraviolet 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. Translational relevance Sex bias affects cancer incidence, mortality and therapy response; and the molecular landscape of cancer differs by sex. However, it is not known if the sex discrepancy is due to a difference in behaviour and exposure to carcinogens, or due to sex-linked susceptibility. This work reveals men are inherently more susceptible to cutaneous aggressive squamous cell carcinoma, in contrast to women who activate stronger immune responses when challenged with the same carcinogens. The loss of immunity particularly affects women. Personalised medicine approaches stratify cancer patients by genotype; however, to date, the potential for cancer stratification, prevention strategies and therapy by sex and immune competency has not been explored. These data indicate men require targeted prevention programs and increased monitoring. Furthermore, we provide a rationale to prioritise men and immunosuppressed women for adjuvant therapy and immunotherapy.

Objectives The density of functioning human lymphatics in vivo and of immunohistochemically defined lymphatics was quantified around melanomas, benign nevi, and matched normal skin, to assess the current lymphangiogenesis paradigm. We investigated whether histological and functioning density increased around melanomas compared with benign nevi or matched skin; whether functioning and histological density increased similarly; and whether larger increases occurred around metastatic melanomas. Methods Functioning density was quantified in vivo as the total amount of human dermal microlymphatics taking up fluorescent marker injected at the lesion margin. After tissue excision, perilesion histological density was quantified using podoplanin marker D2-40. Results Histological density was raised similarly around metastasising and non-metastasising melanomas compared with normal skin (+71%, p

TERT (telomerase reverse transcriptase) is the catalytic component of telomerase. TERT shows little expression in normal somatic cells but is commonly re-expressed in cancers, facilitating immortalization. Recently-discovered TERT promoter mutations create binding sites for ETS-family transcription factors to upregulate TERT. ETS1 is reported to be important for TERT upregulation in melanoma. However it is unclear when in melanoma progression TERT and ETS1 proteins are expressed. To elucidate this question, ETS1 and TERT immunohistochemistry were performed on a panel of benign (n=27) and dysplastic nevi (n=34), radial growth phase (n=29), vertical growth phase (n=25) and metastatic melanomas (n=27). Lesions were scored by percentage of positive cells. ETS1 was readily detectable in all lesions, but not in normal melanocytes. TERT was located in either the nucleolus, the nucleoplasm (non-nucleolar) or both. Non-nucleolar TERT increased in prevalence with progression, from 19% of benign nevi to 78% of metastases. It did not however correlate with cell proliferation (Ki-67 immunostaining), nor differ significantly in prevalence between primary melanomas with or without a TERT promoter mutation. These results demonstrate that ETS1 is expressed very early in melanoma progression, and interestingly only non-nucleolar TERT correlates clearly in prevalence with melanoma progression. It can be acquired at various stages and by mechanisms other than promoter mutations.

Acute generalised exanthematous pustulosis (AGEP) or toxic pustuloderma (TP) is an uncommon though well-recognised cutaneous hypersensitivity reaction that is usually drug-induced. It presents with a triad of scattered sterile pustules, fever and malaise. Acute localised exanthematous pustulosis (ALEP) is a rare and unusual variant of AGEP. We describe a case of ALEP triggered by oral clindamycin that occurred during pregnancy.

Cutaneous adverse reactions to anti-tuberculous medications are known to affect up to 5% of patients 1 . The most common causative agent is pyrazinamide. Reactions to rifamycins are rare affecting only 1% of patients 1 . We describe a case of leucocytoclastic vasculitis (LCV) caused by rifamycins. A 53 year old female presented with cough, night sweats and upper lobe nodules. Bronchial-alveolar lavage confirmed fully sensitive mycobacterium tuberculosis (TB). She commenced treatment with rifampicin, isoniazid, ethambutol and pyrizinazmide. At 4 weeks she developed an extensive purpuric rash, malaise and joint aches. There was no evidence of other infections or connective tissue disorders on extensive screening. Her inflammatory markers were elevated. A punch biopsy of her shin demonstrated leukocytoclastic vasculitis of the superficial dermis. All TB medications were discontinuted and she started oral steroids. The rash resolved within 2 weeks. She started Moxifloxacin, Isoniazid and Ethambutol without complication. After 1 week Rifabutin was introduced. This led to recurrence of the rash. Rifabutin was stopped; the rash resolved and inflammatory markers normalised. She continues on an 18 month course of Moxifloxacin, Isoniazid and Ethambutol. Leukocytoclastic vasculitis (LCV) is a hypersensitivity vasculitis characterised by small vessel damage by nuclear debris from invading neutrophils. It typically affects the skin and joints and can be precipitated by medications and infections 2 . This case illustrates that clinicians should be aware LCV is a rare side affect of Rifamycins. 1. Kim JH et al. Allergy Asthma Immunol Res. 2010 Jan; 2(1): 55–58. 2. Brooke A et al. Medscape Drugs and Diseases.

Microcirculation (2010) 17, 281–296. doi: 10.1111/j.1549-8719.2010.00030.x Abstract Objective: Milroy disease is an inherited autosomal dominant lymphoedema caused by mutations in the gene for vascular endothelial growth factor receptor-3 (VEGFR-3, also known as FLT4). The phenotype has to date been ascribed to lymphatic aplasia. We further investigated the structural and functional defects underlying the phenotype in humans. Methods: The skin of the swollen foot and the non-swollen forearm was examined by (i) fluorescence microlymphangiography, to quantify functional initial lymphatic density in vivo; and (ii) podoplanin and LYVE-1 immunohistochemistry of biopsies, to quantify structural lymphatic density. Leg vein function was assessed by colour Doppler duplex ultrasound. Results: Milroy patients exhibited profound (86–91%) functional failure of the initial lymphatics in the foot; the forearm was unimpaired. Dermal lymphatics were present in biopsies but density was reduced by 51–61% (foot) and 26–33% (forearm). Saphenous venous reflux was present in 9/10 individuals with VEGFR3 mutations, including two carriers. Conclusion: We propose that VEGFR3 mutations in humans cause lymphoedema through a failure of tissue protein and fluid absorption. This is due to a profound functional failure of initial lymphatics and is not explained by microlymphatic hypoplasia alone. The superficial venous valve reflux indicates the dual role of VEGFR-3 in lymphatic and venous development.

Acute generalised exanthematous pustulosis (AGEP) or toxic pustuloderma (TP) is an uncommon though well-recognised cutaneous hypersensitivity reaction that is usually drug-induced. It presents with a triad of scattered sterile pustules, fever and malaise. Acute localised exanthematous pustulosis (ALEP) is a rare and unusual variant of AGEP. We describe a case of ALEP triggered by oral clindamycin that occurred during pregnancy.

An increase in lymph flow from melanomas to draining lymph nodes has been reported in animal studies. It has been postulated that this contributes to metastatic potential of cancers. Data from animal studies are not easily extrapolated to humans; animal studies use immunosuppressed animals modified to overexpress lymphangiogenic growth factors, injected with human tumor cell lines, or manipulated to develop aggressive tumors. Human studies are required to investigate lymph flow in humans with cancers such as melanoma.The present study aims to quantify the removal rate constant k (a measure of local lymph flow per unit volume of distribution of the radiotracer) from the vicinity of melanomas, benign nevi, and normal skin in humans in vivo using quantitative lymphoscintigraphy (QL). 16 patients with pigmented lesions underwent QL to quantify k near the lesion (k(perilesion)) and in contralateral matched normal skin (k(control)). The lesions were then excised and, based on histological outcome, the patients were divided into two groups: benign nevus (n=9) and melanoma (n=7). There was no difference between k(perilesion) and k(control) in either the benign naevus (p=0.29, paired t test) or the melanoma group (p=0.93). k(perilesion) in melanomas (0.233±0.123% min(-1)) was not increased relative to k(perilesion) in benign nevi (0.376±0.231% min(-1), p=0.16, unpaired t test).We found no evidence for increased lymphatic drainage in melanoma relative to benign nevi or normal matched skin in humans.

Milroy disease is an inherited autosomal dominant lymphoedema caused by mutations in the gene for vascular endothelial growth factor receptor-3 (VEGFR-3, also known as FLT4). The phenotype has to date been ascribed to lymphatic aplasia. We further investigated the structural and functional defects underlying the phenotype in humans.The skin of the swollen foot and the non-swollen forearm was examined by (i) fluorescence microlymphangiography, to quantify functional initial lymphatic density in vivo; and (ii) podoplanin and LYVE-1 immunohistochemistry of biopsies, to quantify structural lymphatic density. Leg vein function was assessed by colour Doppler duplex ultrasound.Milroy patients exhibited profound (86-91%) functional failure of the initial lymphatics in the foot; the forearm was unimpaired. Dermal lymphatics were present in biopsies but density was reduced by 51-61% (foot) and 26-33% (forearm). Saphenous venous reflux was present in 9/10 individuals with VEGFR3 mutations, including two carriers.We propose that VEGFR3 mutations in humans cause lymphoedema through a failure of tissue protein and fluid absorption. This is due to a profound functional failure of initial lymphatics and is not explained by microlymphatic hypoplasia alone. The superficial venous valve reflux indicates the dual role of VEGFR-3 in lymphatic and venous development.

A 44-year-old man presented with a 2-year history of an intermittent urticarial rash, malaise, weight loss, night sweats, headaches and bone pains. Initial investigations indicated an elevated erythrocyte sedimentation rate, white cell count and a monoclonal immunoglobulin-M paraprotein. Histological examination revealed a perivascular mixed inflammatory infiltrate with leukocytoclasis, nuclear dust without fibrinoid necrosis and extravasated red blood cells. A diagnosis of Schnitzler's syndrome was made. Over an 8-year period, the patient was treated with continuous oral prednisone (minimum dose 20 mg/day) combined with multiple systemic agents. He was commenced on anakinra, a recombinant form of human interleukin-1 receptor antagonist, at a dose of 100 mg injected subcutaneously daily. On review 1 week later, the patient's systemic symptoms had resolved, and his previously elevated white cell count and inflammatory markers had normalized. The use of anakinra in our patient resulted in resolution of symptoms and has enabled cessation of oral prednisone. Our patient remains symptom free on anakinra after 14 months of follow up.

Dermatology clinics represent a key opportunity to screen patients with psoriasis for psoriatic arthritis (PA) which often remains unrecognised. A significant proportion of adults with psoriasis develop arthropathy [5] with around two-thirds having progressive arthritis.[6] NICE has recognised this by the annual use of a validated screening tool such as psoriasis epidemiological screening tool (PEST) on all psoriasis patients without PA. We introduced the PEST into our dermatology department since there was no established system of screening for PA. Twenty-one percent of patients that were identified through PEST as requiring a referral at baseline were not referred to rheumatology through the current system without PEST. This represented a significantly missed proportion of patients with possible PA. Using the PDSA cycle method, we introduced the PEST into cycle 1 and educated key staff about the tool. All eligible patients were referred appropriately. Through doctor and patient feedback, changes were adopted for cycle 2 and informative emails to all key staff about PEST were sent. We noted a drop in the number of PEST uptake in this cycle possibly due to lack of awareness on the purpose and use of PEST among staff, across the department. An educational teaching session was delivered to a wider audience and posters were placed in strategic areas of the department prior to the final cycle. This resulted in 100% PEST uptake and 100% of those with a score of >3 being referred. A total of 51 patients were studied, comprising of 30 eligible patients for PEST. Of these, 27 patients were actually screened (90%) and five with a PEST score of ≥ 3 were identified and referred appropriately (18.5%). We felt this represented a successful outcome in increasing PEST uptake within the department and in capturing a significant proportion of patients at risk of PA.