Number Of Actinic Keratoses Research Articles

Safety and tolerability of tirbanibulin ointment 1% treatment on 100 cm2 of the face or scalp in patients with actinic keratosis: A phase 3 study

Tirbanibulin is approved for actinic keratosis (AK) field treatment up to 25cm2. However, AK often affects larger areas; thus, AK treatments for larger fields are needed. Evaluate the safety and tolerability of tirbanibulin when applied to a field of approximately 100cm2. Phase 3, multicenter, open-label, single-arm study among adult patients having a treatment field on the face or balding scalp of approximately 100cm2 with 4-12 AKs. Patients received tirbanibulin to cover the treatment field once daily (5 consecutive days). Safety was assessed by evaluating treatment emergent adverse events and tolerability by composite score of 6 local tolerability signs (LTS). A total of 105 patients were included. The most common LTS were erythema (96.1%) and flaking/scaling (84.4%), being mostly mild-to-moderate severity, and resolved/returned to or close to baseline by Day 29. The only severe LTS were erythema (5.8%) and flaking/scaling (8.7%). Most frequent treatment emergent adverse events were application site pruritus (10.5%) and application site pain (8.6%). Mean total number of AKs decreased from 7.7 AKs at baseline to 1.8 AKs at Day 57. Mean percent of change (reduction) from baseline in lesion count was 77.8% at Day 57. No control group. No long-term follow-up. Safety and tolerability profiles in patients treated with tirbanibulin up to 100cm2 were consistent with those previously reported over smaller field. Tirbanibulin could be used on a larger field (>25cm2).

Actinic keratosis: Current challenges and unanswered questions.

Actinic keratoses (AK) are common skin lesions associated with chronic exposure to sun. They are believed to be precursors of malignancy as they potentially may progress to invasive squamous cell carcinomas. The goal of current therapies is to reduce the number of AK and to prevent future cancer development. This review aims at providing an overview of the hallmarks of AK and skin field cancerization. We discuss epidemiology trends, risk factors and the state of the art and evidence of the current treatments. We review key figures of AK prevalence from different countries with regard to skin cancer risk and the associated economic burden of AK. We discuss the mutational status in AK lesions and the difficulties encountered by clinicians in evaluating AK visible and invisible lesions, referring to the concept of field cancerization. Based on a systematic literature review, we further evaluate the available treatment options. The presence of subclinical skin alterations in the periphery of visible AK lesions has gained a particular attention as those non-visible lesions are known to contain the same genetic changes as those found in the AK lesions themselves, prompting the concept of 'field cancerization'. Therefore, AK treatment guidelines now recognize the importance of treating the field in patients with AK. A recent systematic literature review and network meta-analysis showed that 5-FU interventions were associated with the best efficacy and a satisfactory acceptability profile compared with other field-directed therapies used in the treatment of AK. Although AK are considered quite common, they lack an accurate descriptive definition and conclusive epidemiologic data. Limited public awareness is a barrier to early and effective treatment, including prevention strategies. While different treatment options are available, there is still a limited understanding of long-term outcomes of treatment as measured by recurrence of cancer prevention.

Nicotinamide for Skin-Cancer Chemoprevention in Transplant Recipients

BackgroundImmunosuppressed 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.MethodsIn 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.ResultsA 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.ConclusionsIn 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.)

Antidiabetic Treatment in Patients at High Risk for a Subsequent Keratinocyte Carcinoma.

Metformin and sulfonylureas are the most commonly prescribed drugs used for the treatment of type II diabetes. Type II diabetes has been linked to the development of keratinocyte carcinoma (KC), consisting of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Previously we have demonstrated lower risk for a subsequent KC in metformin users. In this study, we aim to investigate the association between sulfonylureas use and the development of KC in patients with KC history. We performed a retrospective cohort study of the Veterans Affairs Keratinocyte Carcinoma Chemoprevention Trial, which was a randomized double-blind vehicle-control cream originally investigating the effect of 5-fluorouracil on KC development. 932 patients with a history of KC were enrolled (98% male, 99% white, median age of 70 years) and followed for a median duration of 2.8 years. 153 patients were on metformin and 94 on sulfonylureas. We performed a survival analysis with cox regression and controlled for body mass index and known predictors: number of prior BCCs and age (for BCC) and for number of prior SCCs (invasive and in situ), number of actinic keratoses at baseline (for SCC). Sulfonylurea-users com-pared to non-users had a HR of 0.67 (CI: 0.40–1.56; P=0.49) and 0.94 (CI: 0.63–1.40; P= 0.77), for SCC and BCC, respectively. Diabetic patients at high risk for KC might benefit from the use of metformin versus sulfonylureas. J Drugs Dermatol. 2022;21(5):502-505. doi:10.36849/JDD.6087.

Use of Topical Calcipotriol Plus 5-Fluorouracil in the Treatment of Actinic Keratosis: A Systematic Review.

Actinic Keratosis (AK) is a premalignant lesion that can progress to cutaneous squamous cell carcinoma (cSCC). Topical 5-Fluorouracil (5-FU) and imiquimod have been used for field-directed therapy for AK; however, their use is limited by intolerable skin reactions and long treatment durations. To assess current data on the efficacy, tolerability, and long-term effectiveness of topical calcipotriol plus 5-FU combination for the field-directed therapy of AK. The systematic review will include a critical evaluation of the available evidence. A systematic review of the literature was performed in August 2021 using the EMBASE and MEDLINE databases. Studies that assess the use of calcipotriol and 5-FU to treat actinic keratosis (AK) and cSCC prevention were included. In total, four studies met the inclusion criteria. Our final analysis included three articles. One clinical trial evaluated the efficacy of calcipotriol plus 5-FU in treating AK. Another clinical trial evaluated the long-term effect of calcipotriol plus 5-FU in prevention of cSCC. A retrospective study evaluated the use of calcipotriol plus 5-FU with cryotherapy. A limitation of this systematic review is the limited number of clinical trials that examine the combination of 5-FU plus calcipotriol in treating AK. The active control arm (Petroleum jelly plus 5-FU combination) is not equivalent to topical 5-FU monotherapy; hence, no superiority claim can be made vs topical 5-FU in terms of efficacy. Calcipotriol plus 5-FU reduced greater number of AKs in the treated area (25 cm2) when compared to 5-FU plus petroleum jelly, but only 27% of participants had complete clearance on the face at week-8. Calcipotriol plus 5-FU lowered the risk of cSCC on the face and scalp area over a 3-year period. Adequate and well-controlled studies are needed to compare the efficacy of calcipotriol plus 5-FU to 5-FU monotherapy, and other FDA-approved topical drugs such as imiquimod cream and tirbanibulin ointment. J Drugs Dermatol. 2022;21(1):60-65. doi:10.36849/JDD.6632.

Use of Topical Calcipotriol Plus 5-Fluorouracil in the Treatment of Actinic Keratosis: A Systematic Review

Background: Actinic Keratosis (AK) is a premalignant lesion that can progress to cutaneous squamous cell carcinoma (cSCC). Topical 5-Fluorouracil (5-FU) and imiquimod have been used for field-directed therapy for AK; however, their use is limited by intolerable skin reactions and long treatment durations. Objective: To assess current data on the efficacy, tolerability, and long-term effectiveness of topical calcipotriol plus 5-FU combination for the field-directed therapy of AK. The systematic review will include a critical evaluation of the available evidence. Methods: A systematic review of the literature was performed in August 2021 using the EMBASE and MEDLINE databases. Studies that assess the use of calcipotriol and 5-FU to treat actinic keratosis (AK) and cSCC prevention were included. Results: In total, four studies met the inclusion criteria. Our final analysis included three articles. One clinical trial evaluated the efficacy of calcipotriol plus 5-FU in treating AK. Another clinical trial evaluated the long-term effect of calcipotriol plus 5-FU in prevention of cSCC. A retrospective study evaluated the use of calcipotriol plus 5-FU with cryotherapy. Limitations: A limitation of this systematic review is the limited number of clinical trials that examine the combination of 5-FU plus calcipotriol in treating AK. The active control arm (Petroleum jelly plus 5-FU combination) is not equivalent to topical 5-FU monotherapy; hence, no superiority claim can be made vs topical 5-FU in terms of efficacy. Conclusion: Calcipotriol plus 5-FU reduced greater number of AKs in the treated area (25 cm2) when compared to 5-FU plus petroleum jelly, but only 27% of participants had complete clearance on the face at week-8. Calcipotriol plus 5-FU lowered the risk of cSCC on the face and scalp area over a 3-year period. Adequate and well-controlled studies are needed to compare the efficacy of calcipotriol plus 5-FU to 5-FU monotherapy, and other FDA-approved topical drugs such as imiquimod cream and tirbanibulin ointment. J Drugs Dermatol. 2022;21(1):60-65. doi:10.36849/JDD.6632Topical Calcipotriol Plus 5-Fluorouracil

Transcriptomic analysis identifies differences in gene expression in actinic keratoses after treatment with imiquimod and between responders and non responders

The presence of actinic keratoses (AKs) increases a patient’s risk of developing squamous cell carcinoma by greater than six-fold. We evaluated the effect of topical treatment with imiquimod on the tumor microenvironment by measuring transcriptomic differences in AKs before and after treatment with imiquimod 3.75%. Biopsies were collected prospectively from 21 patients and examined histologically. RNA was extracted and transcriptomic analyses of 788 genes were performed using the nanoString assay. Imiquimod decreased number of AKs by study endpoint at week 14 (p < 0.0001). Post-imiquimod therapy, levels of CDK1, CXCL13, IL1B, GADPH, TTK, ILF3, EWSR1, BIRC5, PLAUR, ISG20, and C1QBP were significantly lower (adjusted p < 0.05). Complete responders (CR) exhibited a distinct pattern of inflammatory gene expression pre-treatment relative to incomplete responders (IR), with alterations in 15 inflammatory pathways (p < 0.05) reflecting differential expression of 103 genes (p < 0.05). Presence of adverse effects was associated with improved treatment response. Differences in gene expression were found between pre-treatment samples in CR versus IR, suggesting that higher levels of inflammation pre-treament may play a part in regression of AKs. Further characterization of the immune micro-environment in AKs may help develop biomarkers predictive of response to topical immune modulators and may guide therapy.

Comparative study of imiquimod 3.75% vs. photodynamic therapy for actinic keratosis of the scalp.

To assess efficacy, tolerability, adverse effects, recurrence, and aesthetic results of imiquimod 3.75% vs. photodynamic therapy with 5-aminolaevulinic acid (MAL-PDT) for actinic keratosis (AK). A small randomized, intraindividual right-left pilot study for AK treatment of multiple scalp lesions was performed. Patients were treated with imiquimod and subsequently MAL-PDT (on opposite sides of the scalp) 14days apart. Study end points were evaluated with clinical and dermoscopic examinations at 1, 3, 6, and 12months. Nine male bald patients were enrolled. Imiquimod achieved a slightly higher overall clearance rate than MAP-PDT (68.1% vs 56.5%). According to AK degree of severity, clearance rates were greater for degree I and III with imiquimod (68.8%, 64.5% and 75% with imiquimod vs. 48%, 69.8%, and 66.7% for MAL-PDT, respectively). At 12months, a slightly higher total recurrence rate was noted for imiquimod compared with MAL-PDT (9.9% vs. 8.6%); new lesions were 2 degree I for imiquimod and 4 degree I for MAL-PDT. For both treatments, pain was moderate/strong (even if MAL-PDT seems to be less tolerable) adverse effects are common and transient; aesthetic results excellent. Both imiquimod and MAL-PDT were effective in the reduction in the number of AK. In the long-term, both present a good effectiveness maintained over time with excellent aesthetic results. A combination or sequential therapy could optimize the management of the cancerization field.

Abstract PO063: Transcriptomic analysis identifies changes in gene expression in Actinic Keratoses after treatment with imiquimod and differential gene expression

Abstract Background: The presence of actinic keratoses (AKs) increases a patient’s risk of developing squamous cell carcinoma (SCC) by greater than six-fold. It is difficult to predict which AKs will progress to become SCC, and topical treatments such as imiquimod are used to treat the entire affected field indiscriminately, effectively eliminating AKs in 50% of patients but sometimes resulting in severe inflammation and pain. Defining biomarkers to predict response to treatment would be helpful to guide therapy. Objectives: To evaluate the effect of imiquimod on the tumor microenvironment by measuring transcriptomic differences in AKs before and after treatment in patients treated with imiquimod. Methods: Biopsies were collected prospectively from 21 patients with presumptive AK and examined histologically. All patients were treated with imiquimod 3.75% on a short cyclical treatment regimen. 19 patients had available pre-treatment AK biopsies and 14 patients had paired pre- and post-treatment biopsies. RNA was extracted and transcriptomic analyses of 788 genes were performed using the nanoString assay. Results: Imiquimod significantly decreased total number of AKs by study endpoint at week 14 (p&amp;lt;0.0001). Post-imiquimod therapy, levels of CDK1, CXCL13, IL1B, GADPH, TTK, ILF3, EWSR1, BIRC5, PLAUR, ISG20, and C1QBP were significantly lower (p&amp;lt;0.05 after adjustment for multiple comparisons), with CXCL13 and IL1B showing a greater than 2-log2 fold decrease in expression post-treatment. Complete responders (CR) exhibited a distinct pattern of inflammatory gene expression pre-treatment relative to incomplete responders (IR), with significant alterations in 15 inflammatory pathways (p&amp;lt;0.05) reflecting differential expression of 103 genes, of which 95 were upregulated in CR (p&amp;lt;0.05). Presence of adverse effects was found to be related to an improved treatment response. Conclusions: NanoString analysis of AKs pre- and post-treatment with imiquimod shows downregulation of genes implicated in oncogenesis and immune suppression. Differences in gene expression were found between pre-treatment samples in CR versus IR, suggesting that higher levels of inflammation pre-treatment may play a part in regression of AKs. Further, presence of adverse effects in response to therapy was associated with an improved response to imiquimod. These findings show that the pre-treatment immune micro-environment impacts responsiveness of AKs to imiquimod and that clinical inflammation during treatment is associated with AK resolution. Further characterization of the immune micro-environment in AKs may help develop biomarkers predictive of response to topical immune modulators and may guide therapy in patients with high numbers of AKs at risk for SCC. Citation Format: Megan H. Trager, Emanuelle Rizk, Sharon Rose, Branden Lau, Ben Fullerton, Kuixi Zhu, Jaya Pradhan, Michael Moore, Ayush Chandra, Margaret Bogardus, Giselle Singer, Robyn Gartrell-Corrado, Rui Chang, Larisa Geskin, Yvonne Saenger, Gary Goldenbery. Transcriptomic analysis identifies changes in gene expression in Actinic Keratoses after treatment with imiquimod and differential gene expression [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO063.

Chemoprevention of keratinocyte carcinoma and actinic keratosis in solid-organ transplant recipients: Systematic review and meta-analyses

To the Editor: Skin cancers account for 40% of malignancies in solid-organ transplant recipients (SOTRs), who have an 80-fold increased risk of squamous cell carcinoma (SCC) and a 16-fold increased risk of basal cell carcinoma (BCC). Systemic chemoprevention is one method to mitigate this amplified risk. Acitretin, for instance, has been used to prevent keratinocyte carcinomas (KC) and actinic keratoses (AK) in SOTRs since 1995,1Bavinck J.N. Tieben L.M. Van der Woude F.J. et al.Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study.J Clin Oncol. 1995; 13: 1933-1938Crossref PubMed Google Scholar but its adverse effects include mucositis, liver and lipid abnormalities, and teratogenicity.2George R. Weightman W. Russ G.R. et al.Acitretin for chemoprevention of non-melanoma skin cancers in renal transplant recipients.Australas J Dermatol. 2002; 43: 269-273Crossref PubMed Scopus (130) Google Scholar Nicotinamide, an amide form of vitamin B3, is a newer chemoprophylaxis with fewer adverse effects.3Chen A.C. Martin A.J. Dalziell R.A. et al.A phase II randomized controlled trial of nicotinamide for skin cancer chemoprevention in renal transplant recipients.Br J Dermatol. 2016; 175: 1073-1075Crossref PubMed Scopus (61) Google Scholar Here we report results of a pairwise and network meta-analyses to summarize the current evidence regarding chemoprevention. We selected studies that analyzed the efficacy of systemic chemoprevention to prevent KC/AK in patients who are SOTRs or have a history of 2 or more KCs, or both. We limited our search to placebo-controlled, randomized control trials (RCTs) that reported the number of new KC/AK in both arms. Two authors (L.Y.T., S.Y.C.T.) independently conducted the literature search, screened titles and abstracts for eligibility, and extracted data. Statistical synthesis was performed with RevMan 5.3 software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). After the literature search, 6 RCTs with 734 patients were included in the quantitative synthesis (Appendix A, available via Mendeley at https://doi.org/10.17632/m6z2fzkkxn.2). Of the 6 RCTs, 3 studies with 580 patients (range, 17-192 patients) compared nicotinamide to placebo, and 3 studies with 154 patients (range, 19-35 patients) compared acitretin to placebo. Pairwise meta-analysis of all 6 RCTs using a random-effects model demonstrated a significant risk reduction with chemoprevention (Fig 1). The overall mean difference was 0.855 (95% confidence interval, 0.365-1.345; P < .001). In addition, acitretin and nicotinamide were both efficacious, with a combined mean difference of 0.792 (95% confidence interval, 0.298-1.286; P = .00168) for acitretin and a combined mean difference of 4.239 (95% confidence interval, 0.611-7.866; P = .0220) for nicotinamide. A network meta-analysis comparing nicotinamide and acitretin found no significant difference between the 2 treatments (Fig 2, Appendix B).Fig 1Forest plot of the pairwise meta-analysis of randomized controlled trials. The squares indicate the mean difference and are proportional to the weights used in the meta-analysis. The horizontal lines represent the 95% confidence interval (CI). The diamond indicates the weighted mean difference, and the lateral tips of the diamond indicate the associated 95% CI.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig 2Network graph and league table of the network meta-analysis. Mean differences and 95% confidence intervals are calculated using a random-effects model. A mean difference >1 means the top-left treatment is better.View Large Image Figure ViewerDownload Hi-res image Download (PPT) This meta-analysis does not address the optimal dosages of the drugs or the frequency of adverse effects. In addition, owing to the limited numbers of eligible RCTs, we are unable to investigate how chemoprevention is influenced by the duration or type of transplantation, duration of systemic chemoprevention, or existing immunosuppressive regimens. Moving forward, topical chemoprevention may be a suitable alternative to systemic chemoprophylaxis in SOTRs. Notably, large RCTs have evaluated topical chemoprevention for actinic keratosis. For instance, the Veterans Affairs Keratinocyte Carcinoma Chemoprevention trial found that topical 5% 5-fluorouracil cream resulted in a 49% relative risk reduction in the number of AK after 6 months and reduced the risk of SCC requiring surgery by 75% after 1 year but did not lower the risk of BCC.4Hyemin P. Hogan D. Eilers D. et al.Long-term efficacy of topical fluorouracil cream 5% for treating actinic keratosis: a randomized clinical trial.JAMA Dermatol. 2015; 151: 952-960Crossref PubMed Scopus (69) Google Scholar,5Weinstock M.A. Thwin S.S. Siegel J.A. et al.Chemoprevention of basal and squamous cell carcinoma with a single course of fluorouracil, 5%, cream: a randomized clinical trial.JAMA Dermatol. 2018; 154: 167-174Crossref PubMed Scopus (54) Google Scholar To our knowledge, this is the first meta-analysis that statistically integrates the current evidence regarding chemoprevention of KC/AK. This study demonstrates that systemic chemoprevention with nicotinamide or acitretin is effective in lowering the risk of KC/AK. Yet, even with the advent of better chemoprevention, regular physician surveillance and sun protection are still key basic strategies that should be practiced by all SOTRs.

Effects of MAL-PDT, ingenol mebutate and diclofenac plus hyaluronate gel monitored by high-frequency ultrasound and digital dermoscopy in actinic keratosis - a randomized trial.

The efficacy for actinic keratosis (AK) clearance of field-directed treatments has been investigated in randomized studies against placebo, but the comparison of results is difficult for several methodological reasons. The present study aims to compare efficacy of MAL-photodynamic therapy (MAL-PDT), ingenol mebutate gel (IMB) and diclofenac plus hyaluronate gel (DHA) on multiple AKs assessing a new performance index of efficacy, the cumulative AK area and evaluating dermoscopical and high-frequency ultrasound (HFUS) changes. Patients with ≥5 Olsen II AKs in a 25cm2 area of the scalp and face were enrolled and randomized to one of the treatment choices. Number of AKs and cumulative area were assessed before and after treatment. Dermoscopy and HFUS were performed on a single AK and surrounding photo-damaged skin in the treatment area. Cumulative AKs area reduced significantly more with PDT compared to other treatment options and with IMB in comparison to DHA. PDT was also the only treatment option that increased at a significant level the dermal density in both target AK and the surrounding skin and decreased significantly the SLEB thickness in the perilesional skin at HFUS. MAL-PDT is more effective than IMB and DHA for reducing the cumulative AK area which is calculated digitally from 3D pictures and should be the preferred performance index for the evaluation of the efficacy of treatments for AKs, rolling out clinical and dermoscopy evaluation. MAL-PDT improves all HFUS features of chronic photodamages of the dermis of the skin underlying and surrounding the AK spots.

Efficacy of new class I medical device for actinic keratoses: a randomized controlled prospective study

Background The presence of Actinic Keratoses (AKs) represent the most important warning sign of subclinical ultraviolet radiation. Currently, the regular use of sunscreens is considered essential for the prevention of the development of AKs. Aim We evaluated the effectiveness of a new class I Medical Device (MD) for the prevention and treatment of AKs vs traditional sunscreen alone (SPF 100+). Methods We conducted a randomized controlled prospective study in 90 Caucasian patients: 62 immunocompetent and 28 Organ Transplant Recipients (OTRs). We randomly assigned subjects to the MD group or sunscreen alone in a 1:1 assignment ratio. The patients have been reevaluated after three and six months. Results In immunocompetent patients treated with MD, at the end of the study the reduction of the mean number of AKs was 54.7 vs. 9.43% with photoprotector. In OTRs, the global reduction was of 36.7% after MD use compared to 14.3% with the sunscreen. The prevalence of NMSCs, in the patients treated with MD, was 11.11 and 17.18 with sunscreen; the incidence was 19.7 in patients treated with MD and 32.1 in those treated with sunscreen. Conclusion The MD has demonstrated good efficacy in the reduction of visible AKs, encouraging its use also in high-risk category, like OTRs.

Actualités sur la prise en charge des kératoses actiniques chez les patients transplantés d’organes: Management of actinic keratoses in organ transplant recipients: an update

Transplant recipients are at high risk of developing actinic keratosis (AK) and skin cancer. For this reason, initiating treatment at an early stage is crucial. Topical and systemic therapeutic options for AK have widely been described in studies of immunocompetent patients. However, little is known about AK management in organ transplant recipients (OTR). Photodynamic therapy (PDT), along with imiquimod, topical NSAIDs and topical 5-fluorouracil have been used on ORT patients in small non randomized studies. Although these studies seem to suggest that PDT offers best results, solid evidence is lacking. Nicotinamide and oral retinoids have also been described as reasonably effective preventive treatments in ORT patients. Management of immunosuppressive drugs is also considered as a key point for reducing the number of AK in ORT patients; an early switch for m-tor inhibitors has been shown to be protective while azathioprine, ciclosporin and tacrolimus have been shown to heighten the risk of developing AKs and skin cancer in this population. © 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.

Long-Term Efficacy of a New Medical Device Containing Fernblock® and DNA Repair Enzyme Complex in the Treatment and Prevention of Cancerization Field in Patients with Actinic Keratosis

Introduction: Actinic keratosis (AKs) are part of the cancerization field, a region adjacent to AKs containing subclinical and histologically abnormal epidermal tissue due to Ultraviolet (UV)-induced DNA damage. The photoproducts, “as consequence of DNA damage induced by UV”, are mainly cyclobutane pyrimidine dimers (CPDs). Fernblock® demonstrated in previous studies significant reduction of the number of CPDs induced by UV radiation. Photolyases are a specific group of enzymes that remove the major UV-induced DNA lesions by a mechanism called photo-reactivation. Methods: A monocentric, prospective, controlled, and double blind interventional study was performed to evaluate the effect of a new medical device (NMD) containing a DNA-repair enzyme complex (photolyases, endonucleases and glycosilases), a combination of UV-filters, and Fernblock® in the treatment of the cancerization field in 30 AK patients after photodynamic therapy (PDT). Patients were randomized into two groups: patients receiving a standard sunscreen (SS) and patients receiving the NMD. Clinical, dermoscopic, reflectance confocal microscopy (RCM) and histological evaluations were performed. Results: An increase of AKs was noted in all groups after three months of PDT without significant differences between them (p=0.476). A significant increase in the number of AKs was observed in SS group after six (p=0.026) and twelve months of PDT (p=0.038); however, this increase did not reach statistical significance in the NMD group. Regarding RCM evaluation, honeycomb pattern assessment after twelve months of PDT showed significant differences in the extension and grade of the atypia in the NMD group compared to SS group (p=0.030 and p=0.026, respectively). Concerning histopathological evaluation, keratinocyte atypia grade improved from baseline to six months after PDT in all the groups, with no statistically significant differences between the groups. Twelve months after PDT, p53 expression was significantly lower in the NMD group compared to SS group (p=0.028). The product was well-tolerated, with no serious adverse events reported. Conclusion: Our results provide evidence of the utility of this NMD in the improvement of the cancerization field and in the prevention of the development of new AKs.

642 Efficacy and photorejuvenation effect of conventional photodynamic therapy (PDT) and Er:YAG (erbium:yttrium-aluminium-garnet) ablative fractional laser – assisted PDT in multiple actinic keratosis

Actinic keratosis is the precancerous lesion of squamous cell carcinoma. Their multiple appearance on one area reflects field cancerization. Therefore active treatment of the field is necessary to avoid the development of incidental squamous cell carcinoma. Conventional photodynamic therapy (PDT) is a widely used therapeutic method for actinic keratosis. Er:YAG (erbium:yttrium-aluminium-garnet) ablative fractional laser (AFL) - assisted PDT is used to increase the therapeutic efficacy of conventional PDT. The aim of this study was to assess the differences between conventional PDT and Er:YAG - assisted PDT both in efficacy and rejuvenation effect. To investigate the therapeutic efficiency, sixteen patients with actinic keratosis and chronic sun-damaged skin were irradiated with wIRA lamp on the half side of the skin involved in actinic keratosis – after 20% 5-aminolevulinic acid was applied as photosensitizer. The other side of the skin was pre-treated with Er:YAG-AFL before 5-ALA. 24/48 hours and 3 months after the treatment biopsy samples were taken to measure the degree of the keratinocyte dysplasia compared to the control (untreated) samples. P53 mutant keratinocytes were detected with immunohistochemical staining. The number and grade of actinic keratosis and the objective signs of photoaging was also assessed. In our hands, both conventional PDT and Er:YAG-AFL - assisted PDT led to great reduction in the number of actinic keratosis, and this decrease was significantly higher in the case of Er:YAG-AFL PDT. Both improved global photoaging, but we found no significant differences between the two methods. According to the immunohistochemical staining, both decreased the number of p53 mutant keratinocytes in the epidermis. We found no significant differences in the therapeutic efficiency between Er:YAG-AFL PDT and conventional PDT regarding clinical and immunohistochemical evaluation.

Actinic keratosis-related signs predictive of squamous cell carcinoma in renal transplant recipients: a nested case-control study.

Squamous cell carcinoma (SCC) and intraepidermal carcinoma (IEC) commonly arise in actinically damaged skin. To identify clinical features of actinic change that correlate with an increased risk of SCC or IEC in the short-to-medium term as guidance for prioritizing field treatment. In a nested case-control study, cases were renal transplant recipients who developed an incident SCC or IEC within 18 months following baseline examination and photography. Controls without SCC or IEC were matched to cases on age, sex and duration of immunosuppression. Predefined skin sites on the head, neck and upper limbs were examined using baseline photographs to assess objectively the following features of actinic damage: presence of actinic keratosis (AK) patch (defined as AK > 1 cm2 ), number of AK patches, number of AKs and area affected by AK. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using McNemar's test to identify differences in SCC/IEC risk combined and SCC risk alone between case and control skin sites. Thirty-nine cases were matched to 39 controls. Significant associations with the presence of an AK patch, number of AK patches, number of AKs and area affected by AKs were identified. The presence of an AK patch conferred an 18-fold increased risk of SCC (OR 18·00, 95% CI 2·84-750) and more than a sixfold increased risk of SCC/IEC combined (OR 6·60, 95% CI 2·56-21·66). AK patches are predictive of SCC/IEC development within 18 months. This can be used to guide site selection for field treatment in patients with widespread actinic damage.

Ingenol mebutate in low amounts for the treatment of actinic keratosis in Korean patients.

BackgroundIngenol mebutate (IM), a novel agent for field therapy of actinic keratosis (AK), has a drawback of inducing local skin reactions (LSRs), which may cause discomfort in patients. To reduce the LSRs, we tried the application of IM in low amounts.ObjectiveThe purpose of this study was to review Korean patients with AK being treated with IM and evaluate the LSRs and therapeutic outcomes of low amounts of IM.MethodsWe retrospectively reviewed 47 patients with AK on the face. A total of 20 and 27 patients were treated by applying recommended amount of 18.8 mg/cm2 and the lower amount of 10 mg/cm2, respectively.ResultsThe mean composite LSR score for the low amount group (LAG; 12.18±3.29) was significantly lower than that for the recommended amount group (RAG; 15.45±2.70) (P<0.01, independent sample t-test). The 2-month clearance rate calculated by the number of AKs before and after treatment in each patient was significantly higher for RAG (88.16%), compared with 75.56% for LAG (P<0.001).ConclusionLow amount of IM for the treatment of facial AK significantly reduced LSRs in Korean patients. Minimizing LSRs may allow for a secondary targeting treatment of IM for the residual lesions, depending on initial treatment outcomes.

Comparison of “Lesion-by-Lesion” and Field Photodynamic Therapy in the Prevention of Actinic Keratoses: A Randomized, Split-Face, Single-Blind Pilot Study

Background: Actinic keratoses (AKs) are often treated separately, lesion by lesion. However, in the past years, AKs have been described as a field disease and not limited to single clinically apparent lesions. Treatment should therefore target an area of field change which may reduce the risk of development of further AKs, second tumours, and local recurrence. Objective: The primary objective was to determine the number of new lesions at 9 months after methyl aminolevulinate photodynamic therapy (MAL-PDT). Secondary objectives were to determine the number of new lesions at 3 and 6 months after treatment and the percentage reduction of AKs from baseline at 3, 6, and 9 months after MAL-PDT. Methods: This was a single-centre, prospective, randomized, split-face, investigator-blinded pilot study with a study duration of 1 year. The study population comprised patients with AKs on the face or scalp, with a maximum of 10 AKs on each side. One side was treated with 1 session of “lesion-by-lesion” MAL-PDT (LT side) and the other side with 1 session of field MAL-PDT (FT side). Results: At 9 months the FT demonstrated significantly fewer new lesions. At every time point during the follow-up, we found a significant reduction in the number of AKs in the LT as well as in the FT sides. After 3 and 6 months we did not observe significant differences between the sides. However, after 9 months, the LT area showed significantly fewer remaining AKs, whereas the FT area demonstrated significantly fewer new lesions. Conclusions: Field treatment results in significantly fewer new AK lesions compared with lesion-by-lesion treatment.

The use of a sunscreen containing DNA-photolyase in the treatment of patients with field cancerization and multiple actinic keratoses: a case-series

Cutaneous field cancerization (CFC) is associated witha high-risk of developing cutaneous squamous cellcarcinoma (cSCC). It manifests as actinic keratoses(AK) as one of the few macroscopic alterations in CFCpatients. A prospective, single-arm, case-series wasperformed to evaluate the utility of a novel sunscreencontaining DNA-photolyase for treatment of CFCin nine subjects (mean age 70.6 years, male: femaleratio 5:4). The cream was applied topically twicedaily on CFC/AK areas and patients were followedup for three months, with no other treatments. Theprimary outcome was the overall response rate (ORR),categorized as complete response (CR, completeresolution of AKs), partial response (PR, reduction inthe number of AKs), and no-response (NR, similar/increase in number of AKs). A 100% PR was observed.All subjects displayed at minimum, a 50% reductionin their lesion number and most patients experiencedalmost CR. Evaluation of AK numbers revealed anabsolute count reduction of 76.6% in the number oflesions, with the mean number of lesions reducedfrom 13.4 to 3.1 (p &lt; 0.0001). No adverse events werereported. Patients with CFC may benefit from noveltopical applications containing DNA-photolyase,at minimum, as complementary therapy for themanagement of CFC disease. We propose a newconcept called "active photoprotection" because of itsdual mechanism involving therapy and protection.

Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy.

Actinic keratosis is a precursor to cutaneous squamous cell carcinoma. Long treatment durations and severe side effects have limited the efficacy of current actinic keratosis treatments. Thymic stromal lymphopoietin (TSLP) is an epithelium-derived cytokine that induces a robust antitumor immunity in barrier-defective skin. Here, we investigated the efficacy of calcipotriol, a topical TSLP inducer, in combination with 5-fluorouracil (5-FU) as an immunotherapy for actinic keratosis. The mechanism of calcipotriol action against skin carcinogenesis was examined in genetically engineered mouse models. The efficacy and safety of 0.005% calcipotriol ointment combined with 5% 5-FU cream were compared with Vaseline plus 5-FU for the field treatment of actinic keratosis in a randomized, double-blind clinical trial involving 131 participants. The assigned treatment was self-applied to the entirety of the qualified anatomical sites (face, scalp, and upper extremities) twice daily for 4 consecutive days. The percentage of reduction in the number of actinic keratoses (primary outcome), local skin reactions, and immune activation parameters were assessed. Calcipotriol suppressed skin cancer development in mice in a TSLP-dependent manner. Four-day application of calcipotriol plus 5-FU versus Vaseline plus 5-FU led to an 87.8% versus 26.3% mean reduction in the number of actinic keratoses in participants (P < 0.0001). Importantly, calcipotriol plus 5-FU treatment induced TSLP, HLA class II, and natural killer cell group 2D (NKG2D) ligand expression in the lesional keratinocytes associated with a marked CD4+ T cell infiltration, which peaked on days 10-11 after treatment, without pain, crusting, or ulceration. Our findings demonstrate the synergistic effects of calcipotriol and 5-FU treatment in optimally activating a CD4+ T cell-mediated immunity against actinic keratoses and, potentially, cancers of the skin and other organs. ClinicalTrials.gov NCT02019355. Not applicable (investigator-initiated clinical trial).