Nicotinamide for Skin-Cancer Chemoprevention in Transplant Recipients.

BACKGROUND: Immunosuppressed organ-transplant recipients have an increased incidence of, and mortality from, skin cancer. Nicotinamide (vitamin B3) enhances the repair of ultraviolet (UV) radiation-induced DNA damage, reduces the cutaneous immunosuppressive effects of UV radiation, and reduces the incidence of keratinocyte cancers (including squamous-cell and basal-cell carcinomas) and actinic keratoses among high-risk immunocompetent patients. Whether oral nicotinamide is useful for skin-cancer chemoprevention in organ-transplant recipients is unclear. METHODS: In this phase 3 trial, we randomly assigned, in a 1:1 ratio, organ-transplant recipients who had had at least two keratinocyte cancers in the past 5 years to receive 500 mg of nicotinamide or placebo twice daily for 12 months. Participants were examined for skin lesions by dermatologists at 3-month intervals for 12 months. The primary end point was the number of new keratinocyte cancers during the 12-month intervention period. Secondary end points included the numbers of squamous-cell and basal-cell carcinomas during the 12-month intervention period, the number of actinic keratoses until 6 months after randomization, safety, and quality of life. RESULTS: A total of 158 participants were enrolled, with 79 assigned to the nicotinamide group and 79 to the placebo group. The trial was stopped early owing to poor recruitment. At 12 months, there were 207 new keratinocyte cancers in the nicotinamide group and 210 in the placebo group (rate ratio, 1.0; 95% confidence interval, 0.8 to 1.3; P = 0.96). No significant between-group differences in squamous-cell and basal-cell carcinoma counts, actinic keratosis counts, or quality-of-life scores were observed. Adverse events and changes in blood or urine laboratory variables were similar in the two groups. CONCLUSIONS: In this 12-month, placebo-controlled trial, oral nicotinamide therapy did not lead to lower numbers of keratinocyte cancers or actinic keratoses in immunosuppressed solid-organ transplant recipients. (Funded by the National Health and Medical Research Council; ONTRANS Australian New Zealand Clinical Trials Registry number, ACTRN12617000599370.).

Assessment of reflectance confocal microscopy for monitoring treatment of actinic keratosis and field cancerization with daylight photodynamic therapy.

Actinic keratosis (AK) is the most common pre-malignant cutaneous lesion of the skin, often associated with field cancerization. Daylight photodynamic therapy (DL-PDT) is used as treatment, showing good histological results. Reflectance confocal microscopy (RCM) may be useful as a non-invasive, real-time approach to monitor treatment, however, there is a lack of data on the correlation between RCM and histopathological findings in AK patients treated with DL-PDT. To correlate histological and RCM findings and evaluate the efficacy of DL-PDT in patients with AK and field cancerization treated with DL-PDT. Patients with field cancerization and a minimum of six AK lesions on the face were included in the study. A single session combining methyl aminolevulinate followed by two-hour daylight exposure of the face was performed. RCM and biopsy were performed before and after three months of the intervention to compare efficacy between patients using the Wilcoxon test, and concordance of the findings based on the different methods was analysed using the Kappa test. Twenty-four patients completed the study. An improvement in photodamage and a decrease in the number of AK lesions (45.3% reduction) was observed. Regression in atypia and dysplasia was observed via histopathology and RCM, however, there was poor agreement between the methods. No changes were observed after treatment for inflammation, fibroplasia and acantholysis. Concordance between histological and RCM findings was poor, suggesting that RCM cannot replace the histopathological examination, however, it may be used as an adjuvant test for follow-up of patients. Despite this, DL-PDT proved to be an effective method for treating AK.

The Preventive Value of Sun Protection.

BACKGROUND: With more than 200,000 new cases per year, skin tumours have been the most frequently reported cancers in Germany for years. We performed a systematic review to summarise the current evidence concerning the preventive value of regular sunscreen use. METHODS: Systematic literature review of controlled and randomised controlled trials were performed in Ovid Embase and Ovid Medline on 21 January 2020. We included studies evaluating the effectiveness of sunscreens on epithelial skin cancer, actinic keratosis or photoageing, or side effects in humans. RESULTS: Five eligible trials, each involving 28 to 1,621 participants from various populations, were identified. All 4 studies on actinic keratoses showed a significant beneficial effect of sunscreens. The 2 studies on squamous cell carcinoma demonstrated significant beneficial effects of sunscreens. The 2 studies on photoageing observed a significant reduction in the sunscreen groups. The 2 studies on basal cell carcinoma reported no significant results, but both studies reported some non-significant protective effects of sunscreen use. Sunscreens as well as vehicles sometimes had side effects affecting skin and eyes. Compared with controls, sunscreens had no significant side effects on vitamin D, bone mass density and mortality. CONCLUSION: The evidence from published controlled and randomised controlled studies is limited. Especially for basal cell carcinoma, further high-quality studies including young populations are required to investigate possible protective effects of modern broad-spectrum sunscreens. The results of this systematic review do not change the current recommendations for UV protection. Sunscreens are recommended as a second-line measure against solar radiation whenever protective clothing and seeking shake are inadequate.

Consensus-Based Recommendations on the Prevention of Squamous Cell Carcinoma in Solid Organ Transplant Recipients: A Delphi Consensus Statement.

IMPORTANCE: There is a paucity of evidence to guide physicians regarding prevention strategies for cutaneous squamous cell carcinoma (CSCC) in solid organ transplant recipients (SOTRs). OBJECTIVE: To examine the development and results of a Delphi process initiated to identify consensus-based medical management recommendations for prevention of CSCC in SOTRs. EVIDENCE REVIEW: Dermatologists with more than 5 years' experience treating SOTRs were invited to participate. A novel actinic damage and skin cancer index (AD-SCI), consisting of 6 ordinal stages corresponding to an increasing burden of actinic damage and CSCC, was used to guide survey design. Three sequential web-based surveys were administered from January 1, 2019, to December 31, 2020. Pursuant to Delphi principles, respondents thoroughly reviewed all peer responses between rounds. Supplemental questions were also asked to better understand panelists' rationale for their responses. FINDINGS: The Delphi panel comprised 48 dermatologists. Respondents represented 13 countries, with 27 (56%) from the US. Twenty-nine respondents (60%) were Mohs surgeons. Consensus was reached with 80% or higher concordance among respondents when presented with a statement, question, or management strategy pertaining to prevention of CSCC in SOTRs. A near-consensus category of 70% to less than 80% concordance was also defined. The AD-SCI stage-based recommendations were established if consensus or near-consensus was achieved. The panel was able to make recommendations for 5 of 6 AD-SCI stages. Key recommendations include the following: cryotherapy for scattered actinic keratosis (AK); field therapy for AK when grouped in 1 anatomical area, unless AKs are thick in which case field therapy and cryotherapy were recommended; combination lesion directed and field therapy with fluorouracil for field cancerized skin; and initiation of acitretin therapy and discussion of immunosuppression reduction or modification for patients who develop multiple skin cancers at a high rate (10 CSCCs per year) or develop high-risk CSCC (defined by a tumor with approximately ≥20% risk of nodal metastasis). No consensus recommendation was achieved for SOTRs with a first low risk CSCC. CONCLUSIONS AND RELEVANCE: Physicians may consider implementation of panel recommendations for prevention of CSCC in SOTRs while awaiting high-level-of-evidence data. Additional clinical trials are needed in areas where consensus was not reached.

Dopamine Prevents Ultraviolet B-induced Development and Progression of Premalignant Cutaneous Lesions through its D2 Receptors.

Although the role of dopamine (DA) in malignant tumors has been reported, its function in premalignant lesions is unknown. Herein we report that the stimulation of DA D2 receptors in endothelial cells in ultraviolet B (UVB)-induced cutaneous lesions in mice significantly reduced the tumor number, tumor burden, and malignant squamous cell carcinoma in these animals. DA D2 receptor agonist inhibited VEGFA-dependent proangiogenic genes in vitro and in vivo. However, the mice pretreated with selective DA D2 receptor antagonist inhibited the actions of the agonist, thereby suggesting that the action of DA was through its D2 receptors in the endothelial cells. To our knowledge, this study is the first to report DA-mediated regulation of pathogenesis and progression of UVB-induced premalignant skin lesions. PREVENTION RELEVANCE: This investigation demonstrates the role of dopamine and its D2 receptors in UVB induced premalignant squamous cell skin lesions and how DA through its D2 receptors inhibits the development and progression of these lesions and subsequently prevents squamous cell carcinoma of the skin.

Loss of retinoic acid receptor-related receptor alpha (Rorα) promotes the progression of UV-induced cSCC.

Cutaneous squamous cell carcinoma (cSCC) is prevalent in the world, accounting for a huge part of non-melanoma skin cancer. Most cSCCs are associated with a distinct pre-cancerous lesion, the actinic keratosis (AK). However, the progression trajectory from normal skin to AK and cSCC has not been fully demonstrated yet. To identify genes involved in this progression trajectory and possible therapeutic targets for cSCC, here we constructed a UV-induced cSCC mouse model covering the progression from normal skin to AK to cSCC, which mimicked the solar UV radiation perfectly using the solar-like ratio of UVA and UVB, firstly. Then, transcriptome analysis and a series of bioinformatics analyses and cell experiments proved that Rorα is a key transcript factor during cSCC progression. Rorα could downregulate the expressions of S100a9 and Sprr2f in cSCC cells, which can inhibit the proliferation and migration in cSCC cells, but not the normal keratinocyte. Finally, further animal experiments confirmed the inhibitory effect of cSCC growth by Rorα in vivo. Our findings showed that Rorα would serve as a potential novel target for cSCC, which will facilitate the treatment of cSCC in the future.

Actinic Keratoses: Reconciling the Biology of Field Cancerization with Treatment Paradigms.

This Perspective briefly reviews the relationship between UV-induced mutations in habitually sun-exposed human skin and subsequent development of actinic keratoses (AKs) and skin cancers. It argues that field therapy rather than AK-selective therapy is the more logical approach to cancer prevention and hypothesizes that treatment early in the process of field cancerization, even prior to the appearance of AKs, may be more effective in preventing cancer as well as more beneficial for and better tolerated by at-risk individuals. Finally, the Perspective encourages use of rapidly advancing DNA analysis techniques to quantify mutational burden in sun-damaged skin and its reduction by various therapies.

P53 staining index and zonal staining patterns in actinic keratoses.

Actinic keratoses (AKs) are common dysplastic lesions resulting from chronic excessive ultraviolet exposure. Neither the clinical grade of thickness nor the histological grade of dysplasia seems valid predictors of aggressive potential of AKs. Instead, the mutational status in AKs appears to predict well the clinical course. TP53 gene mutations result in a non-functional protein resistant to degradation, thus immunohistochemical staining for p53 can suggest mutation status. Increased p53 was associated with progression from AK to squamous cell carcinoma. To investigate how the intensity of p53 staining (p53 staining index) varies according to body site, histological subtype and grade dysplasia of AKs. Secondly, we sought to investigate the distribution in the epidermal layers of non-functional p53 (zonal staining patterns). p53 staining index was greater than 50% in 90.7% of AKs. p53 staining index was significantly higher in older age (p < 0.0093) and in facial AKs compared to other body areas (p = 0.03). A significant correlation between p53 staining index and grade of dysplasia was observed (p = 0.006) and between p53 staining index and zonal p53 staining pattern (p = 0.003). No significant differences in p53 staining index among the various histological AK types were observed. No correlation between clinical and histological grade. All AKs, independently from their clinical appearance, should be treated but special attention is required for AKs on severely photodamaged skin on the face and in older patients.

Field Therapy in Solid Organ Transplant Recipients: Are We Initiating Early Enough?

Organ transplant recipients (OTRs) are at increased risk for more aggressive non-melanoma skin cancer (NMSC). Recent emphasis on field therapy has complimented the canonical surgical treatment paradigm. This retrospective analysis of survey responses by patients seen at Oregon Health and Science University from 2013-2018 offers insights into patient trends and practice gaps in caring for OTRs. All patients completed a 57-point questionnaire at their first clinic visit, which included questions regarding demographics, transplant history, dermatologic history, and use of field therapy. Of the 295 patients (mean age, 56 years; M/F: 193/102) who completed the questionnaire, field therapy was reported by 31 (11%) patients. Field therapy patients noted an overall higher AK and SCC burden, with a greater proportion of patients reporting >20 AKs and >10 SCCs. Field therapy use was sparse in the low AK/low SCC group (n=25) when compared to those reporting high AK/high SCC (n=11) burden (n=4 (16%) vs n=8 (73%), P<0.01). This data suggests that OTRs with several clinically evident AKs and/or a low number of SCCs are less likely to have been treated with field therapy modalities compared to OTRs who have developed >10 AKs or ≥6 SCCs. A delay in initiation of preventative measures or field therapy in this population, however, may be a missed opportunity for intervention. Early intervention with field therapy in particularly high-risk OTRs with a low skin cancer burden may mitigate future skin cancer development.J Drugs Dermatol. 2020;19(3): doi:10.36849/JDD.2020.4759.

Current therapies for actinic keratosis.

Actinic keratosis (AK) is a very common skin disease caused by chronic sun damage, which in 75% of cases arises on chronically sun-exposed areas, such as face, scalp, neck, hands, and forearms. AKs must be considered an early squamous cell carcinoma (SCC) for their probable progression into invasive SCC. For this reason, all AK should be treated, and clinical follow-up is recommended. The aims of treatment are: (i) to clinically eradicate evident and subclinical lesions, (ii) to prevent their evolution into SCC, and (iii) to reduce the number of relapses. Among available treatments, it is possible to distinguish lesion-directed therapies and field-directed therapies. Lesion-directed treatments include: (i) cryotherapy; (ii) laser therapy; (iii) surgery; and (iv) curettage. Whereas, field-directed treatments are: (i) 5-fluorouracil (5-FU); (ii) diclofenac 3% gel; (iii) chemical peeling; (iv) imiquimod; and (v) photodynamic therapy (PDT). Prevention plays an important role in the treatment of AKs, and it is based on the continuous use of sunscreen and protective clothing. This review shows different types of available treatments and describes the characteristics and benefits of each medication, underlining the best choice.

Neoantigen Fitness Model Predicts Lower Immune Recognition of Cutaneous Squamous Cell Carcinomas Than Actinic Keratoses.

A low percentage of actinic keratoses progress to develop into cutaneous squamous cell carcinoma. The immune mechanisms that successfully control or eliminate the majority of actinic keratoses and the mechanisms of immune escape by invasive squamous cell carcinoma are not well-understood. Here, we took a systematic approach to evaluate the neoantigens present in actinic keratosis and cutaneous squamous cell carcinoma specimens. We compared the number of mutations, the number of neoantigens predicted to bind MHC class I, and the number of neoantigens that are predicted to bind MHC class I and be recognized by a T cell receptor in actinic keratoses and cutaneous squamous cell carcinomas. We also considered the relative binding strengths to both MHC class I and the T cell receptor in a fitness cost model that allows for a comparison of the immune recognition potential of the neoantigens in actinic keratosis and cutaneous squamous cell carcinoma samples. The fitness cost was subsequently adjusted by the expression rates of the neoantigens to examine the role of neoantigen expression in tumor immune evasion. Our analyses indicate that, while the number of mutations and neoantigens are not significantly different between actinic keratoses and cutaneous squamous cell carcinomas, the predicted immune recognition of the neoantigen with the highest expression-adjusted fitness cost is lower for cutaneous squamous cell carcinomas compared with actinic keratoses. These findings suggest a role for the down-regulation of expression of highly immunogenic neoantigens in the immune escape of cutaneous squamous cell carcinomas. Furthermore, these findings highlight the importance of incorporating additional factors, such as the quality and expression of the neoantigens, rather than focusing solely on tumor mutational burden, in assessing immune recognition potential.

Albinism: epidemiology, genetics, cutaneous characterization, psychosocial factors.

Oculocutaneous albinism is an autosomal recessive disease caused by the complete absence or decrease of melanin biosynthesis in melanocytes. Due to the reduction or absence of melanin, albinos are highly susceptible to the harmful effects of ultraviolet radiation and are at increased risk of actinic damage and skin cancer. In Brazil, as in other parts of the world, albinism remains a little known disorder, both in relation to epidemiological data and to phenotypic and genotypic variation. In several regions of the country, individuals with albinism have no access to resources or specialized medical care, and are often neglected and deprived of social inclusion. Brazil is a tropical country, with a high incidence of solar radiation during the year nationwide. Consequently, actinic damage and skin cancer occur early and have a high incidence in this population, often leading to premature death. Skin monitoring of these patients and immediate therapeutic interventions have a positive impact in reducing the morbidity and mortality associated with this condition. Health education is important to inform albinos and their families, the general population, educators, medical professionals, and public agencies about the particularities of this genetic condition. The aim of this article is to present a review of the epidemiological, clinical, genetic, and psychosocial characteristics of albinism, with a focus in skin changes caused by this rare pigmentation disorder.

Modern view on epidermal dysplasia carcinogenesis.

Squamous cell carcinoma of the skin develops from the spectrum of facultative precancerous conditions, which in the course of malignant transformation through cancer stage in situ without early treatment fully transform into invasive squamous cell carcinoma. According to classical model of carcinogenesis, the transformation of actinic keratosis into squamous cell carcinoma of the skin occurs due to a mutation in one gene, more often a tumor suppressor, and undergoes a stage of development with lack of control of cell cycle. The aim of the research is to supplement current knowledge of genetic determination of pathogenetic mechanisms of epidermal dysplasia of the skin by studying the genetic determinant in the skin lesion of varying degrees of malignancy. MATERIALS AND METHODS: We analyzed 85 skin bioptates of patients with epidermal dysplasia of the skin (Gr 1 - 43 patients with actinic keratosis; Gr 2 - 21 patients with non-invasive squamous cell carcinoma of the skin; Gr 3 - 21 patients with invasive squamous cell carcinoma of the skin) by molecular genetic testing of gene polymorphisms: TP53 (G13494A), L-myc (T3109G), TNF-α (G308A) in tumor tissue. The histological examination revealed the levels of dysplasia of the epidermis. RESULTS: In case of the same disease duration in patients of Gr1/Gr3, L-myc (3109TT) is a genetic component of malignant transformation of epithelial skin cells (p = 0.004) and the development of invasive squamous cell carcinoma. Other variants of 3109TG and 3109GG genes do not have such prognostic value for the risk of skin cancer compared to 3109TT. Significant differences were found in the distribution of (13494GA) when comparing Gr 1 with Gr 3 (p = 0.014) and Gr 2 with Gr 3 (p = 0.038). A significant increase in the distribution of 13494GA genotype was revealed in patients with invasive form of keratinocyte intraepidermal neoplasia. 13494A allele was more likely to be detected in patients of Gr 3 compared to Gr 2 (p = 0.030) that proves the association of this allele with the development of invasive malignancies of the skin. The association of 308GG genotype and TNF-α (308G) allele with the development of malignant skin lesions was found. Comparing the distribution of 308G allele in patients of Gr 1 and Gr 2, we found its significant increase in patients of Gr 1. Comparative analysis of gene polymorphism with tumor invasion level showed a significant difference only in 308GG genotype between patients with grade III of KIN (keratinocyte intraepidermal neoplasia) in Gr 2 and patients with KIN III of Gr 1 (p = 0.007), and 308GA between patients with KIN III of Gr 2 and KIN III of Gr 1 (p = 0.027). CONCLUSIONS: Our work has supplemented modern vision of genetic component in pathogenetic mechanism of the development of epidermal dysplasia of the skin. Thus, the association of L-myc (3109TT) with the development of malignant skin lesions of different invasiveness and the modifying effect of TNF-α (G308A) and TP53 (G13494A) gene variants on pathological transformation in the focus of EDS depending on the level of epithelial dysplasia was revealed.

Albinism: epidemiology, genetics, cutaneous characterization, psychosocial factors

Abstract Oculocutaneous albinism is an autosomal recessive disease caused by the complete absence or decrease of melanin biosynthesis in melanocytes. Due to the reduction or absence of melanin, albinos are highly susceptible to the harmful effects of ultraviolet radiation and are at increased risk of actinic damage and skin cancer. In Brazil, as in other parts of the world, albinism remains a little known disorder, both in relation to epidemiological data and to phenotypic and genotypic variation. In several regions of the country, individuals with albinism have no access to resources or specialized medical care, and are often neglected and deprived of social inclusion. Brazil is a tropical country, with a high incidence of solar radiation during the year nationwide. Consequently, actinic damage and skin cancer occur early and have a high incidence in this population, often leading to premature death. Skin monitoring of these patients and immediate therapeutic interventions have a positive impact in reducing the morbidity and mortality associated with this condition. Health education is important to inform albinos and their families, the general population, educators, medical professionals, and public agencies about the particularities of this genetic condition. The aim of this article is to present a review of the epidemiological, clinical, genetic, and psychosocial characteristics of albinism, with a focus in skin changes caused by this rare pigmentation disorder.

Erythrosis interfollicularis colli and cutis rhomboidalis nuchae: two sides of a coin.

INTRODUCTION: Chronic exposure to sunlight accelerates extrinsic aging due to changes in the extracellular matrix. Cutis rhomboidalis nuchae and erythrosis interfollicularis colli are two benign skin disorders related to extrinsic aging. METHODS: The study investigated possible co-occurrence in 50 male patients that developed skin cancer due to professional outdoor work, and demonstrated cutis rhomboidalis nuchae clinically and by dermoscopy. RESULTS: The study observed 11 cases of co-existent erythrosis interfollicularis colli characterized by perifollicular white halos in dermoscopy. These patients had Fitzpatrick skin type II or III but not type I. The severity of erythrosis interfollicularis colli was diminished in the area of cutis rhomboidalis nuchae. Basal cell carcinomas were seen in only one patient on the borders of cutis rhomboidalis nuchae, whereas erythrosis interfollicularis colli did not prevent development of basal cell carcinomas. Actinic keratoses were seen in nine of 11 patients with erythrosis interfollicularis colli, but not with cutis rhomboidalis skin. CONCLUSIONS: This study argues for a local protective effect of cutis rhomboidalis nuchae against other ultraviolet light-induced cutaneous pathologies.

Épidémiologie des kératoses actiniques: Epidemiology of actinic keratosis.

Actinic keratosis is a premalignant skin lesion resulting from proliferation of atypical epidermal keratinocytes. Actinic keratoses are very frequent and their prevalence is increasing. Risk factors for actinic keratosis include intrinsic and environmental factors, particularly exposure to ultraviolet radiation and advanced age. The main factor is the exposition to ultraviolet radiation. Better sun protection decreases the risk of actinic keratosis and also the risk of progression to squamous cell carcinoma, even though not all actinic keratoses progress to invasive squamous cell carcinoma. A diagnosis of actinic keratosis should encourage patients to do an annual dermatological screening of skin cancers. Given the economic cost of actinic keratoses, a global approach of health authorities could be interesting for their management. © 2019 Elsevier Masson SAS. All rights reserved. Cet article fait partie du numéro supplément Kératoses actiniques : comprendre et traiter réalisé avec le soutien institutionnel de Galderma International.