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Basal cell carcinoma (BCC), the most common keratinocyte cancer, presents a substantial public health challenge due to its high prevalence. Traditional diagnostic methods, which rely on visual examination and histopathological analysis, do not include metabolomic data. This exploratory study aims to molecularly characterize BCC and diagnose tumour tissue by applying matrix‐assisted laser desorption ionization mass spectrometry imaging (MALDI‐MSI) and machine learning (ML). BCC tumour development was induced in a mouse model and tissue sections containing BCC (n = 12) were analysed. The study design involved three phases: (i) Model training, (ii) Model validation and (iii) Metabolomic analysis. The ML algorithm was trained on MS data extracted and labelled in accordance with histopathology. An overall classification accuracy of 99.0% was reached for the labelled data. Classification of unlabelled tissue areas aligned with the evaluation of a certified Mohs surgeon for 99.9% of the total tissue area, underscoring the model's high sensitivity and specificity in identifying BCC. Tentative metabolite identifications were assigned to 189 signals of importance for the recognition of BCC, each indicating a potential tumour marker of diagnostic value. These findings demonstrate the potential for MALDI‐MSI coupled with ML to characterize the metabolomic profile of BCC and to diagnose tumour tissue with high sensitivity and specificity. Further studies are needed to explore the potential of implementing integrated MS and automated analyses in the clinical setting. [ABSTRACT FROM AUTHOR]

Introduction: Ultraviolet radiation (UVR) is the primary risk factor for keratinocyte carcinomas. Oral supplementation with nicotinamide (NAM) is reported to reduce the formation of new keratinocyte carcinomas. NAM's photoprotection is mediated by enhanced DNA repair. We wanted to explore whether NAM in combination with antiproliferative (metformin [Met]) or antioxidant (phloroglucinol [PG]) compounds could potentially enhance its photoprotective effects. Methods: Hairless mice (C3.Cg-Hrhr/TifBomTac) were treated orally with either a standard dose of NAM monotherapy (NAM-mono; 600 mg/kg) or NAM (400 mg/kg) combined with Met (200 mg/kg) (NAM-Met) or PG (75 mg/kg) (NAM-PG). Mice were irradiated with 3.5 standard erythema doses of UVR three times per week to induce tumour development. Photoprotective effects were based on (i) tumour onset of the first three tumours, (ii) skin photodamage, and (iii) DNA damage (cyclobutane pyrimidine dimers [CPDs] and pyrimidine-pyrimidone (6–4) photoproducts [6-4PPs]). Results: All mice treated with NAM demonstrated a delay in tumour onset and reduced tumour burden compared to the UV control group (NAM, NAM-Met, NAM-PG vs. UV control: p ≤ 0.015). NAM-mono and NAM-PG increased time until all three tumours with no difference between them, indicating a similar degree of photoprotection. NAM-mono had no effect on DNA damage compared to the UV control group (p > 0.05), whereas NAM-PG reduced 6-4PP lesions (p < 0.01) but not CPDs (p > 0.05) compared to NAM-mono. NAM-Met delayed the onset of the third tumour compared to the UV control but demonstrated a quicker onset compared to NAM-mono, suggesting inferior photoprotection compared to nicotinamide monotherapy. Conclusion: NAM-PG was as effective in delaying UVR-induced tumour onset as NAM-mono. The reduction in 6-4PP lesions may indicate that the mechanism of NAM-PG is better suited for photoprotection than NAM-mono. NAM-mono was superior to NAM-Met, indicating a dose dependency of NAM's photoprotection. These results highlight the potential for combining photoprotective compounds to enhance photoprotection. Plain Language Summary: Skin cancer is the most common type of cancer seen in the clinic. The amount of lifelong sun exposure and the degree of sunburns are important contributors to the development of skin cancer. Despite massive prevention campaigns promoting better sun habits by staying in the shade and applying sufficient sunscreen, skin cancer cases are still increasing. To address this, researchers are exploring different compounds for oral sun protection. In this study, we tested whether combining vitamin B3 (nicotinamide) with the well-known medication metformin or a known antioxidant called phloroglucinol could enhance its protection against sun-induced skin cancer. Hairless mice were given either nicotinamide alone or nicotinamide at a lower dose combined with either metformin or phloroglucinol through their drinking water and exposed to simulated sunlight 3 times per week to induce skin cancer. We show for the first time that mice treated with all three nicotinamide groups had a delay in skin cancer onset compared to sun-exposed control. Furthermore, we show that the nicotinamide and phloroglucinol combination provides the same sun protection as nicotinamide alone, whereas the combination with metformin did not. Notably, the nicotinamide combined with phloroglucinol provided a reduction in DNA damage, suggesting a better-suited mechanism of action for preventing skin cancer. Overall, the study indicates a potential strategy of combining compounds to enhance oral sun protection to prevent skin cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Skin cancer is the most common cancer in transplant recipients; however, screening may reduce advanced disease. The study aimed to determine referral rates to screening, the incidence, and risk factors of skin cancer in a Danish liver transplant recipient cohort. Of the 246 recipients, 89% were referred to screening and 15.6% were diagnosed with skin cancer or preneoplastic lesions during the screening period. Basal cell carcinoma was the most common skin cancer type followed by squamous cell carcinoma. Actinic keratosis was the most common preneoplastic lesion, followed by Bowen's disease. The time since transplantation and actinic keratosis were identified as independent risk factors of skin cancer. The study determined the incidence and risk factors of skin cancer/preneoplastic lesions in liver transplant recipients enrolled in a screening program, while demonstrating a high screening referral rate. (1) Background: Skin cancer is the most common cancer in transplant recipients. Timely and regular screening may reduce advanced disease. The study aimed to determine referral rates to screening, the incidence, and risk factors of skin cancer in a Danish liver transplant recipient cohort. (2) Methods: All first-time liver transplant recipients, >18 years old, attending outpatient care between January 2018 and December 2021 were included. The referral rates and incidence of skin cancer/preneoplastic lesions were calculated. Risk factors were assessed using Cox regression analyses. (3) Results: Of the 246 included recipients, 219 (89.0%) were referred to screening, and 102 skin cancer/preneoplastic lesions were diagnosed in 32 (15.6%) recipients. The IR of any skin cancer/preneoplastic lesion was 103.2 per 1000 person-years. BCC was the most frequent skin cancer followed by SCC, IR: 51.3 vs. 27.1 per 1000 person-years, respectively. No cases of MM were observed. The IR of actinic keratosis and Bowen's Disease were 48.1 vs. 13.2 per 1000 person-years, respectively. Time since transplantation was independently associated with skin cancer/preneoplastic lesions, HR (95%CI) 2.81 (1.64–4.80). (4) Conclusions: The study determined the incidence and risk factors of skin cancer/preneoplastic lesions in liver transplant recipients enrolled in a screening program, while demonstrating a high screening referral rate. [ABSTRACT FROM AUTHOR]

Keratinocyte-derived skin cancers comprise basal cell carcinoma, squamous cell carcinoma, its precursor actinic keratosis, and Bowen's disease. Historically, this group of neoplasms has been subsumed under the term non-melanoma skin cancer. However, the term nonmelanoma skin cancer can be misleading and lacks precision. Therefore, more precise and reasonable terminology, valuing the relevance of keratinocyte-derived cancer, appears pertinent to meet its clinical and scientific significance. A group of experienced dermatooncologists initiated a consensus approach to promote the use of the term "keratinocyte cancer" instead of "non-melanoma skin cancer" when referring to carcinomas and their precursors that are derived from keratinocytes. The vote among members of the consensus group indicated unanimous agreement on the consistent use of the term "keratinocyte cancer" instead of "non-melanoma skin cancer". International delegates also voted in favour of the revised terminology. The more precise and, by means of etiopathogenesis, correct term "keratinocyte cancer" should be consistently used for malignancies originated from keratinocytes. This is expected to have a positive impact on patient--physician communication and gives better justice to this important group of keratinocyte-derived cancers. [ABSTRACT FROM AUTHOR]

Background and Objectives: Solid organ transplant recipients (SOTRs) are at increased risk of skin cancer and suffer from greater disease-specific morbidity and mortality. To risk stratify the expanding SOTR population for more targeted skin cancer screening, a detailed understanding of risk factors is needed. Using combined clinical and pathological data to capture prevalence of actinic keratosis (AK) and skin cancer, this study aimed to identify risk factors of skin cancer development in a Danish SOTR cohort. Methods: The trial comprised a retrospective cohort study of patients attending organ transplant clinics at the dermatological departments of Bispebjerg and Gentofte Hospitals in Copenhagen, Denmark, between 2009 and 2021. In addition to pathology records, AK prevalence was determined by review of electronic medical records (EMRs) of SOTR visits which specifically included descriptions of clinical AK. Prevalence of skin cancer, here defined as basal cell carcinoma (BCC), squamous cell carcinoma (SCC) (invasive or in situ), or melanoma (invasive or in situ), was determined by EMR and pathology code review. Additional data extracted from EMRs included age, sex, Fitzpatrick skin type, transplantation date and type, and immunosuppressive therapy. The effect of risk factors on skin cancer was calculated by Cox proportional hazards regression. Results: A total of 822 SOTRs were included with a mean follow-up duration of 10.8 years (SD 2.4 years). A skin dysplasia diagnosis was identified in 30% (n = 250) of the population, consisting of either AK (22%; n = 177), skin cancer (23%; n = 186) or both (14%; n = 113). An AK diagnosis predicted both SCC (odds ratio [OR]: 31.5 [95% CI: 9.8–100.6], p < 0.0001) and BCC development (OR: 2.3 [95% CI: 1.6–3.3], p < 0.0001), with AKs diagnosed an average 3.1 years before the first SCC (p < 0.0001). Correspondingly, while the risk of SCC in SOTRs without AK was 1.4% 25 years after transplantation, SOTRs with AKs had a 23% SCC risk only 10 years posttransplant. Other identified risk factors included Fitzpatrick skin type I (BCC: OR: 2.4 [95% CI: 1.2–5.0], p = 0.018; SCC: 3.2 [95% CI: 1.2–8.2], p = 0.016) and transplantation duration >15 years (BCC: OR: 1.8 [95% CI: 1.2–2.7], p = 0.007). No significant association between skin cancer development and sex or immunosuppressive regimen was shown. Conclusion: Keratinocyte carcinoma is strongly associated with an AK diagnosis in SOTRS and should prompt intensified skin cancer screening in affected individuals. [ABSTRACT FROM AUTHOR]

Actinic keratoses are pre-malignant skin lesions that require personalized care, a lack of which may result in poor treatment adherence and suboptimal outcomes. Current guidance on personalizing care is limited, notably in terms of tailoring treatment to individual patient priorities and goals and supporting shared decisionmaking between healthcare professionals and patients. The aim of the Personalizing Actinic Keratosis Treatment panel, comprised of 12 dermatologists, was to identify current unmet needs in care and, using a modified Delphi approach, develop recommendations to support personalized, long-term management of actinic keratoses lesions. Panellists generated recommendations by voting on consensus statements. Voting was blinded and consensus was defined as ≥75% voting ’agree’ or ’strongly agree’. Statements that reached consensus were used to develop a clinical tool, of which, the goal was to improve understanding of disease chronicity, and the need for long-term, repeated treatment cycles. The tool highlights key decision stages across the patient journey and captures the panellist’s ratings of treatment options for attributes prioritized by patients. The expert recommendations and the clinical tool can be used to facilitate patient-centric management of actinic keratoses in daily practice, encompassing patient priorities and goals to set realistic treatment expectations and improve care outcomes. [ABSTRACT FROM AUTHOR]

Background: The suspected link between human papillomavirus (HPV) and the development of premalignant and malignant skin lesions remains inadequately examined in clinical settings. This case series describes HPV vaccination as an off-label adjuvant therapy for actinic keratosis (AK). Methods: Twelve immunocompetent AK patients underwent HPV vaccination at a private dermatology clinic in Naestved, Denmark. Prior to vaccination, all patients demonstrated a high AK burden that required regular control visits. At 0, 2, and 6 months, the patients received an intramuscular injection of a commercially available 9-valent HPV vaccine. Concurrently, patients continued conventional AK therapies at 3-month intervals. Clinical response, consisting of reduction in AK number and general change in skin appearance, was assessed by a dermatologist over 12 months following first vaccination. Results: All patients (mean age 76.2 years; 10 M and 2 F) completed the vaccine schedule. Overall, an average 85% reduction in total AK burden was recorded 12 months after beginning vaccination. Median AK burden thus fell from 56 (IQR: 44–80) to 13.5 (IQR: 1–18) lesions after 12 months. Lesion reduction was observable by the second inoculation at month 2 (34 AKs; IQR 22–80), continuing steadily until month 6 (15 AKs; IQR 5–30) and plateauing between 6 and 12 months. Clinically, HPV vaccination elicited fading of lesions' erythematous background after the first dose, often followed by sloughing of hyperkeratotic elements in subsequent weeks. Patients reported no adverse effects related to HPV vaccination. Conclusion: This case series introduces the possibility that 9-valent HPV vaccination in combination with conventional treatments may be used as a therapeutic strategy for AK. [ABSTRACT FROM AUTHOR]

Bleomycin exhibits antiproliferative effects desirable for use in dermato-oncology but topical use is limited by its 1415 Da molar mass. Ablative fractional laser (AFL)-assisted drug delivery has been shown to enhance drug uptake in skin. The aim of this study was with AFL to deliver bleomycin into skin, quantify uptake, and visualize biodistribution with mass spectrometry. In a Franz diffusion cell study, pig skin samples (n = 66) were treated with AFL (λ = 10,600 nm), 5% density, and 0, 5, 20, or 80 mJ/microbeam (mb) pulse energies before exposure to bleomycin for 0.5, 4, or 24 h. Bleomycin was quantified in biopsy cryosections at depths of 100, 500, and 1500 µm using high-performance liquid chromatography-mass spectrometry (LC-MS), and drug biodistribution was visualized for 80 mJ/mb samples by matrix assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). The pulse energies 5, 20, and 80 mJ/mb resulted in microscopic ablation zones (MAZs) reaching superficial, mid, and deep dermis respectively. Bleomycin was successfully delivered into the skin and deeper MAZs and longer exposure time resulted in higher skin concentrations. After 24 h, AFL exposure resulted in significant amounts of bleomycin throughout all skin layers (≥510 µg/cm3, p ≤.002). In comparison, concentrations in intact skin exposed to bleomycin remained below limit of quantification. MALDI-MSI supported the quantitative LC-MS results by visualizing bleomycin biodistribution and revealing high uptake around MAZs with delivery into surrounding skin tissue. In conclusion, topical drug delivery of the large and hydrophilic molecule bleomycin is feasible, promising, and should be explored in an in vivo setting. [ABSTRACT FROM AUTHOR]

The article "Reply to 'Commentary on: A European Consensus on the Consistent Use of the Term 'Keratinocyte Cancer': Keratinocyte Cancer (KC) or Keratinocyte Skin Cancer (KSC) -- Does the 'S' Matter?" discusses the terminology surrounding keratinocyte cancer and the importance of consistent usage. The authors express gratitude for the acknowledgment of their work in advancing understanding in patient and physician communication. They emphasize the established use of the term "KC" in Anglo-American literature and its integration into modern European dermatology. [Extracted from the article]

The efficacy of nonablative fractional laser resurfacing of acne scars has been described in case reports and uncontrolled trials. The present study is the first randomized controlled trial in this field. The aim of this study was to examine the efficacy and adverse effects of 1,540-nm nonablative fractional laser treatment of acne scars. Ten patients with acne scars were included. Two intraindividual areas of similar size and appearance within contralateral anatomical regions were randomized to (1) 3-monthly laser treatments with a StarLux 1,540-nm fractional handpiece, and (2) no treatment. Blinded on-site clinical evaluations were performed before treatment, and at 4 and 12 weeks after the final treatment. End-points were overall change in scar texture (from score 0, even texture, to 10, worst possible scarring), adverse effects, change in skin colour (from score 0, absent, to 10, worst possible), and patient satisfaction (from score 0, no satisfaction, to 10, best imaginable satisfaction). Before treatment, scars were moderately atrophic and uneven in texture on both treated and untreated sides (median score 6.5, interquartile range 4.5-8; P=1). After treatment, laser-treated scars appeared more even and smooth than untreated control areas (4.5, 2-6.5, versus 6.5, 4.5-8, P=0.0156, at 4 weeks; 4.5, 2.5-6.5, versus 6.5, 4.5-8, at 12 weeks; P=0.0313). Patients were satisfied with the treatment (5.5, 1-7, after 12 weeks) and five of the ten patients evaluated their acne scars as moderately or significantly improved. No differences were found in skin redness or pigmentation between before and after treatment. Patients experienced moderate pain, erythema, oedema, bullae, and crusts. No adverse effects were seen in untreated control areas. The nonablative 1,540-nm fractional laser improves acne scars with a minimum of adverse effects. [ABSTRACT FROM AUTHOR]

Aim of database: The Danish Nonmelanoma Skin Cancer Dermatology Database was established in 2008. The aim of this database was to collect data on nonmelanoma skin cancer (NMSC) treatment and improve its treatment in Denmark. NMSC is the most common malignancy in the western countries and represents a significant challenge in terms of public health management and health care costs. However, high-quality epidemiological and treatment data on NMSC are sparse. Study population: The NMSC database includes patients with the following skin tumors: basal cell carcinoma (BCC), squamous cell carcinoma, Bowen's disease, and keratoacanthoma diagnosed by the participating office-based dermatologists in Denmark. Main variables: Clinical and histological diagnoses, BCC subtype, localization, size, skin cancer history, skin phototype, and evidence of metastases and treatment modality are the main variables in the NMSC database. Information on recurrence, cosmetic results, and complications are registered at two follow-up visits at 3 months (between 0 and 6 months) and 12 months (between 6 and 15 months) after treatment. Descriptive data: In 2014, 11,522 patients with 17,575 tumors were registered in the database. Of tumors with a histological diagnosis, 13,571 were BCCs, 840 squamous cell carcinomas, 504 Bowen's disease, and 173 keratoakanthomas. Conclusion: The NMSC database encompasses detailed information on the type of tumor, a variety of prognostic factors, treatment modalities, and outcomes after treatment. The database has revealed that overall, the quality of care of NMSC in Danish dermatological clinics is high, and the database provides the necessary data for continuous quality assurance. [ABSTRACT FROM AUTHOR]

Objectives The incidence of actinic keratosis ( AK) is increasing, and several treatment options are available. The aim of this study was to describe clinical characteristics and treatment patterns in patients with AK treated by Danish dermatologists. Methods A multicenter, non-interventional, cross-sectional study was conducted. Three dermatology hospital departments and seven private dermatology clinics enrolled eligible AK patients consecutively during one week. Results A total of 312 patients were included. Non-melanoma skin cancer ( NMSC) was previously reported in 51.0% of patients and currently suspected in 9.4% of AK-affected anatomical regions. Lesions of AK were located primarily on the face (38.6%), scalp (12.8%), and hands (11.2%). Actinic keratosis commonly presented with multiple AK lesions (38.6%) and field cancerization (38.5%). The treatments used most frequently were cryotherapy (57.7%) and photodynamic therapy ( PDT) with methyl aminolevulinate (17.1%) and imiquimod (11.2%). The likelihood of receiving cryotherapy was higher for men (odds ratio [OR] 1.65, 95% confidence interval [CI] 1.10-2.47) and increased with age (2.2% per year, 0.4-4.0%). PDT represented the most frequently applied treatment for severe actinic damage and was more likely to be prescribed to women ( OR 4.08, 95% CI 2.22-7.47) and young patients ( OR 0.97 per year, 95% CI 0.95-0.99). The prevalence of severe actinic damage (17.3% versus 9.6%) and intake of immunosuppressive medication (29.0 versus 2.0) were higher among hospital patients compared with those treated in private practices ( P < 0.0001). Conclusions The majority of AK patients in Danish dermatology clinics have a history of skin cancer, and NMSC is suspected in almost 10% of AK-affected regions. Cryotherapy is the most frequently used treatment overall, except in instances of severe actinic damage, in which PDT is the first-choice treatment. [ABSTRACT FROM AUTHOR]

Topical photodynamic therapy (PDT) with methyl-aminolevulinate (MAL) is a well-established treatment for precancerous skin lesions and non-melanoma skin cancer. Treatment outcomes are less effective for thick than for superficial lesions, which are presumed to be due to insufficient PpIX biodistribution in tumour tissue. Hexyl-aminolevulinate (HAL) is a more lipophilic photosensitizer precursor than MAL and may penetrate the skin to a greater depth and more homogeneously. We compared HAL- and MAL-induced PpIX accumulation in specific skin compartments using concentrations of 2%, 6% and 20% HAL and MAL on long-term UV-irradiated mouse skin. Furthermore, 20% HAL and 20% MAL were applied to non-irradiated skin. Porphyrin fluorescence was measured by fluorescence microscopy in selected skin regions: the epidermis, superficial dermis, deep dermis and sebaceous gland epithelium down to a depth of 1 mm. We found higher PpIX fluorescence intensities in epidermis and sebaceous gland epithelium from 2%, 6% and 20% HAL (median 72-104 au) than in corresponding concentrations of MAL (median 35-69 au) ( P < 0.01). Fluorescence intensities in the superficial (35 au) and deep dermis (32 au) were similar for HAL and MAL ( P = 0.51) and lower than epidermal fluorescence intensities ( P < 0.001). Significantly, higher median PpIX fluorescence intensities (64 au) were found in 20% MAL-incubated skin irradiated with UV than in non-irradiated skin (48 au) ( P < 0.001). HAL-induced fluorescence intensities did not depend on UV exposure (HAL 20%, UV: 72 au, non-UV: 70 au) ( P = 0.87). In conclusion, HAL express high affinity for epidermis and sebaceous gland epithelium, and MAL for actinically damaged skin, which raises future perspectives for improved selectivity in PDT. [ABSTRACT FROM AUTHOR]

Background: Ultraviolet (UV) radiation induces non-melanoma skin cancer (NMSC), and UV prophylaxis is essential to prevent skin cancer. It is unclear whether patients diagnosed with squamous cell carcinomas (SCC) may benefit from reduced UV exposures in terms of delaying the development of new tumors. The objective was to evaluate the significance of discontinued or reduced UV exposure for the development of subsequent skin tumors. Methods: Seven groups of mice ( n=175) were irradiated with UV doses of 2 and 4 standard erythema doses (SED) that were continued, reduced or discontinued at the time of appearance of the first skin tumor. Results: The development of new tumors was delayed, corresponding to the degree of reductions in UV dose in an inversely linear manner. Discontinuation of UV doses delayed the median times to the second tumor by 24 days (2 SED, P=0.0549) and 33.5 days (4 SED, P<0.0001), and when reduced to 1 SED, the median delays were 18 days (2 SED, P=0.0469) and 33 days (4 SED, P<0.0001). The median delay to the third tumor was after UV reduction 47 days (4 SED, P<0.0001) and 35 days (2 SED, P=0.151), and after UV discontinuation 49 days (4 SED, P<0.0001) and 44 days (2 SED, P=0.111). Conclusion: This suggests that patients with SCC may benefit from reduced UV exposure. [ABSTRACT FROM AUTHOR]

Short-wave ultraviolet radiation (UVB) is the most carcinogenic part of the ultraviolet spectrum. The target cells of skin cancer are believed to be the bulge stem cells and/or their offspring, the transit-amplifying cells that reside in the epidermis. However, the amount of UVB penetrating epidermis and reaching the bulge cells is very low, which questions if these cells suffer sufficient DNA damage to transform into cancer stem cells. We performed this study to determine whether UV-induced squamous cell carcinoma (SCC) originates from the epidermis or the hair follicles in mice. Hairless mice had their epidermis removed at different levels using CO2 laser ablation. Simulated solar irradiations were administered either preoperatively (in total 7 weeks) or pre- and postoperatively (in total 30 weeks). Control groups were untreated or treated only with solar-simulated radiation or with laser. Blinded clinical assessments of skin tumors were carried out weekly during 12 months observation. Only mice irradiated with solar-simulated radiation both pre- and postoperatively developed tumors. Median time to first, second and third tumor ranged from 19 to 20.5 weeks and was not significantly different between the non-laser and laser-treated groups ( P > 0.05). The tumor response was thus similar in UV-exposed mice whether they had their epidermis removed or not. No tumors appeared in control groups. Hence, UV-induced SCC of mice originates from cells of the hair follicle, presumably the bulge stem cells, indicating that ultraviolet radiation penetrates epidermis sufficiently to cause irreversible DNA damage in cells located beneath the epidermis. [ABSTRACT FROM AUTHOR]

Simple Summary: Keratinocyte carcinoma is the most common type of cancer. Sun exposure and ultraviolet radiation are significant contributors to the development of carcinogenesis, mediated by DNA damage, increased oxidative stress, inflammation, immunosuppression and dysregulated signal transduction. Photoprevention involves using different compounds to delay or prevent ultraviolet radiation-induced skin cancer. In this review, we look at new avenues for systemic photoprevention that are based on pharmaceuticals, plant-derived phytochemicals and vitamins. We also investigate the mechanisms underlying these strategies for preventing the onset of carcinogenesis. Ultraviolet radiation (UVR) arising from sun exposure represents a major risk factor in the development of keratinocyte carcinomas (KCs). UVR exposure induces dysregulated signal transduction, oxidative stress, inflammation, immunosuppression and DNA damage, all of which promote the induction and development of photocarcinogenesis. Because the incidence of KCs is increasing, better prevention strategies are necessary. In the concept of photoprevention, protective compounds are administered either topically or systemically to prevent the effects of UVR and the development of skin cancer. In this review, we provide descriptions of the pathways underlying photocarcinogenesis and an overview of selected photoprotective compounds, such as repurposed pharmaceuticals, plant-derived phytochemicals and vitamins. We discuss the protective potential of these compounds and their effects in pre-clinical and human trials, summarising the mechanisms of action involved in preventing photocarcinogenesis. [ABSTRACT FROM AUTHOR]

Importance Ultraviolet radiation (UVR)-induced skin cancers varies among organ transplant recipients (OTRs). To improve individual risk assessment of skin cancer, objectively quantified skin photodamage is needed. Objectives We measured personal UVR-exposure dose in OTRs and assessed the relation between individual UVR exposure, skin cancer and objectively measured photodamage in terms of skin autofluorescence, pigmentation, and black light-evaluated solar lentigines. Materials and Methods Danish OTRs with (n = 15) and without a history of skin cancer (n = 15) kept sun diaries from May to September and wore personal dosimeters recording time-stamped UVR doses in standard erythema doses (SED). Photodamage was quantified as skin autofluorescence with excitation at 370 nm ( F 370) and 430 nm ( F 430), skin pigmentation (pigment protection factor, PPF), and black light-evaluated solar lentigines. Results OTRs with skin cancer received a higher UVR dose than OTRs without skin cancer (median 116 SED vs. 67 SED, p = 0.07) and UVR exposure doses were correlated with increased PPF (p = 0.052) and F 370 on the shoulder ( F 370 shoulder ) (p = 0.04). We found that skin cancer was associated with F 370 shoulder (OR 10.53, CI 3.3–31,938; p = 0.018) and time since transplantation (OR 1.34, CI 0.95–1.91, p = 0.097). A cut-off at 7.2 arbitrary units, 89% of OTRs with skin cancer had F 370 shoulder values above 7.2 arbitrary units and F 370 shoulder was additionally related to patient age (p = 0.09) and black light-evaluated solar lentigines (p = 0.04). Conclusion F 370 autofluorescence indicates objectively measured photodamage and may be used for individual risk assessment of skin cancer development in OTRs. [ABSTRACT FROM AUTHOR]

The effectiveness of topical drugs for treatment of non-melanoma skin cancer is greatly reduced by insufficient penetration to deep skin layers. Ablative fractional lasers (AFLs) are known to enhance topical drug uptake by generating narrow microchannels through the skin, but information on AFL-drug delivery in in vivo conditions is limited. In this study, we examined pharmacokinetics, biodistribution and toxicity of two synergistic chemotherapy agents, cisplatin and 5-fluorouracil (5-FU), following AFL-assisted delivery alone or in combination in in vivo porcine skin. Detected at 0–120 h using mass spectrometry techniques, we demonstrated that fractional CO 2 laser pretreatment (196 microchannels/cm 2 , 852 μm ablation depth) leads to rapid drug uptake in 1500 μm deep skin layers, with a sixfold enhancement in peak cisplatin concentrations versus non-laser-treated controls (5 h, P  = 0.005). Similarly, maximum 5-FU deposition was measured within an hour of AFL-delivery, and exceeded peak deposition in non-laser-exposed skin that had undergone topical drug exposure for 5 days. Overall, this accelerated and deeper cutaneous drug uptake resulted in significantly increased inflammatory and histopathological effects. Based on clinical scores and transepidermal water loss measurement, AFL intensified local toxic responses to drugs delivered alone and in combination, while systemic drug exposure remained undetectable. Quantitative histopathologic analyses correspondingly revealed significantly reduced epidermal proliferation and greater cellular apoptosis after AFL-drug delivery; particularly after combined cisplatin + 5-FU exposure. In sum, by overcoming the primary limitation of topical drug penetration and providing accelerated, enhanced and deeper delivery, AFL-assisted combination chemotherapy may represent a promising treatment strategy for non-melanoma skin cancer. [ABSTRACT FROM AUTHOR]

Ultraviolet radiation is the primary risk factor for keratinocyte carcinoma. Because of increasing incidence rates, new methods of photoprotection must be explored. Oral supplementation with photoprotective compounds presents a promising alternative. Phytochemical compounds like hesperidin methyl chalcone, phloroglucinol, and syringic acid are particularly of interest because of their antioxidant properties. Our primary outcome was to evaluate the effects of oral phytochemicals on photocarcinogenesis with time until tumour onset as the primary endpoint. A total of 125 hairless C3.Cg- Hr hr /TifBom Tac mice were randomised to receive tap water supplemented with either 100 mg/kg hesperidin methyl chalcone, phloroglucinol, or syringic acid, 600 mg/kg nicotinamide as a positive control, or no supplementation. The mice were irradiated with 3.5 standard erythema doses thrice weekly to induce photocarcinogenesis. Supplementation with the phytochemicals phloroglucinol and syringic acid and nicotinamide delayed tumour onset from a median of 140 days to 151 (p = 0.036), 157 days (p = 0.02), and 178 (p = 2.7·10−5), respectively. Phloroglucinol and nicotinamide supplementation reduced tumour number. Nicotinamide increased UV-induced pigmentation and reduced oedema formation, while phloroglucinol supplementation reduced epidermal thickness. These results indicate that oral supplementation with phloroglucinol and syringic acid protects against photocarcinogenesis in hairless mice, but not to the same extent as nicotinamide. • Keratinocyte carcinoma incidence rates are increasing. • Oral photoprotection is a promising alternative to other prevention methods. • Phytochemical supplementation protects against photocarcinogenesis in hairless mice. • Oral nicotinamide increases UV radiation-induced pigmentation. [ABSTRACT FROM AUTHOR]

Background and Aim The incidence of squamous cell carcinomas (SCC) is increasing, and effective chemopreventative strategies are needed. We hypothesized that repeated treatments with ingenol mebutate (IngMeb) would postpone development of SCC in hairless mice, and that application of a corticosteroid would reduce IngMeb-induced local skin responses (LSRs) without affecting tumor postponement. Methods Hairless mice ( n = 150; 6 groups á 25 mice) were irradiated with solar simulated ultraviolet radiation (UVR) until SCC developed. During UV-irradiation and before tumor development, five single treatments (Tx) with IngMeb were given at four-week intervals (days 21, 49, 77, 105, 133). Clobetasol propionate (CP) was applied once daily for 5 days prior to IngMeb, as well as 6 h and 1 day post treatment. Tumor formation was evaluated weekly for 52 weeks. LSR (scale 0–24) were assessed at baseline, 1 h, 6 h, 1-, 2-, 3-, 4-, 5-, 6-, and 7 days after each IngMeb treatment. Results IngMeb significantly delayed tumor development compared to UVR alone (UVR day 168 vs. UVR + IngMeb day 189; p = 0.025). LSR included erythema, flaking, crusting, bleeding, vesiculation, and ulceration. The composite LSR-scores were of moderate intensity in non-UV irradiated skin (max LSR IngMeb Tx 1–5: 1.5–2.5) and more pronounced in photodamaged skin (max LSR Tx 5; IngMeb 1.5 vs. UVR + IngMeb 1.8; p < 0.001). LSR intensity correlated with tumor development by means of greater composite LSR-score resulted in longer tumor-free survival (r 2 = 0.257, p < 0.001). Contrary to our hypothesis, concurrent CP increased LSR (max LSR Tx 1–5: UVR + CP + IngMeb 3.2–4.9 vs. UVR + IngMeb 1.3–2.2, p < 0.001) and postponed tumor development compared to IngMeb alone (UVR + CP + IngMeb day 217 vs. UVR + IngMeb day 189, p < 0.001). Conclusion Repeated field-directed treatments with IngMeb delay development of UV-induced SCC in hairless mice, and increased IngMeb induced LSRs correlated with improved clinical outcomes. The findings highlight the potential of IngMeb as a prophylactic remedy for SCC in humans. [ABSTRACT FROM AUTHOR]