Sun-exposed Skin Research Articles

Systemic treatment of patients with inoperable and metastatic Merkel cell carcinoma: A multicenter study.

e21521 Background: Merkel cell carcinoma (MCC) is an uncommon, aggressive neuroendocrine skin cancer. The prognosis in the unresectable and metastatic setting is very poor. Distant metastases develop in more than 30%. Chemotherapy (CHT), the previous mainstay of treatment, is associated with the high response rates (RR) of limited duration. The main cytotoxic drugs have been platinum derivatives, taxoids, anthracyclines, and etoposide. The standard systemic treatment for this disease has changed in the last few years. Immunotherapy (IO) is currently the basis of systemic therapy in the metastatic setting. This study aimed to analyze outcomes for unresectable and metastatic MCC pts treated in routine clinical practice, mostly before the era of IO availability. Methods: We conducted the retrospective analysis of data from 36 MCC pts in unresectable (n= 23) and metastatic (n=13) settings treated in three oncological centers, diagnosed between 01/2010 and 12/2019, with data cut-off on 31/12/2020. The data collected included epidemiological and clinical information. Survival analyses were performed using the Kaplan-Meier method and log-rank test. Results: The median patient age at diagnosis was 72 years (57-88); 58.3% were male. The most common primary tumor (PT) locations were lower limbs (41.7%), head and neck (30.6%), and upper limbs (16.7%). In 63.9% the PT was located in the sun-exposed skin. The most common location of distant metastases were nonregional lymph nodes (n=9) and lungs (n=3). Thirty-six pts received 1st line CHT with the median progression-free survival (mPFS) of 5.3 months (95%CI 2.88-7.7) and objective response of 61.1%, with 13.9% complete responses (CR). The most commonly used regimens were platinum-based and anthracycline-based regimens (n=26). Disease progression (PD) was observed in 91.7% of pts treated with 1st line CHT. Twenty-one pts received 2nd line therapy, IO (n=14), or CHT (n=7), with PD in 19 pts (90.6%), mPFS 2.83 months (95% CI 0.59-5.06) and RR of 33.3% (0% CR). 13 pts were treated with avelumab (AVE), all in the 2nd line, with RR of 38.5% (0% CR). The mPFS in the 2nd line was 5 months (95%CI 0-11.46) on AVE compared to 2.82 (95%CI 0.46-5.19) on CHT (HR 0.65, 95%CI 0.25-1.70, p=0.378). During 1st line systemic therapy, 16 pts underwent palliative surgery (n=7, 19.4%) or received radiation therapy (RT) (n=9, 25%), and during 2nd line, one patient was treated with surgery, and five pts received RT. The median overall survival was 10.38 months (95% CI 2.90-17.87). Local treatment did not improve the treatment outcomes in the 1st (p=0.119) nor 2nd line (p=0.821). Conclusions: Our results confirm the poor prognosis of pts with unresectable and metastatic MCC. The response rates and median PFS for CHT in the 1st and 2nd line setting are consistent with historical data. The treatment with AVE in the 2nd line allows achieving better results, similar to the results reported in the clinical trials.

Differential gradients of efficacy of immunotherapy according to the sun-exposure pattern of the site of occurrence of primary melanoma: A multicenter prospective cohort study (MELBASE).

e21545 Background: The tumor mutational burden (TMB) is usually high in Cutaneous melanomas owing to ultraviolet radiation-induced oncogenesis. While a high TMB is a predictive biomarker of response to PD-1 inhibitors, it may be associated with the rise of resistant clones to targeted therapy over time. We hypothesized that the response pattern to immunotherapy and targeted therapy in advanced melanoma may vary depending on the sun-exposure profile of the site of primary melanoma. Methods: Patients were screened from MelBase, a French multicenter biobank dedicated to the prospective follow-up of unresectable stage III/IV melanoma. Within Melbase, all patients with a known cutaneous primary melanoma who received a first-line systemic treatment by immunotherapy or combined targeted therapy between January 2013 and November 2019 were included. Outcomes were progression-free survival (PFS ) and overall survival (OS). Results: 973 patients received either anti PD-1 monotherapy (n=466), anti CTLA-4 monotherapy (n=143), a combination of both (n=118), dabrafenib plus trametinib (n=187) or vemurafenib plus cobimetinib (n=59). Patients’ characteristics at treatment initiation were: male gender (62%), median age of 62 years old, BRAF WT (58%), AJCC stage IV (84%), brain metastases (18%), ECOG 0-1 (84%) and normal LDH (52%). Median follow-up was 15.5 months. The primary melanoma was located on chronically sun-exposed skin in 175 patients (G1: head neck), on intermittently sun-exposed skin in 615 patients (G2: trunk, arms, legs), and on sun-protected areas in 65 patients (G3: palms, soles, nails). Median PFS was significantly higher in G1 under anti PD-1 treatment (8,7 months vs 3,3 and 3,4 months for G2 and G3, respectively) (p=0.011), (19,2 months vs 8,1 and 6 months for G2 and G1) (p=0. although it is worthwhile to note that the number of G3 patients treated with targeted therapy was relatively low (n=8). PFS did not significantly differ between all groups under ipilimumab. Similarly, median OS was significantly higher in G1 receiving first-line anti PD-1 treatment (45,6 months vs 31,6 and 21,4 months for G2 and G3) (p=0.04), while OS was higher in G3 under targeted therapy (21,1 months vs 16,3 and 19,5 months for G2 and G1) (p=0.97). Conclusions: Our study suggests that first-line immunotherapy with anti PD-1 is particularly recommended for melanomas originating from chronically sun-exposed areas. On the other hand, melanomas originating from sun-protected areas may benefit more from first-line targeted therapy when possible (presence of BRAF mutation), but this finding needs to be confirmed by further research.

Treatment of patients with locally advanced Merkel cell carcinoma: A multicenter study.

e21566 Background: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with a high risk of recurrence and poor prognosis. The treatment of locally advanced disease includes surgery (SUR) and radiotherapy (RTH) to achieve high locoregional control rates. The sentinel lymph node biopsy (SLNB) is recommended procedure in cases without clinical nodal involvement. In selected cases, chemotherapy (CHT) may also be considered, but its role is not confirmed. This study aimed to analyze outcomes for locally advanced MCC pts treated in routine clinical practice. Methods: We conducted the retrospective analysis of data from 156 MCC pts treated with curative surgery in four oncological centers, diagnosed between 01/2010 and 12/2019, with data cut-off on 31/12/2020. The data collected included epidemiological and clinical information. Survival analyses were performed using the Kaplan-Meier method, log-rank test and multivariate Cox regression. Results: The median patient age at diagnosis was 72 years (30-94); 50.6% were male. The primary tumor (PT) locations were lower limbs (33.3%), upper limbs (30.1%), and head and neck (28.2%). MCC with no PT was diagnosed in 3.9%. In 62.0% the PT was located in the sun-exposed skin. The median tumor size was 25 mm (4-170). Lymph node (LN) involvement (clinical or positive SLNB or LND) at diagnosis was found in 26.9% (n = 42). The scar excision was done in 50.0% (positive in 16.6%), SLNB in 36.5% (positive in 10.5 %), 51.9% of pts received perioperative treatment, including RTH- 86.4%, CHT- 21%. The relapse rate was 38.3% (35.8% local-regional, 11.1% distant). With the median follow-up of 2.2-years, the median disease-free survival (DFS), local relapse-free survival (LRFS), and distant metastases-free survival (DMFS) were not reached. The 1-year DFS, LRFS and DMFS rates were 65%, 68%, and 90%. The negative independent risk factors for DFS were male gender (HR 1.42, 95%CI 1.06-3.01), metastases in LN at diagnosis (HR 5.41, 95%CI 2.39-12.26), no SLNB in pts with no clinical metastases in LN (HR 5.45, 95%CI 2.41-12.3), and no perioperative RTH (HR 2.19, 95%CI 1.29-3.76). The median overall survival (OS) was 6.9 years (95%CI 4.64-9.15). The negative independent risk factors for OS were male gender (HR 1.95, 95%CI 1.16-3.27), age above 70 (HR 2.0, 95%CI 1.15-3.48), metastases in LN at diagnosis (HR 3.15, 95%CI 1.49-6.68), and no SLNB in pts with no clinical metastases in LN (HR 2.30, 95%CI 1.10-4.82). PT location, UV-exposure, and perioperative CHT or RTH were not independent risk factors for OS. Conclusions: Our results confirm that the MCC treatment should be done in an experienced multidisciplinary team. Male gender, nodal involvement at diagnosis, and no SLNB in pts without clinical metastases in LN are associated with poor prognosis in DFS and OS. The perioperative RTH improves the treatment outcomes and reduces disease progression risk but does not impact OS. Perioperative CHT does not affect pts survival.

Facial Treatment with 3-O-Cetyl Ascorbic Acid for Improvement of Skin Texture: Uptake, Effectiveness, and In Vitro Carcinogenicity Assessment

Ascorbic acid (AA) is a water-soluble vitamin that is found at high concentrations in normal skin. The important and well-known benefits of using AA in skin health include the stimulation of collagen synthesis and the assistance of protection against photo-oxidative damages. To maintain stability and improve drug delivery to the active site, a variety of AA derivatives have been chemically synthesized. Among these compounds, we focus here on a lipophilic derivative, 3-O-cetyl ascorbic acid (3-CetylAA), which remains poorly characterized for cosmetic applications. Uptake analysis in three healthy human volunteers’ skin was conducted using a serial tape-stripping technique detecting 3-CetylAA (on average, 128 ± 27 pmol per µg) in the stratum corneum after a 5-h topical treatment when treated with 25 mM 3-CetylAA-containing cream for 13 days twice daily and continuously. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) imaging of vertical cryosections of pig skin revealed the presence of 3-CetylAA in the epidermal layer after topical treatment with 3-CetylAA-containing cream. In sun-exposed human skin, 3-CetylAA improved the texture after treatment with 25 mM 3-CetylAA-containing cream for 4 weeks or more when used twice daily or continuously. An in vitro transformation assay using BALB/c 3T3 A31-1-1 cells demonstrated that 10 µM 3-CetylAA, which is the same concentration exhibited in vitro biological activities in another lipophilic AA derivative, 2-O-octadecyl ascorbic acid, was non-carcinogenic and did not potentiate the UVC-induced transformation frequency when applied for 3 days after UVC irradiation. These results demonstrate that 3-CetylAA is a promising candidate as a lipophilic derivative of AA for cosmetic purposes.

Clinical Relevance of Elastin in the Structure and Function of Skin.

Elastin is the main component of elastic fibers, which provide stretch, recoil, and elasticity to the skin. Normal levels of elastic fiber production, organization, and integration with other cutaneous extracellular matrix proteins, proteoglycans, and glycosaminoglycans are integral to maintaining healthy skin structure, function, and youthful appearance. Although elastin has very low turnover, its production decreases after individuals reach maturity and it is susceptible to damage from many factors. With advancing age and exposure to environmental insults, elastic fibers degrade. This degradation contributes to the loss of the skin’s structural integrity; combined with subcutaneous fat loss, this results in looser, sagging skin, causing undesirable changes in appearance. The most dramatic changes occur in chronically sun-exposed skin, which displays sharply altered amounts and arrangements of cutaneous elastic fibers, decreased fine elastic fibers in the superficial dermis connecting to the epidermis, and replacement of the normal collagen-rich superficial dermis with abnormal clumps of solar elastosis material. Disruption of elastic fiber networks also leads to undesirable characteristics in wound healing, and the worsening structure and appearance of scars and stretch marks. Identifying ways to replenish elastin and elastic fibers should improve the skin’s appearance, texture, resiliency, and wound-healing capabilities. However, few therapies are capable of repairing elastic fibers or substantially reorganizing the elastin/microfibril network. This review describes the clinical relevance of elastin in the context of the structure and function of healthy and aging skin, wound healing, and scars and introduces new approaches being developed to target elastin production and elastic fiber formation.

Frequent FGFR3 and Ras Gene Mutations in Skin Tags or Acrochordons

The skin is subject to age-dependent development of benign tumors, the most common of which are seborrheic keratoses (SKs) and skin tags (STs). SKs are flat or dome-shaped nodules that develop predominantly on sun-exposed skin, whereas STs, also called acrochordons, are polypoid skin lesions that develop predominantly on the neck and axilla. Although polypoid or pedunculated protrusions sometimes develop from a part of SKs, SKs and STs are considered distinct tumors.

073 A non-invasive genomic test for early assessment of UV damage in human skin

UV-exposure leads to mutations in skin cells, which may clonally expand and ultimately turn into cancerous lesions ('field cancerization'). Early detection of low-frequency cancer-causing UV-signature mutations in still normal-appearing skin remains a challenge. We have developed a non-invasive genomic test capable of quantifiably detecting UV-signature mutations with high sensitivity to change this paradigm. This genomic test combines DermTech's non-invasive skin sample collection technology 'adhesive skin collection kits' with an ultrasensitive and multiplexed MALDI-TOF mass spectrometry-based mutation detection platform, 'the MassARRAY' from Agena Bioscience. The test includes over two dozen DNA driver mutations in genes such as TP53, CDKN2A, NOTCH1, and NOTCH2, known to be associated with the development of non-melanoma skin cancers. In a proof-of-concept study, contralaterally collected skin samples from sun-exposed body sites in subjects of varying race, age, and gender were tested. UV-signature mutations were detected in sun-exposed skin, with the numbers of mutations increasing with the subjects' age. In our reference control neonatal keratinocytes, no UV signature mutations were detected. This genomic test demonstrates reliable detection of UV-signature mutations in sun-exposed skin samples collected using DermTech's non-invasive skin sample collection technology and offers the opportunity to non-invasively assess UV-damage of skin that lacks visual elements of UV damage. Additional studies will help understand the correlation of UV-damage detected in normal-appearing skin to future non-melanoma skin cancer risk. We envision this proactive genomic approach to measure UV damage to change how photoaging is assessed and treated.

064 Genome analysis reveals UV signature mutations in sun-exposed skin tumors in tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is a tumor syndrome caused by pathogenic variants in TSC1 or TSC2. Individuals with TSC develop skin tumors with second-hit somatic mutations in TSC1 or TSC2 in fibroblast-like tumor cells. These somatic mutations in facial angiofibromas, but not fibrous tumors in non-sun-exposed areas, are commonly UV signature mutations, prompting recommendations to limit UV exposure to reduce the severity of TSC skin tumors. In order to investigate whether UV light induces additional genetic alterations that promote TSC tumor pathogenesis, we performed whole genome sequencing of DNA from patient peripheral blood and fibroblast-like cells grown from TSC skin tumors. Unique dual-indexed PCR-free libraries were sequenced as pools on an Illumina NovaSeq 6000 generating 2x150 read pairs with a Picard mean coverage of ∼38X for blood samples and ∼63X for tumor samples. TSC1 and TSC2 germline mutations were identified in 39 out of 48 patients (5 TSC1, 34 TSC2 including 12 mosaic). TSC1 and TSC2 somatic mutations were found in 27 out of 45 tumor samples (2 TSC1, 25 TSC2), including copy neutral LOH, point mutations, large deletions, and intra- and interchromosomal gene fusions. The mutation rate per Mb was higher in sun-exposed (median 5.7/Mb, IQR 4.1-11.8) than non-sun-exposed locations (median 1.7/Mb, IQR 1.5-2.0). C>T mutations and a UV signature were more frequent throughout the genome in sun-exposed than other sites, but there were no recurrent mutations in known driver genes. In summary, TSC skin tumors have relatively low somatic mutation rates that are increased in sun-exposed sites; however, somatic alteration of TSC1 or TSC2, whether random or UV-induced, combined with a TSC1/TSC2 germline mutation, appears to be sufficient to drive tumorigenesis.

In vivo reflectance confocal microscopy for monitoring actinic keratosis treated with 5-aminolevulinic acid photodynamic therapy.

Actinic keratosis (AK) occurs frequently in sun-exposed skin while its diagnosis and treatment were still in exploration. Thirty two patients with facial AK lesions were selected and examined with reflective confocal microscopy (RCM) firstly, followed by biopsy at the same site. RCM was used to observe AK lesions before 5-aminolevulinic acid photodynamic therapy (ALA-PDT) treatment, after the first treatment, after 4 treatments, and at 1 and 6months follow-up. Retrospective analysis of RCM images was performed. Thirty two AK cases showed initial RCM microscopic features including disorderly arranged epidermal cells (100%), atypical keratinocytes (100%), and blurry border between the epidermis and dermis (100%). 4 patients quitted trail. After treatments, 24 cases showed basically regular arrangement of epidermal cells, absent atypical keratinocytes, and clear border between epidermis and dermis, while 4 cases improved little. At 1 and 6months follow-up, 23 cases remained relapse-free while 1 case developed recurrent symptoms. Effective rate of 4 ALA-PDT treatments for AK was 100%; recurrence and cure rates were 4.2% and 82.1%, respectively. ALA-PDT is effective to treat AK, while RCM can be recommended for in vivo evaluating and monitoring the effect of ALA-PDT on AK.

Dnmt3a deficiency in the skin causes focal, canonical DNA hypomethylation and a cellular proliferation phenotype

DNA hypomethylation is a feature of epidermal cells from aged and sun-exposed skin, but the mechanisms responsible for this methylation loss are not known. Dnmt3a is the dominant de novo DNA methyltransferase in the skin; while epidermal Dnmt3a deficiency creates a premalignant state in which keratinocytes are more easily transformed by topical mutagens, the conditions responsible for this increased susceptibility to transformation are not well understood. Using whole genome bisulfite sequencing, we identified a focal, canonical DNA hypomethylation phenotype in the epidermal cells of Dnmt3a-deficient mice. Single-cell transcriptomic analysis revealed an increased proportion of cells with a proliferative gene expression signature, while other populations in the skin were relatively unchanged. Although total DNMT3A deficiency has not been described in human disease states, rare patients with an overgrowth syndrome associated with behavioral abnormalities and an increased risk of cancer often have heterozygous, germline mutations in DNMT3A that reduce its function (Tatton-Brown Rahman syndrome [TBRS]). We evaluated the DNA methylation phenotype of the skin from a TBRS patient with a germline DNMT3AR882H mutation, which encodes a dominant-negative protein that reduces its methyltransferase function by ∼80%. We detected a focal, canonical hypomethylation phenotype that revealed considerable overlap with hypomethylated regions found in Dnmt3a-deficient mouse skin. Together, these data suggest that DNMT3A loss creates a premalignant epigenetic state associated with a hyperproliferative phenotype in the skin and further suggest that DNMT3A acts as a tumor suppressor in the skin.

Basement Membrane Helps Maintain Epidermal Hyaluronan Content

Hyaluronan (HA) is the major glycosaminoglycan in the extracellular matrix of most mammalian tissues, including the epidermis. It is synthesized in epidermis, and mainly metabolized after transfer to the liver via lymphatic vessels in the dermis following its passage through the basement membrane (BM) at the dermal-epidermal junction. The aim of the present study was to investigate the influence of BM integrity on the level of HA in the epidermis. Epidermal HA content was decreased in sun-exposed skin of older subjects, whose BM structure was impaired, compared with sun-exposed young skin and sun-protected skin, in which BM integrity was well maintained. In an organotypic culture model of sun-exposed facial skin, epidermal HA was increased in the presence of inhibitors of BM-degrading matrix metalloproteinases and heparanase. In a skin equivalent model treated with these inhibitors, HA content was increased in the epidermis, but decreased in conditioned medium. These findings suggest that the BM at the dermal-epidermal junction plays an important role in maintaining epidermal HA levels.

Red light photodynamic therapy with BF-200 ALA showed superior efficacy in the treatment of actinic keratosis on the extremities, trunk, and neck in a vehicle-controlled phase III study

Actinic keratoses (AK) may occur in all sun-exposed skin areas. Those occurring outside the head area are generally more resistant to treatment than those on the face. To determine efficacy and safety of BF-200 ALA versus vehicle in the treatment of mild-to-severe AK located on extremities, trunk, and neck with red light photodynamic therapy (PDT). This phase III study had an intra-individual design with 50 patients in 6 centers in Germany. Each patient received a maximum of 2 field-directed PDTs. Clinical end points and 1-year follow-up results were recorded. BF-200 ALA was superior to the vehicle with respect to total lesion clearance rates (86.0% vs 32.9%; P<.0001) and patient complete clearance per patient's side (67.3% vs 12.2%, P<.0001). One-year overall lesion recurrence rate was 14.1% versus 27.4% (BF-200 ALA vs vehicle; P=.0068). Patients were more satisfied by the cosmetic outcome of BF-200 ALA/PDT than the vehicle/PDT. Adverse events were consistent with the known safety profile of BF-200 ALA/PDT. Small number of severe lesions; limited sample size; unbalanced but representative distribution of AK. BF-200 ALA showed significantly higher AK clearance rates on extremities, trunk, and neck than the vehicle and was well tolerated.

Red Dot Basal Cell Carcinoma: Literature Review of a Unique Clinical Subtype of Basal Cell Carcinoma.

Red dot basal cell carcinoma is a distinctive clinical subtype of basal cell carcinoma. It has been reported in eight individuals with a male to female ratio of 1:1; and the patients’ ages ranged from 50 to 74 years. All patients had prior history of actinic keratoses and basal cell carcinoma. In addition, some patients also had prior squamous cell carcinoma, malignant melanoma, and/or dysplastic nevus. The tumor was usually of recent onset, asymptomatic, and on sun-exposed skin. It was most commonly located on the nose (five patients); other sites were the upper lip, the mid back, or thigh—each in one patient. The red dot basal cell carcinoma was solitary and small—usually 4 mm or less in diameter. It typically presented as a red macule or papule; however, it sometimes appeared as a flesh-colored or pink to light-red papule with a bright-red central area. Microscopic features showed basaloid tumor cells (arranged as either nodular aggregates or superficial buds or both). In the central portion of the lesion, there was a proliferation of erythrocyte-containing vascular spaces between the epidermis and the neoplasm. The basal cell carcinoma pathology subtype was either nodular and superficial (three patients), nodular (two patients), or superficial (one patient). The clinical differential diagnosis of red dot basal cell carcinoma included not only benign vascular lesions (such as hemangioma and telangiectasia) but also inflammatory conditions and adnexal tumors. Other basaloid cell neoplasms were in the pathologic differential diagnosis. The pathogenesis of red dot basal cell carcinoma is similar to that of other basal cell carcinoma clinical subtypes. Mohs surgery is the treatment of choice for red dot basal cell carcinomas. Red dot basal cell carcinoma has two categories of biologic behavior based on the ratio of the postoperative wound size as compared with the size of the preoperative tumor: nonaggressive (for which the ratio was 5:1 or less for three patients) and aggressive (for which the ratio was greater than 12:1 for three patients). There was no recurrence of the red dot basal cell carcinoma after treatment. In conclusion, the incidence of red dot basal cell carcinoma—a unique morphologic variant of basal cell carcinoma—may be higher than suggested by the number of reported patients with this basal cell carcinoma subtype.

Risk factors for early-onset basal cell carcinomas and the trend towards their female predominance.

A dramatic rise in the incidence rates of basal cell carcinoma (BCC) in young women has been reported. We investigate potential risk factors (RF) for sporadic BCC in young patients and the current distribution of such RF in the general population of Catalonia, comparing the differences among men and women. A case-control study was performed, 69 BCCs diagnosed in patients ≤45 years of age vs. 69 healthycontrols. Afterward, 1,078 participants from the general population completed an RF questionnaire. Repeated sunburns were more frequent in instances of early-onset BCC in covered skin than in sun-exposed skin (P = 0.029). In the general population, 39.1% of participants reported sunbed use (50.1% in women, 10.9% in men). Sunbed use was the only relevant RF more predominant in women than men, favoring the trend to female predominance of BCCs above other RF. Additionally, we found a significant trend in young participants for reduced sunbed use (P<0.001), although they had the same percentage of repeated sunburns. Repeated sunburns are the most relevant RF for early-onset BCCs that can be targeted in prevention campaigns. We should be aware of the more relevant RF for early-onset BCCs and their distribution among the general population to address preventive campaigns.

Skin cancer and sun protection practices in Fanconi anemia patients: A cross-sectional study

Skin cancer and sun protection practices in Fanconi anemia patients: A cross-sectional study

The T414G mitochondrial DNA mutation: a biomarker of ageing in human eye.

The mitochondrial mutation T414G (mtDNAT414G) has been shown to accumulate in aged and sun-exposed skin. The human eye is also exposed to solar harmful rays. More precisely, the anterior structures of the eye (cornea, iris) filter UV rays and the posterior portion of the eye (retina) is exposed to visible light. These rays can catalyse mutations in mitochondrial DNA such as the mtDNAT414G, but the latter has never been investigated in the human ocular structures. In this study, we have developed a technique to precisely assess the occurrence of mtDNAT414G. Using this technique, we have quantified mtDNAT414G in different human ocular structures. We found an age-dependent accumulation of mtDNAT414G in the corneal stroma, the cellular layer conferring transparency and rigidity to the human cornea, and in the iris. Since cornea and iris are two anterior ocular structures exposed to solar UV rays, this suggests that the mtDNAT414G mutation is resulting from cumulative solar exposure and this could make the mtDNAT414G a good marker of solar exposure. We have previously shown that the mtDNACD4977 and mtDNA3895 deletions accumulate over time in photo-exposed ocular structures. With the addition of mtDNAT414G mutation, it becomes feasible to combine the levels of these different mtDNA mutations to obtain an accurate assessment of the solar exposure that an individual has accumulated during his/her lifetime.

Disseminated superficial actinic porokeratosis in a patient with generalized vitiligo: A case report

Disseminated superficial actinic porokeratosis (DSAP) is the most common type of porokeratosis, occurring mainly on sun-exposed skin. Chronic sun exposure is one of the main risk factors, in addition to genetic susceptibility. Most published data concerning the relationship between vitiligo and its predisposition to nonmelanoma skin cancer suggests that patients with vitiligo show the same or even a lower incidence than other populations. Herein, we report a case of disseminated superficial actinic porokeratosis occurring in vitiligo in which chronic sun exposure was the main risk factor

Xanthophyll Carotenoids Reduce the Dysfunction of Dermal Fibroblasts to Reconstruct the Dermal Matrix Damaged by Carbonylated Proteins.

Although extracellular carbonylated proteins (CPs) are found at higher levels in sun-exposed skin, their impact on the cellular functions of fibroblasts and their involvement in the progression of photoaging skin are not fully clarified. In our previous study, we reported that extracellular CPs increase levels of intracellular oxidative stress and result in the accumulation of newly synthesized CPs in normal human dermal fibroblasts (NHDF). Furthermore, fibroblasts exposed to CP-BSA, which is a model of extracellular CPs, had upregulated expression levels of mRNAs encoding matrix metalloproteinase-1 (MMP-1) and interleukin-8/CXCL8 (IL-8/CXCL8). These facts suggested the possibility that extracellular CPs induce a fragile structure in the dermis through the degradation of collagen and elastin. The purpose of this study was to characterize the efficacy of natural carotenoids, such as astaxanthin analogs, produced by Hematococus pluvialis (CHPs) to improve the impaired functions of fibroblasts exposed to CPs. CHPs suppressed the intracellular CP levels elevated by CP-BSA, restored mRNA expression levels of factors involved in the formation and assembly of collagen and elastin fibers and improved the formation of those fibers impaired by CP-BSA. We conclude that CHPs function as antiaging substances due to their restoration of the impaired formation of collagen and elastin fibers caused by extracellular soluble CPs.

The effect of age on the acquisition and selection of cancer driver mutations in sun-exposed normal skin

The accumulation of somatic mutations contributes to ageing and cancer. Sunlight is the principal aetiological factor associated with skin cancer development. However, genetic and phenotypic factors also contribute to skin cancer risk. This study aimed at exploring the role of photoaging, as well as other well-known epidemiological risk factors, in the accumulation of somatic mutations in cancer-free human epidermis. We deeply sequenced 46 genes in normal skin biopsies from 123 healthy donors, from which phenotypic data (including age, pigmentation-related genotype and phenotype) and sun exposure habits were collected. We determined the somatic mutational burden, mutational signatures, clonal selection and frequency of driver mutations in all samples. Our results reveal an exponential accumulation of UV-related somatic mutations with age, matching skin cancer incidence. The increase of mutational burden is in turn modified by an individual's skin phototype. Somatic mutations preferentially accumulated in cutaneous squamous cell carcinoma cancer genes and clonally expanded with age, with distinct mutational processes underpinning different age groups. Our results suggest a loss of fidelity in transcription-coupled repair later in life. Our findings reveal that ageing is not only associated with an exponential increase in the number of somatic mutations accumulated in normal epidermis, but also with selection and expansion of cancer-associated mutations. Aged, sun-exposed normal skin is thus an extended mosaic of multiple clones with driver mutations, poised for the acquisition of transforming events.

14937 Keratoacanthomas associated with anti–TGF-β immunotherapy

Keratoacanthomas (KAs) are rapid-growing skin tumors that resemble well differentiated cutaneous squamous cell carcinomas (SCCs) and typically present as solitary lesions on sun-exposed skin. KAs can arise in association with medications, including inhibitors of BRAF or transforming growth factor beta (TGF-β). A novel bifunctional fusion protein that blocks both programmed death ligand 1 (PD-L1) and TGF-β signaling has shown a manageable safety profile and clinical efficacy in patients with heavily pretreated solid tumors. In these patients, we have observed adverse events (AEs) that include both immune-related AEs and biopsy-proven KAs. In total, 18 of 93 treated patients (19%) developed at least 1 KA. These lesions appeared on chronically sun-damaged skin, typically months after starting therapy. KA-like papules were managed by observation with destructive therapy (cryotherapy or excision) used for symptomatic or clinically atypical lesions. Patients generally did not require treatment discontinuation. Whereas most patients had small numbers of treatment-emergent KAs, 3 patients developed numerous eruptive KAs. These patients’ presentations resembled Grzybowski-type eruptive KAs in that they also demonstrated generalized pruritus, macular erythema, and/or lesions in areas of prior instrumentation suggestive of an isomorphic response. Acitretin was helpful in controlling the eruptive KAs and associated AEs. The occurrence of isolated and eruptive KAs in this patient population adds to a growing body of evidence supporting an association between KA development and reduced TGF-β signaling. Ongoing studies are investigating the predisposing genetic and molecular factors required for TGF-β inhibitor–related KAs and exploring strategies to prevent these cutaneous neoplasms.