pep005 and Keratosis--Actinic

Myriad interventions are available for the treatment of actinic keratosis located on the face or scalp. However, lesions located outside the head and neck have received little attention until now. We aimed to synthesize the current knowledge of interventions for actinic keratosis in nonscalp and nonface localizations. Randomized controlled trials reporting data for these localizations were searched in MEDLINE, Embase, and The Cochrane Library CENTRAL, as well as in pertinent trial registers until 25 March 2020. A total of 13 randomized controlled trials with 1,380 patients were included in a systematic review. Five treatment modalities were evaluated and compared with placebo in a frequentist network meta-analysis, including cryosurgery, ingenol mebutate, photodynamic therapy, colchicine, and 5-fluorouracil. In the network meta-analysis, cryosurgery showed the highest participant complete clearance rates (risk ratio, 7.73; 95% confidence interval = 3.21-18.61; 10 studies; I

Topics: Colchicine; Cryosurgery; Diterpenes; Fluorouracil; Humans; Immunosuppressive Agents; Keratosis, Actinic; Network Meta-Analysis; Photochemotherapy; Photosensitizing Agents; Randomized Controlled Trials as Topic; Treatment Outcome

While a wide range of treatments exist for actinic keratosis and skin field cancerisation, the long-term benefits of the most common topical therapies are poorly defined. This report reviews the efficacy of the most commonly used topical therapies to treat regional or field lesions. Limited clinical and histopathological data are available on clearance rates at 12 months post-treatment for the most commonly used agents, with varied outcome measures making any comparison difficult. In general, total field clearance rates at 12 months are suboptimal for the most commonly employed agents. Given the increasing incidence of actinic keratosis and skin field cancerisation due to an ageing population, further research into the efficacy of therapies is critical to guide treatment choice.

Topics: Antineoplastic Agents; Diclofenac; Disease Progression; Diterpenes; Fluorouracil; Humans; Imiquimod; Keratosis, Actinic; Photochemotherapy; Recurrence; Skin Neoplasms

Skin cancer is a broad term used to describe a number of different malignant indications of the skin. Skin cancers mostly comprise of the keratinocyte cancers [Basal Cell Carcinoma (BCC) and cutaneous Squamous Cell Carcinoma (SCC)], and melanoma. Surgical excision of these malignancies has been the preferred treatment of patients for decades. However, the decision to perform surgery can be affected by various considerations, including co-morbidities of the patient, the anatomical site of the lesion and potential intolerance for repeated excisions. Topical treatment of skin cancer may therefore be more appropriate in certain instances. Topical treatment potentially allows for higher drug levels at the tumor site, and may result in less overall toxicity than systemic agents. This review will specifically address the current agents used in topical treatment of skin cancers, and introduce emerging treatments from the natural product field that may also find utility in these indications.

Topics: Administration, Cutaneous; Antineoplastic Agents; Carcinoma, Basal Cell; Clinical Trials as Topic; Diterpenes; Drug Delivery Systems; Fluorouracil; Humans; Hutchinson's Melanotic Freckle; Imiquimod; Keratosis, Actinic; Melanoma; Neoplasms, Squamous Cell; Photochemotherapy; Retinoids; Skin; Skin Neoplasms; Ultraviolet Rays

Actinic keratosis (AK) is a lesion that arises as a result of excessive exposure to solar radiation and appearing predominantly on Fitzpatrick phototype I and II skin. Given that some AKs evolve into squamous cell carcinoma, these lesions are considered premalignant in nature, occurring mostly in elderly men and immunosuppressed individuals chronically exposed to ultraviolet (UV) radiation. There are several mechanisms for the formation of AKs; among them are oxidative stress, immunosuppression, inflammation, altered proliferation and dysregulation of cell growth, impaired apoptosis, mutagenesis, and human papillomavirus (HPV). Through the understanding of these mechanisms, several treatments have emerged. Among the options for AK treatment, the most commonly used include 5-fluorouracil (5-FU), cryotherapy, diclofenac, photodynamic therapy (PDT), imiquimod (IQ), retinoids, and ingenol mebutate (IM). There have been recent advances in the treatment options that have seen the emergent use of newer agents such as resiquimod, betulinic acid, piroxicam, and dobesilate. The combination between therapies has presented relevant results with intention to reduce duration of therapy and side effects. All AK cases must be treated because of their propensity to transform into malignancy and further complicate treatment. In addition to medical or surgical care, education about sun exposure prevention remains the best and most cost-effective method for AK prevention. The objective of this article is to conduct a literature review of the clinical presentation of AK including advances in treatment options available.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antimetabolites, Antineoplastic; Antineoplastic Agents; Cryotherapy; Diclofenac; Diterpenes; Fluorouracil; Humans; Imiquimod; Keratosis, Actinic; Photochemotherapy; Retinoids

Actinic keratosis (AK) is a common skin condition that results from exposure to chronic ultraviolet (UV) radiation. AK is characterized by visible, scaly lesions; sub-clinical lesions may also be present within a field of UV-exposed skin. These lesions exist on a disease continuum with squamous cell carcinoma. Field therapies, such as ingenol mebutate, aim to treat the visible and sub-clinical lesions within an area of sun-damaged skin. Areas covered: According to the SmPC, ingenol mebutate has a proposed dual mechanism of action that induces cell death necrosis with the production of a local pro-inflammatory response and stimulation of apoptosis. In clinical trials, efficacy of ingenol mebutate has been shown through clearance of AK lesions. Adverse events and local skin responses generally resolved within 2-4 weeks from the end of treatment, depending on body location. Expert opinion: AK can be treated using lesion-directed or topical therapies. Topical treatment with ingenol mebutate has been shown to have superior efficacy compared with diclofenac/sodium hyaluronate. The short and simple treatment regimen may improve patient adherence to ingenol mebutate and satisfaction with treatment. It might be worth evaluating further indications for ingenol mebutate including treatment of basal cell carcinoma.

Topics: Administration, Cutaneous; Animals; Apoptosis; Dermatologic Agents; Diclofenac; Diterpenes; Humans; Hyaluronic Acid; Keratosis, Actinic; Medication Adherence; Ultraviolet Rays

Ingenol mebutate gel is a recent stirring weapon recommended for the treatment of multiple actinic keratoses (AKs) and field cancerization. This review brings a summary of recent data on the treatment of AKs with ingenol mebutate (IM) providing critical commentary with regard to drug's characteristics, drug's safety profile, treatment regimen, treatment outcome, patient compliance, AK recurrence, costeffectiveness and cost-utility, as well as guidelines for the management of the treatment of AK.. We undertook a structured search of bibliographic databases for peer-reviewed scientific articles, including review articles, original research articles as well as case report articles based on inclusion/exclusion criteria. Reports on ingenol mebutate from U.S. Food and Drug Administration and European Medical Agency were also included.. Sixty-six papers were included in this review. We report current data on ingenol mebutate chemical properties, pharmacology, efficacy, safety, and tolerability, potential new indications in dermatology, costeffectiveness, and cost-utility analysis.. Treatment of AKs is necessary in order to prevent possible transition to invasive SCC. Although the mechanism of action of ingenol mebutate is not fully elucidated, dual mechanism of action is presumed. Ingenol mebutate is an effective and cost-saving topical agent for the treatment of AK, especially multiple AKs and field cancerization, with acceptable safety profile. It may also have perspective in dermatology regarding the treatment of superficial BCC, Bowen disease, actinic cheilitis, and anogenital warts that has to be evaluated in clinical trials. Patients' adherence to recommended treatment regimen and auspicious safety profile make this drug attractive.

Topics: Antineoplastic Agents; Diterpenes; Dose-Response Relationship, Drug; Humans; Keratosis, Actinic; Molecular Structure; Neoplasm Recurrence, Local; Structure-Activity Relationship

This systematic review compared the relative efficacy of 5-fluorouracil 0.5% in salicylic acid 10% (5-FU/SA), ingenol mebutate (IMB) and imiquimod 2.5%/3.75% (IMI) for actinic keratosis on the face, forehead or scalp. Only 11 publications, relating to 7 randomised controlled trials, met inclusion criteria and it was only possible to compare the effect of all 3 treatments on complete clinical clearance, and the effect of 5-FU/SA and IMB on actinic keratosis recurrence rate. Despite a higher vehicle response rate for 5-FU/SA, complete clinical clearance was higher than IMB and IMI (55.4, 42.2, and 25.0-30.6/34.0-35.6%, [corrected] respectively). 5-FU/SA was also associated with lower actinic keratosis recurrence rate than IMB at 12 months post-treatment (32.7 vs. 53.9%). Although qualitative assessment suggested a numerical advantage of 5-FU/SA over IMB and IMI in terms of complete clinical clearance and sustained clearance, clinical data from longer term trials, with comparable outcome measures, are required to corroborate these findings.

Topics: Administration, Cutaneous; Aminoquinolines; Dermatologic Agents; Diterpenes; Drug Combinations; Facial Dermatoses; Fluorouracil; Humans; Imiquimod; Keratosis, Actinic; Randomized Controlled Trials as Topic; Salicylic Acid; Scalp Dermatoses; Skin; Treatment Outcome

There is a need for early, effective field treatments for actinic keratosis (AK) that target subclinical as well as clinically visible lesions to minimize the recurrence and emergence of new lesions. Ingenol mebutate gel is an effective and well-tolerated topical field therapy that has demonstrated sustained clearance and long-term reduction of AKs. This article reviews findings from the FIELD study program and highlights health-related quality of life (HRQoL) outcomes for patients receiving ingenol mebutate. Efficacy data from the FIELD study program are discussed and the tolerability profile of ingenol mebutate in the treatment of areas of up to 100 cm2 is considered. These findings are then placed in the context of HRQoL outcomes and their relevance for patients.

J Drugs Dermatol. 2016;15(5):535-542.

Topics: Administration, Cutaneous; Animals; Clinical Trials, Phase III as Topic; Diterpenes; Humans; Keratosis, Actinic; Quality of Life; Treatment Outcome

Actinic keratoses are premalignant skin lesions with the risk of converting into squamous cell carcinoma, and therefore they should be treated. Treatment modalities include cryotherapy, photodynamic therapy, carbon dioxide laser and also topical treatments such as imiquimode, ingenol mebutate, 5-fluorouracil and diclophenac. In the future, the treatment of actinic keratosis can be more often done in primary health care. The most favorable treatment modality depends on patient age, general health, and the thickness, size and localization of the lesion.

Topics: Administration, Topical; Aminoquinolines; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Cryotherapy; Diclofenac; Diterpenes; Fluorouracil; Humans; Imiquimod; Keratosis, Actinic; Laser Therapy; Photochemotherapy; Precancerous Conditions; Primary Health Care

Ingenol mebutate is a topical therapeutic agent for the treatment of actinic keratosis (AK). It has a novel mode of action and has shown comparable efficacy to other topical field therapies. This article summarizes and provides perspective on the safety profile of ingenol mebutate from clinical studies of this agent.. The unique mechanism of action of ingenol mebutate, the basis for a rapid clinical effect, is outlined. Safety and tolerability data, including mean composite local skin response (LSR) scores, type of LSR, and adverse events from a range of clinical studies both in healthy volunteers and patients with AK, are reviewed. The safety profile of ingenol mebutate is then compared with other agents used to treat AK lesions.. Ingenol mebutate has a dosing period of 2 - 3 days, which is short compared with other field therapies, and there is no evidence of systemic absorption. The fact that most of the LSRs observed are mild to moderate in intensity and transient, with a majority resolved within 2 weeks, makes for a favorable safety profile. Ingenol mebutate enhances the armamentarium available to the dermatologist for the treatment of AK.

Topics: Administration, Cutaneous; Animals; Dermatologic Agents; Diterpenes; Humans; Keratosis, Actinic

In recent decades, 'Big Pharma' has invested billions of dollars into ingenious and innovative strategies designed to develop drugs using high throughput screening of small molecule libraries generated on the laboratory bench. Within the same time frame, screening of natural products by pharmaceutical companies has suffered an equally significant reduction. This is despite the fact that the complexity, functional diversity and druggability of nature's natural product library are considered by many to be superior to any library any team of scientists can prepare. It is therefore no coincidence that the number of New Chemical Entities reaching the market has also suffered a substantial decrease, leading to a productivity crisis within the pharmaceutical sector. In fact, the current dearth of New Chemical Entities reaching the market in recent decades might be a direct consequence of the strategic decision to move away from screening of natural products. Nearly 700 novel drugs derived from natural product New Chemical Entities were approved between 1981 and 2010; more than 60% of all approved drugs over the same time. In this review, we use the example of ingenol mebutate, a natural product identified from Euphorbia peplus and later approved as a therapy for actinic keratosis, as why nature's natural product library remains the most valuable library for discovery of New Chemical Entities and of novel drug candidates.

Topics: Animals; Biological Products; Clinical Trials as Topic; Disease Models, Animal; Diterpenes; Drug Discovery; Euphorbia; Humans; Keratosis, Actinic; Medicine, Traditional

Actinic keratosis (AK) is a common premalignant skin lesion that is frequently treated by cryosurgery. Basal cell carcinoma is the most common malignancy of man, and early-stage lesions are usually cured via surgery. Advanced basal cell carcinoma may require more extensive surgery resulting in deformity, and many advanced lesions cannot be treated surgically. Several recent developments have improved therapeutic options for both conditions. Cryosurgery is still a mainstay of treatment for AK, but the introduction of effective topical agents, imiquimod cream and ingenol mebutate, has provided alternatives to cryosurgery. For advanced basal cell carcinoma, the small-molecule inhibitor vismodegib has proven to be an effective therapy for lesions that are not amenable to surgery and has demonstrated ability to achieve dramatic improvement in advanced, potentially disfiguring cancer.

Topics: Aminoquinolines; Anilides; Antineoplastic Agents; Carcinoma, Basal Cell; Cryosurgery; Diterpenes; Humans; Imiquimod; Keratosis, Actinic; Mutation; Patched Receptors; Pyridines; Receptors, Cell Surface; Skin Neoplasms; Treatment Outcome

The conclusions of pairwise meta-analyses of interventions for actinic keratosis (AK) are limited due to the lack of direct comparison between some interventions. Consequently, we performed a network meta-analysis for eight treatments [5-aminolaevulinic acid (ALA)-photodynamic therapy (PDT), cryotherapy, diclofenac 3% in 2·5% hyaluronic acid (DCF/HA), 5-fluorouracil (5-FU) 0·5% or 5·0%, imiquimod (IMI) 5%, ingenol mebutate (IMB) 0·015-0·05%, methyl aminolaevulinate (MAL)-PDT and placebo/vehicle (including placebo-PDT)] to determine their relative efficacies. As part of a prior Cochrane systematic review, different databases and grey literature were searched for randomized controlled trials up to April 2012. The inclusion criteria were parallel-group studies with nonimmunosuppressed participants: (i) reporting 'participant complete clearance' and (ii) comparing at least two of the interventions. Thirty-two publications met the criteria and they included the following number of individual or pooled studies (n) and total number of participants (N) for the different interventions: 5-FU 0·5% (n = 4, N = 169), 5-FU 5·0% (n = 2, N = 44), ALA-PDT (n = 6, N = 739), cryotherapy (n = 2, N = 174), DCF/HA (n = 5, N = 299), IMI (n = 14, N = 1411), IMB (n = 3, N = 560), MAL-PDT (n = 7, N = 557) and placebo (n = 32, N = 2520). Network analyses using a random-effects Bayesian model were carried out with the software ADDIS v1.16.1. The interventions were ranked as follows based on calculated probabilities and odd ratios: 5-FU > ALA-PDT ≈ IMI ≈ IMB ≈ MAL-PDT > cryotherapy > DCF/HA > placebo. This efficacy ranking was obtained based on the current available data on 'participant complete clearance' from randomized controlled trials and the analysis model used. However, several other factors should also be considered when prescribing a treatment for AK.

Topics: Adjuvants, Immunologic; Aged; Aminolevulinic Acid; Aminoquinolines; Anti-Inflammatory Agents, Non-Steroidal; Cryotherapy; Diclofenac; Diterpenes; Drug Combinations; Female; Fluorouracil; Follow-Up Studies; Humans; Hyaluronic Acid; Imiquimod; Immunocompetence; Immunosuppressive Agents; Keratosis, Actinic; Male; Middle Aged; Photochemotherapy; Photosensitizing Agents; Randomized Controlled Trials as Topic; Treatment Outcome

Actinic keratosis, one of the most common dermatological pathologies manifests as ultraviolet- or sun-induced macules, papules or plaques, and is considered a biomarker for the risk of skin cancer. Ingenol mebutate (Picato®), extracted from the sap of the Euphorbia peplus plant, is a small molecule with a unique mechanism of action involving direct cytotoxicity and immune stimulation. In 2012, ingenol mebutate was approved by the FDA and the EMA for the treatment of actinic keratosis. In phase III trials, ingenol mebutate gel applied topically once daily at 0.015% for 3 days or 0.05% for 2 days, respectively, significantly reduced head and non-head actinic keratosis lesions. Adverse events were mostly mild or moderate. Local skin responses elicited by the treatment, i.e., erythema, flaking/scaling and crusting, were transient, and resolved spontaneously without sequelae. Adherence to the therapy can be facilitated by the short duration of the treatment.

Topics: Administration, Topical; Animals; Dermatologic Agents; Diterpenes; Gels; Humans; Keratosis, Actinic; Skin; Treatment Outcome

Current topical agents for field therapy of actinic keratoses have single mechanisms of action and must be applied for weeks. Ingenol mebutate gel, a novel drug for field therapy of actinic keratoses, appears to have a dual mechanism of action: (1) rapid lesion necrosis and (2) specific neutrophil-mediated, antibody-dependent cellular cytotoxicity. Because of the rapid destruction of actinic keratosis lesions after application of ingenol mebutate gel, treatment is necessary for only 2 or 3 days. The subsequent immune-mediated response targets any residual dysplastic epidermal cells. This dual mechanism of action should provide efficacy equivalent to that of current topical agents with a substantially shorter treatment period.

Topics: Administration, Topical; Dermatologic Agents; Diterpenes; Gels; Humans; Keratosis, Actinic; Necrosis

Ingenol mebutate is the main active constituent of sap from the plant Euphorbia peplus, which has traditionally been used as a home remedy for various skin conditions. Ingenol mebutate gel is approved in the US, EU, Australia and Brazil for the topical treatment of actinic keratosis. A short course of field-directed therapy with topical ingenol mebutate gel was effective in the treatment of actinic keratoses on the face or scalp (ingenol mebutate gel 0.015% once daily for 3 consecutive days) and on the trunk or extremities (ingenol mebutate gel 0.05% once daily for 2 consecutive days), according to the results of four randomized, double-blind, vehicle-controlled, multicentre studies. Significantly higher complete clearance rates (primary endpoint) and partial clearance rates were seen at day 57 in patients receiving ingenol mebutate gel than in those receiving vehicle gel. Treatment with ingenol mebutate gel was generally associated with sustained clearance of actinic keratoses in the longer term. Topical ingenol mebutate gel was generally well tolerated in the treatment of patients with actinic keratoses on the face or scalp and on the trunk or extremities. Application-site conditions were the most commonly occurring adverse events.

Topics: Diterpenes; Gels; Humans; Keratosis, Actinic; Protein Kinase C; Randomized Controlled Trials as Topic; Treatment Outcome

Topical antineoplastic agents have a well-established role in the treatment of several dermatological conditions. Their use in the treatment of mucosal skin disease also has gained increasing recognition. Topical 5-fluorouracil (5-FU), an antimetabolite, and imiquimod, an immunomodulatory agent with antitumor properties, are the two principal topical antineoplastic agents used in the treatment of mucocutaneous diseases. Although the vast majority of their mucosal uses are currently not approved by the Federal Drug Administration, there are numerous case series, open-label studies and randomized controlled trials supporting their uses in the treatment of mucocutaneous diseases. Both topical 5-FU and imiquimod have been successfully utilized in the treatment of a wide range of mucosal diseases, including actinic cheilitis, Bowen's disease of the anal and vulvar mucosa, and genital and perianal condyloma. Reports of their uses in the treatment of mucocutaneous diseases indicate that these agents can be safely administered, though adverse effects such as local inflammation may be augmented when these agents are applied to mucosal surfaces. Additionally, locally acting intralesional chemotherapeutic agents, such as bleomycin and interferon, have well-defined applications in the treatment of mucosal skin diseases such as condyloma acuminata. As further studies are conducted, these topical and intralesional neoplastic agents, in addition to emerging agents that are in various stages of development, such as Toll-like receptor 9 agonists and ingenol mebutate, may play an increasingly important role in the future treatment of mucocutaneous diseases.

Topics: Administration, Topical; Aminoquinolines; Antineoplastic Agents; Diterpenes; Fluorouracil; Humans; Imiquimod; Keratosis, Actinic; Mucositis; Mucous Membrane; Skin Diseases; Skin Neoplasms

It is unclear if there are any distinct AK patient populations that might respond best to a given treatment.. To identify if a distinct subgroup of patients with AK might respond better to treatment with ingenol mebutate (IngMeb) versus diclofenac sodium (DS).. Complete clearance of AK and mean lesion reduction at end of first treatment course and week 17 were evaluated within subgroups.. 502 patients (255 IngMeb; 247 DS) were included in the analysis. At week 17, complete clearance was achieved by more patients treated with IngMeb versus DS within the majority of patient subgroups, including patients with <6 lesions and ≥6 lesions at baseline, aged ≥65 years, males, females, Fitzpatrick skin types II and III, and facial lesions. Mean lesion reduction at week 17 was greater with IngMeb than DS within the same subgroups, and in patients with scalp lesions.. This responder analysis did not identify any distinct population that responded more optimally than others with IngMeb or DS. More patients achieved complete clearance and higher lesion reduction of AK with IngMeb compared with DS in most subgroups.

Topics: Aged; Diclofenac; Diterpenes; Female; Humans; Keratosis, Actinic; Male; Middle Aged; Treatment Outcome

Topics: Aged; Aged, 80 and over; Aminolevulinic Acid; Diterpenes; Female; Fluorouracil; Humans; Imiquimod; Keratosis, Actinic; Male; Patient Reported Outcome Measures; Photochemotherapy; Quality of Life; Skin Cream; Surveys and Questionnaires; Treatment Outcome

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 25 cm. 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.

Topics: Aminolevulinic Acid; Dermoscopy; Diclofenac; Diterpenes; Humans; Keratosis, Actinic; Photochemotherapy; Photosensitizing Agents; Treatment Outcome

Actinic keratosis (AK) is a common premalignant skin condition that might have the ability to progress into squamous cell carcinoma. Due to the high incidence of AK, treatment of this disease significantly impacts healthcare spending.. To determine which commonly prescribed field-directed treatment is the most cost-effective, when comparing 5-fluorouracil (5-FU) 5%, imiquimod (IMQ) 5%, ingenol mebutate (IM) 0·015% and methyl aminolaevulinate photodynamic therapy (MAL-PDT) for AK in the head and neck region.. We performed an economic evaluation from a healthcare perspective. Data were collected alongside a single-blinded, prospective, multicentre randomized controlled trial with 624 participants in the Netherlands. The outcome measure was expressed as the incremental cost-effectiveness ratio, which is the incremental costs per additional patient with ≥ 75% lesion reduction compared with baseline. This trial was registered at ClinicalTrials.gov, number NCT02281682.. The trial showed that 5-FU was the most effective field treatment for AK in the head and neck region. Twelve months post-treatment, the total mean costs for 5-FU were significantly lower (€433) than the €728, €775 and €1621 for IMQ, IM and MAL-PDT, respectively. The results showed that 5-FU was a dominant cost-effective treatment (more effective and less expensive) compared with the other treatments, 12 months post-treatment.. Based on these results, we consider 5-FU 5% cream as the first-choice treatment option for multiple AKs in the head and neck area. What's already known about this topic? Due to the increasing incidence of actinic keratosis (AK), the recommended treatment results in a considerable socioeconomic burden for (dermatological) healthcare. Although cost-effectiveness modelling studies have been performed in which different treatments for AK were compared, a prospective clinical trial comparing four frequently prescribed treatments on effectiveness and resource consumption within a time horizon of 12 months has never been conducted. What does this study add? This is the first study examining the cost-effectiveness of 5-fluorouracil 5% cream, imiquimod 5% cream, ingenol mebutate 0·015% gel and methyl aminolaevulinate photodynamic therapy, with data collected in a randomized controlled trial over a time horizon of 12 months. We found that 5-fluorouracil was a dominant cost-effective treatment (more effective and less costly), based on data from the Netherlands. Linked Comment: Steeb et al. Br J Dermatol 2020; 183:612.

Topics: Aminolevulinic Acid; Cost-Benefit Analysis; Diterpenes; Fluorouracil; Humans; Imiquimod; Keratosis, Actinic; Netherlands; Photochemotherapy; Photosensitizing Agents; Prospective Studies; Treatment Outcome

Actinic keratosis (AK) is a chronic, precancerous skin disease. Various treatments options exist, including ingenol mebutate gel. The aim of this study was to compare its effectiveness and tolerability as well as the impact of therapy on patients' quality of life in standard clinical practice.. A multicenter study was carried out involving a 12-month follow-up period. A sample of 440 patients was included. Medical history details were recorded. Effectiveness, compliance to treatment, quality of life (EQ-5D-5L), and treatment satisfaction questionnaire for medication (TSQM-9) at week 8 were assessed.. Of the total 440 patients, 428 (97.3%) attended at 8 weeks assessment. The number of patients with complete clearance was 337 (78.7%). EQ VAS score was significantly increased (P < 0.001). As far as TSQM-9 is concerned, patients with complete clearance reported statistically significantly higher satisfaction in effectiveness, convenience, and global satisfaction. At the 12-month follow-up visit, 323 patients (95.8%) retained their clearance status. Nineteen patients did not apply the ingenol mebutate gel on consecutive days. For these patients, the complete clearance rate was 42.1%, while for those who were treated on consecutive days, the complete clearance rate was 80.6%. None of our patients developed skin cancer.. This study supports that ingenol mebutate is effective for the treatment of AK with a good safety profile. It significantly improves quality of life. Limited adherence to treatment might be associated with reduced effectiveness.

Topics: Administration, Cutaneous; Adult; Aged; Diterpenes; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Greece; Humans; Keratosis, Actinic; Male; Middle Aged; Patient Satisfaction; Prospective Studies; Quality of Life; Recurrence; Severity of Illness Index; Surveys and Questionnaires; Treatment Outcome; Visual Analog Scale; Young Adult

Ingenol mebutate (IngMeb) 0.015% or 0.05% is approved for actinic keratosis (AK) areas of 25 cm. To determine efficacy and safety of IngMeb 0.027% in areas of AK of up to 250 cm. This phase 3, randomized, double-blind, vehicle-controlled trial (NCT02361216) enrolled adult patients with 5 to 20 AK lesions on the face/scalp (25-250 cm. IngMeb was superior to vehicle for complete AK clearance (21.4% vs 3.4%, P < .001) and AK clearance of 75% or greater (59.4% vs 8.9%, P < .001) at week 8. Probability of sustained clearance during the 12-month follow-up was 22.9% for patients treated with IngMeb. Increased treatment satisfaction and cosmetic outcomes were observed with IngMeb versus vehicle. No unexpected safety signals were identified.. Localized skin responses hindered maintenance of double-blinding.. IngMeb 0.027% was superior to vehicle for treatment of AK areas of up to 250 cm

Topics: Adult; Aged; Aged, 80 and over; Diterpenes; Double-Blind Method; Facial Dermatoses; Female; Gels; Humans; Keratosis, Actinic; Male; Middle Aged; Scalp Dermatoses; Thorax; Treatment Outcome

The use of ingenol mebutate (IM) as a field-directed therapy over a short period of time has been shown to be effective and well tolerated in randomized Phase III trials.. To assess the efficacy and patient-reported outcomes for IM as treatment for actinic keratosis (AK) under daily "real-life" practice conditions.. A total of 826 adult patients with AK were enrolled by 292 dermatologists in Germany in a prospective, open, non-interventional, non-controlled, multicentre study. All patients were treated with IM and followed for eight weeks.. The mean number of clinically visible AK lesions decreased significantly from 7.1±6.8 to 2.8±4.5 (p<0.0001). Most dermatologists (79.0%) rated global efficacy of IM as "very good"/"good" and 82.6% of the patients were "very satisfied" or "rather satisfied" with the efficacy of IM. Patient-reported outcomes showed greater efficacy and treatment comfort with IM compared to any last previous AK treatment with a comparable tolerability profile. Skin-related QoL data revealed a significant improvement of 50.2% after IM treatment (p<0.0001). Adverse events were reported in 7.0% of all patients, which were in most cases mild in intensity.. Field-directed treatment with IM over a short period was associated with a high level of treatment satisfaction, as reported by dermatologists and patients. This observational study demonstrates the effectiveness and tolerability of IM in everyday clinical practice in addition to the known efficacy and safety obtained by randomized controlled clinical trials.

Topics: Administration, Topical; Adult; Diterpenes; Dose-Response Relationship, Drug; Drug Administration Schedule; Follow-Up Studies; Germany; Humans; Keratosis, Actinic; Middle Aged; Patient Reported Outcome Measures; Prospective Studies; Quality of Life; Risk Assessment; Severity of Illness Index; Time Factors; Treatment Outcome

Topics: Antineoplastic Agents; Cryosurgery; Diterpenes; Erythema; Humans; Image Processing, Computer-Assisted; Keratosis, Actinic; Photography; Software

Actinic keratosis is the most frequent premalignant skin disease in the white population. In current guidelines, no clear recommendations are made about which treatment is preferred.. We investigated the effectiveness of four frequently used field-directed treatments (for multiple lesions in a continuous area). Patients with a clinical diagnosis of five or more actinic keratosis lesions on the head, involving one continuous area of 25 to 100 cm. A total of 624 patients were included from November 2014 through March 2017. At 12 months after the end of treatment, the cumulative probability of remaining free from treatment failure was significantly higher among patients who received fluorouracil (74.7%; 95% confidence interval [CI], 66.8 to 81.0) than among those who received imiquimod (53.9%; 95% CI, 45.4 to 61.6), MAL-PDT (37.7%; 95% CI, 30.0 to 45.3), or ingenol mebutate (28.9%; 95% CI, 21.8 to 36.3). As compared with fluorouracil, the hazard ratio for treatment failure was 2.03 (95% CI, 1.36 to 3.04) with imiquimod, 2.73 (95% CI, 1.87 to 3.99) with MAL-PDT, and 3.33 (95% CI, 2.29 to 4.85) with ingenol mebutate (P≤0.001 for all comparisons). No unexpected toxic effects were documented.. At 12 months after the end of treatment in patients with multiple actinic keratosis lesions on the head, 5% fluorouracil cream was the most effective of four field-directed treatments. (Funded by the Netherlands Organization for Health Research and Development; ClinicalTrials.gov number, NCT02281682.).

Topics: Aged; Aged, 80 and over; Aminolevulinic Acid; Diterpenes; Female; Fluorouracil; Follow-Up Studies; Gels; Humans; Imiquimod; Intention to Treat Analysis; Keratosis, Actinic; Male; Middle Aged; Patient Compliance; Photochemotherapy; Photosensitizing Agents; Proportional Hazards Models; Scalp Dermatoses; Single-Blind Method; Skin Cream; Treatment Outcome

Actinic keratosis (AK) is a precancerous skin lesion that is common in HIV-positive patients. Without effective treatment, AKs can progress to squamous cell carcinoma. Ingenol mebutate, a PKC agonist, is a US Food and Drug Administration-approved (FDA-approved) topical treatment for AKs. It can induce reactivation of latent HIV transcription in CD4+ T cells both in vitro and ex vivo. Although PKC agonists are known to be potent inducers of HIV expression from latency, their effects in vivo are not known because of the concerns of toxicity. Therefore, we sought to determine the effects of topical ingenol mebutate gel on the HIV transcription profile in HIV-infected individuals with AKs, specifically in the setting of suppressive antiretroviral therapy (ART). We found that AKs cleared following topical application of ingenol mebutate and detected marginal changes in immune activation in the peripheral blood and in skin biopsies. An overall increase in the level of HIV transcription initiation, elongation, and complete transcription was detected only in skin biopsies after the treatment. Our data demonstrate that application of ingenol mebutate to AKs in ART-suppressed HIV-positive patients can effectively cure AKs as well as disrupt HIV latency in the skin tissue microenvironment in vivo without causing massive immune activation.

Topics: Administration, Cutaneous; Anti-HIV Agents; Biopsy; CD4-Positive T-Lymphocytes; Diterpenes; HIV Infections; HIV-1; Humans; Keratosis, Actinic; Male; Middle Aged; Pilot Projects; Skin; Transcriptional Activation; Treatment Outcome; United States; Virus Activation; Virus Latency

Actinic keratoses (AKs) exist on a continuum with squamous cell carcinoma and can occur as sub-clinical and clinically visible lesions in cancerized fields on sun-damaged skin. Ingenol mebutate effectively treats AKs on areas up to 25 cm. Phase I, multicenter, open-label, uncontrolled, non-randomized trial. Patients received ingenol mebutate gel for three consecutive days on approximately 250 cm. Of 61 patients, 10 (face =8; arm =2) had ingenol mebutate in whole blood at subnanomolar levels (0.235-0.462 nM). The assayed metabolites were below the lower limit of quantification. Local skin responses increased during Days 1-4 and declined thereafter, approaching baseline by Day 16. Most adverse events were pain/pruritus of mild or moderate intensity.. Subnanomolar systemic exposure to ingenol mebutate was measured after application of the gel to approximately 250 cm

Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Area Under Curve; Arm; Diterpenes; Face; Female; Gels; Half-Life; Humans; Keratosis, Actinic; Male; Middle Aged; Pruritus; ROC Curve; Scalp; Skin; Treatment Outcome

No studies have examined the use of topical ingenol mebutate for improvement of photoaged skin.. To evaluate clinical results of ingenol mebutate gel applied to photoaged skin and to quantify improvement at 7, 30, and 60 days after application.. Twenty-five subjects were enrolled in the study. Picato (ingenol mebutate) (LEO Pharma, Parsippany, NJ) gel was applied to an area with a known actinic keratosis daily for 3 days. Subjects self-evaluated and were investigator evaluated on 6 characteristics on Days 7, 30, and 60 using an objective scale. The scale evaluated actinic keratosis, overall skin appearance, wrinkling, dyschromia, erythema, and texture. The subjects were also evaluated using the Griffiths' Photonumeric Photoaging Scale for overall improvement.. Twenty-two subjects completed the clinical study and demonstrated statistically significant improvement by Day 60 in actinic keratosis, overall skin appearance, wrinkling, dyschromia, erythema, and texture (p < .05).. Topical ingenol mebutate 0.015% gel produces cosmetic improvement of photoaged skin within 60 days of application.

Topics: Aged; Dermatologic Agents; Diterpenes; Female; Gels; Humans; Keratosis, Actinic; Male; Middle Aged; Prospective Studies; Skin Aging

Ingenol mebutate (IngMeb) and diclofenac sodium (DS) are approved treatments for actinic keratosis (AK).. To compare the efficacy and safety of IngMeb 0·015% gel with DS 3% gel (NCT02406014).. Patients with 4-8 visible, discrete AK lesions on the face/scalp in a 25 cm. AKCLEAR 100 at end of first treatment course was higher with IngMeb (34%) vs. DS (23%; P = 0·006). AKCLEAR 100 at end of last IngMeb course (53%) and Week 17 (45%) was higher than DS (both P < 0·001). The most frequent AE was application-site erythema (IngMeb 19%; DS 12%). Treatment-related AE (TRAE) duration was shorter with IngMeb. TRAE withdrawals were lower for IngMeb (2%) vs. DS (6%). TSQM scores for global satisfaction (P < 0·001) and effectiveness (P = 0·002) were higher with IngMeb, as was dosing instruction adherence (≥ 90% vs. 70%).. AKCLEAR 100, patient treatment satisfaction and effectiveness were significantly higher with IngMeb compared with DS, demonstrating superiority of IngMeb for AK treatment on face/scalp.

Topics: Administration, Cutaneous; Adult; Aged; Aged, 80 and over; Dermatologic Agents; Diclofenac; Diterpenes; Drug Administration Schedule; Facial Dermatoses; Female; Gels; Humans; Keratosis, Actinic; Male; Middle Aged; Scalp Dermatoses; Treatment Outcome

Ingenol mebutate gel is a novel, field-directed topical treatment for actinic keratosis (AK). Most pivotal studies have targeted Western populations. No clinical study has been conducted to investigate its efficacy and safety in Asian populations.. To evaluate the efficacy and safety of ingenol mebutate gel for treating AK of face/scalp and trunk/extremities in a large Asian (Korean) population.. In this multicentre, open-label, interventional, parallel-group, prospective phase IV study (PERFECT, trial registration no.: NCT02716714), the eligible patients were allocated into either the face/scalp or the trunk/extremities group, according to their selected treatment area location. After application of ingenol mebutate gel, the participants were followed up for 6 months. The primary efficacy endpoint was complete clearance (CC) of AK lesions in the selected treatment area at day 57. Quality of life was evaluated using Skindex-29. Safety endpoints included local skin responses, scar, pigmentation, pain and adverse events.. In total, 78·1% [95% confidence interval (CI) 66·86-86·92%] of subjects had CC at day 57, with 76·6% (95% CI 64·31-86·25%) in the face/scalp group and 88·9% (95% CI 51·75-99·72%) in the trunk/extremities group. Among them, CC was sustained in 88·9% (48 of 54, 95% CI 77·37-95·81%) at month 6. The local skin responses significantly increased 1 day after the treatment compared with baseline, and decreased afterwards. Among the total subjects, 7·8% (6 of 77) had hyperpigmentation on the application area. Scars were not reported.. Ingenol mebutate is effective for the treatment of AK in Asians, with tolerable safety profiles.

Topics: Administration, Topical; Adult; Aged; Aged, 80 and over; Diterpenes; Extremities; Facial Dermatoses; Female; Follow-Up Studies; Humans; Hyperpigmentation; Keratosis, Actinic; Male; Middle Aged; Prospective Studies; Quality of Life; Republic of Korea; Scalp Dermatoses; Torso; Treatment Outcome

Actinic keratosis (AK) is a common skin lesion in adults which usually occurs on chronically photoexposed areas and considered as a precancerous lesion or a superficial squamous-cell carcinoma. Many classifications have been proposed and its diagnosis is generally clinical but, sometimes, its wide variety of presentations can make diagnosis difficult, even among expert observers. The malignant potential of AKs imposes an early diagnosis and treatment in order to reduce morbidity and mortality, and, for the characterization of photodamaged skin, noninvasive diagnostic techniques, such as dermoscopy, have proved to be useful, while multiple therapeutic strategies, lesion-directed versus field-directed therapies, are available for the treatment of AKs. In this study, we evaluated the efficacy of ingenol mebutate for the treatment of AKs, with a particular focus on patients' compliance, correlating it to clinical and dermoscopic grading, pre- and posttreatment, of these lesions. Fifty-two enrolled patients with AKs received treatment with ingenol mebutate gel (0.015% for face and scalp; 0.05% for trunk and extremities) and multiple dermatological evaluations. End points of the study were complete and partial clearance of clinically visible AKs on day 90. All acquired data were recorded and statistical analyses were performed. Univariate and multivariate analyses were used to identify possible predictive factors. We retrospectively analyzed patient-related and lesion-related factors to identify which variables, among age, gender, lesion site, pain, LSR score, and pretreatment clinical and dermoscopic grading, could independently predict the response to ingenol mebutate treatment. Our findings showed that pretreatment dermoscopic grade II represents an independent predictive factor of the efficacy of ingenol mebutate therapy (OR=14.78, 95% CI: 1.83-119.59, P=0.012) and that response rates differ on the basis of the treated anatomical sites (OR=0.16, 95% CI: 0.03-0.85, P=0.031). Data from this study provide evidence that ingenol mebutate gel is an effective treatment for AK, with relative ease of use, short exposure, and rapid resolution of local reactions, benefits contributing to high adherence of this therapy. Moreover, dermoscopic analysis of skin lesions offers more information than clinical evaluation alone and can be helpful in identifying different groups of AKs, thus selecting the adequate therapeutic choice.

Topics: Aged; Aged, 80 and over; Animals; Dermoscopy; Diterpenes; Female; Humans; Keratosis, Actinic; Male; Retrospective Studies; Treatment Outcome

Background: Actinic keratosis (AK) can affect large skin areas. Ingenol mebutate (IngMeb) gel (0.015% and 0.05%) is approved for topical treatment of AK in a single contiguous area of ~25 cm2.

Objective: The study sought to determine the maximum tolerated dose (MTD), efficacy, and tolerability of IngMeb applied to AK on a contiguous area less than equal to 250 cm2.

Methods: Part 1 determined the MTD of IngMeb at 7 concentrations for 2 or 3 days. Part 2 assessed efficacy and tolerability at the MTD and one dose lower for 2 or 3 days vs vehicle.

Results: Four dosing regimens with an acceptable benefit-to-risk ratio were identified: 0.018% and 0.027% once daily for 2 or 3 days. Complete clearance at 8 weeks was achieved by 21.3% to 39.1% of IngMeb-treated patients vs 0% to 3.2% treated with vehicle. Composite local skin response scores peaked on the day after the last application, rapidly declined, and were near baseline at 2 weeks. Adverse events were predominantly mild or moderate.

Limitations: The study evaluated a limited number of doses in a population of only white patients.

Conclusion: IngMeb gel was effective and well tolerated as field treatment of AK on the full face, full scalp, and up to 250 cm2 on the chest.

J Drugs Dermatol. 2017;16(5):438-444.

Topics: Administration, Topical; Aged; Diterpenes; Dose-Response Relationship, Drug; Face; Female; Humans; Keratosis, Actinic; Male; Middle Aged; Pain; Pruritus; Scalp; Thorax; Treatment Outcome

To date, studies with ingenol mebutate gel have used clinical clearance, not histological clearance, as a primary efficacy endpoint.. This phase I, multicentre, single-arm, open-label study sought to confirm histologically the clinical clearance of actinic keratoses (AKs) to support a treatment effect deep in the epidermis.. Patients (n = 108) aged ≥ 18 years with histologically confirmed AK within a 25-cm. The observed agreement rate between clinical and histological assessments of clearance of a single AK was 81·9% and the positive predictive value of a clinical assessment of clearance was 87%. Agreement between the two pathologists was 88%. The common composite 8-week complete clearance rate was 41% (95% confidence interval 32-50). Observed agreement rates between RCM and pathologist I and II assessments of clearance were 72·9% and 81·4%, respectively. Overall, 30 patients (27·8%) experienced 38 adverse events (AEs). Application-site pain (four patients, 3·7%) was the most common treatment-related AE inside the treatment area.. Ingenol mebutate achieves histopathological clearance of AKs that correlates with observed clinical clearance. Clinical clearance is a good predictor for histological clearance.

Topics: Administration, Cutaneous; Aged; Dermatologic Agents; Diterpenes; Female; Gels; Humans; Keratosis, Actinic; Male; Microscopy, Confocal; Observer Variation; Treatment Outcome

Ingenol mebutate (IngMeb) is a novel patient-applied topical field therapy for actinic keratosis.. To demonstrate the efficacy and safety of follow-up IngMeb field treatment of actinic keratoses (AKs) present at 8 weeks after initial treatment or emerging in a previously cleared field.. In this phase III, randomized, double-blind study in patients with 4-8 clinically visible AKs within a contiguous 25-cm(2) treatment area on the face or scalp, all patients were treated initially with IngMeb 0·015% gel for three consecutive days. If lesions were present in the field at 8 weeks, or emerged at weeks 26 or 44, patients were randomized (2 : 1) to follow-up IngMeb or vehicle gel for three consecutive days. The main outcome was complete clearance rates of AKs 8 weeks after randomization.. Of 450 patients who received initial treatment with IngMeb, 61·6% demonstrated complete clearance at 8 weeks. Patients with AKs present at 8 weeks or emerging at weeks 26 or 44 were randomized to IngMeb (n = 134) or vehicle (n = 69). IngMeb achieved a higher complete clearance rate than vehicle 8 weeks after randomization in AKs present at 8 weeks (46·7% vs. 18·4%; P < 0·01) and in emergent AKs (59·5% vs. 25·0%; P = 0·01). Based on those who completed 12 months of follow-up (n = 340), the overall 12-month clearance rate was estimated at 50·0%. Follow-up IngMeb treatment was well tolerated.. This study demonstrated the long-term benefit of IngMeb 0·015% gel for initial and follow-up therapy of AKs.

Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Dermatologic Agents; Diterpenes; Double-Blind Method; Female; Follow-Up Studies; Gels; Humans; Keratosis, Actinic; Male; Middle Aged; Retreatment; Treatment Outcome; Young Adult

Daylight-photodynamic therapy (D-PDT) and ingenol mebutate (IM) are novel therapies directed to actinic keratoses (AK). The purpose of our study was to compare effectiveness, tolerability, cosmetic outcome and patient preference of D-PDT versus IM in the treatment of grade I and II AK. Twenty-seven patients with AK on the face or scalp were enrolled. Each patient received, in a 25 cm(2) target area, D-PDT on right side and IM on left side. Overall 323 AK were treated. Both target areas achieved complete response in 40.47% of the cases and average AK clearance rate was similar for D-PDT and IM (p=0.74). In D-PDT areas mean grade II AK clearance rate was lower compared with that of grade I AK (p=0.015). In IM areas grade I and II AK average clearance rates were similar (p=0.28). At week 1 and month 1, mean local skin responses (LSR) score were higher in areas treated with IM. IM areas showed more severe pain and cosmetic sequelae. D-PDT had similar effectiveness to IM, even if IM demonstrated higher grade II AK clearance rate. Tolerability profile was superior for D-PDT in terms of LSR and pain. D-PDT was more cosmetically acceptable. Patients preferred D-PDT to IM in most cases.

Topics: Aged; Aged, 80 and over; Aminolevulinic Acid; Dermatologic Agents; Diterpenes; Facial Dermatoses; Female; Humans; Keratosis, Actinic; Male; Middle Aged; Patient Preference; Photochemotherapy; Photosensitizing Agents; Remission Induction; Scalp Dermatoses; Sunlight; Surveys and Questionnaires; Time Factors; Treatment Outcome

Ingenol mebutate (IngMeb) is approved for treatment of actinic keratoses (AK) and may cause unpredictable local skin responses (LSR).. We sought to investigate whether IngMeb-induced LSR, pain, and pruritus could be alleviated with a topical glucocorticoid and, further, to assess efficacy, cosmetic outcome, and patient satisfaction in patients with severe photodamage.. In this blinded, randomized controlled clinical trial, patients with multiple AK and field cancerization of the face or scalp were treated in 2 areas with IngMeb (0.015%) daily for 3 days. After finalized IngMeb treatment, 1 area was randomized to receive topical clobetasol propionate (0.05%) twice daily for 4 days. Assessments included LSR (0-24; days 1, 4, 8, 15, 57), pain (0-10) and pruritus (0-3; days 1-15), AK clearance (days 15, 57), and cosmetic outcome (0-3; day 57).. Clobetasol propionate application had no influence on LSR (P = .939), pain (P = .500), pruritus (P = .312), or AK cure rate (P = .991). Overall, IngMeb cleared 86% of all AK lesions, exerting a therapeutic effect on all AK severity grades; cure rates were 88%, 70%, and 60% for grade I, II, and III AK, respectively. Skin texture improved significantly in remedied areas (2.0 vs 1.0; P < .001); no hypopigmentation, hyperpigmentation, or scarring were observed.. These results do not provide safety and efficacy beyond 2 months of follow-up.. Application of clobetasol propionate does not alleviate IngMeb-induced LSR after 3 days of IngMeb treatment.

Topics: Administration, Topical; Adrenal Cortex Hormones; Aged; Aged, 80 and over; Clobetasol; Denmark; Diterpenes; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Facial Dermatoses; Female; Follow-Up Studies; Gels; Humans; Keratosis, Actinic; Male; Middle Aged; Pain; Pruritus; Risk Assessment; Scalp Dermatoses; Severity of Illness Index; Single-Blind Method; Treatment Outcome

Treatments for actinic keratosis (AK) can elicit adverse local skin responses (LSRs). Knowledge regarding the burden of AK treatment on health related quality of life (HRQoL) is however limited.. To investigate whether treatment of AK improved HRQoL; to assess whether LSRs had an impact on HRQoL during treatment and to analyze the relationship between LSRs and HRQoL.. Patients (n = 329) were randomized for treatment with cryosurgery (CRY) followed by ingenol mebutate (IngMeb) (CRY + IngMeb) or CRY followed by vehicle (CRY + vehicle). HRQoL was analyzed using DLQI, EQ-5D and EQ-VAS at baseline, three days, two weeks and eight weeks post treatment.. Statistically significant HRQoL improvements were seen in all measures in both treatment groups (p < 0.001). Impairments in DLQI in CRY + IngMeb at LSR peak were within a range interpreted as having "a small impact on patients' life" (2-5), which normalized within two weeks.. DLQI may not be sensitive to change in the AK disease as it mainly captures symptoms and has a limited focus on feelings.. The treatment burden of IngMeb is small, manageable and short-lasting. Since AK is a chronic condition, often requiring repeated treatment courses, combining treatments that provide enhanced effectiveness, while limiting HRQoL impairment is essential.

Topics: Adult; Combined Modality Therapy; Cryosurgery; Diterpenes; Drug Eruptions; Female; Gels; Humans; Keratosis, Actinic; Male; Middle Aged; Quality of Life; Treatment Outcome

Daylight photodynamic therapy with methyl aminolaevulinate (dlPDT) and ingenol mebutate gel (IMB) are approved therapeutic options for multiple actinic keratoses (AKs). The aim of this comparative, intra-patient, split-face, randomized clinical trial was to compare treatment outcomes of dlPDT and IMB.. Two symmetrical contralateral areas of 25cm. 22 patients with a total of 311 AKs were enrolled. The mean pain VAS score was 3.55±1.82 with IMB and 2.05±0.72 with dlPDT (p<0.01). The mean LSR score was 9.91±4.24 and 4.59±4.03 (p<0.01), respectively. The mean days necessary for wound closure were 9.45±3.51 and 4.36±1.18days (p<0.01), respectively. After 3 months, 119 lesions with IMB and 120 lesions with dlPDT were healed and the CR rate with IMB (75.8%) was non-inferior to the CR rate with dlPDT (77.9%). The comparisons of CR rates of grade I and II AKs did not show any inferiority for one treatment compared to the other. Eight patients (36.4%) had all lesions cleared with IMB and 7 (31.8%) with dlPDT (p=NS). The cosmetic outcome was better with dlPDT and 17 patients evaluated dlPDT as their preferred treatment.. A 3days' treatment cycle with IMB and a single session of dlPDT had a similar efficacy for both grade I AKs and grade II AKs but dl PDT showed lower pain and inflammation scores, quicker wound closure, better cosmetic outcome and higher patients' preference.

Topics: Aged; Aged, 80 and over; Aminolevulinic Acid; Diterpenes; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Drug Administration Schedule; Facial Dermatoses; Female; Gels; Humans; Keratosis, Actinic; Male; Middle Aged; Patient Preference; Photochemotherapy; Scalp Dermatoses; Treatment Outcome

Photodynamic therapy with methyl aminolevulinate (MAL-PDT) and ingenol mebutate gel (IMB) are approved therapeutic options for multiple actinic keratoses (AKs).. The aim of this intraindividual, split-face, randomized clinical trial was to compare treatment outcomes of MAL-PDT and IMB.. Two symmetrical contralateral areas with a similar number of AKs were selected and randomly assigned to 3 days of an IMB treatment cycle or a single session of MAL-PDT. The next day, the local skin reaction (LSR) score was registered. The patients scored pain and time to healing of the treatment area.. After 90 days, the complete remission rate of lesions, the number of patients with complete remission of all lesions, cosmetic outcome, and patient preference were assessed.. According to our results, IMB and MAL-PDT had a similar efficacy, but the cosmetic outcome was superior with MAL-PDT. Pain was higher with PDT, but LSR was more severe and time to healing was longer with IMB. Patients preferred MAL-PDT.

Topics: Administration, Topical; Aged; Aged, 80 and over; Aminolevulinic Acid; Diterpenes; Face; Facial Dermatoses; Female; Follow-Up Studies; Gels; Humans; Keratosis, Actinic; Male; Middle Aged; Photochemotherapy; Photosensitizing Agents; Remission Induction; Retrospective Studies; Scalp; Scalp Dermatoses; Skin; Treatment Outcome

Ingenol mebutate represents a topical treatment for fields with actinic keratosis (AK). The biological effects of ingenol mebutate in AK, subclinical (SC)-AK, and reference-skin were assessed and graded by in vivo reflectance confocal microscopy (RCM) and histology. Patients with AK and SC-AK lesions in one 25 cm2 field on hands or forearms, and with an area of reference skin on the inner upper arm, were included. The two fields were each treated with ingenol mebutate 0.05% gel (n=16), or vehicle (n=8), on 2 consecutive days; clinical and RCM assessments were performed on days 1, 2, 3, 8, and 57, and biopsies on day 3. Local skin responses were more pronounced in AK fields (6.1 (mean) ± 2.6 (SD)) compared with reference skin (3.5 ± 1.5). The clinical AK lesion reduction was 43.8% and 6.3% with ingenol mebutate and vehicle, respectively. RCM and histology evaluations showed that ingenol mebutate induced a significant pronounced cell death and immune response in AK and SC-AK lesions, compared with reference skin. Ingenol mebutate induced RCM-measured reduction in (investigator-1/investigator-2): AK lesions (34/28%), SC-AK lesions (72/56%), and solar elastosis in AK fields (mean, -0.22/-0.25). In conclusion, ingenol mebutate showed selective pronounced biological responses in AK and SC-AK as compared with reference skin.

J Drugs Dermatol. 2016;15(10):1181-1189.

Topics: Aged; Diterpenes; Female; Gels; Humans; Keratosis, Actinic; Male; Microscopy, Confocal; Severity of Illness Index; Treatment Outcome

Five per cent 5-fluorouracil (5-FU) cream is a well-established treatment for actinic keratosis (AK), and ingenol mebutate gel (IMB) is a novel topical field-directed therapy.. To compare the tolerability and safety of IMB with that of 5-FU for the treatment of facial AK.. An open-label, prospective, randomized, controlled clinical trial with 100 patients with AKs within a 25-cm(2) contiguous field on the face was conducted. IMB was applied daily for three consecutive days. 5-FU was applied twice a day for 4 weeks. The treatment effect and the adverse events were evaluated at baseline and on days 2, 3, 4, 8, 15, 22, 29, 36 and 43 for intent-to-treat populations.. The mean (± SD) maximum local skin reactions (LSR) for patients treated with IMB was 10.85 (± 3.12), compared with 10.86 (± 3.55) for those who received 5-FU. Patients in the IMB group presented LSR that peaked at day 4 and almost completely regressed after 15 days. Differently, in the 5-FU group, the LSR peaked at day 29 and lasted until visit 36. Additionally, the area under the curve (LSR × visit) was significantly smaller for IMB. No differences between the treatments for pruritus, pain, tearing, conjunctival hyperaemia or headaches were noted, but the eyelid oedema rate was higher for IMB group. No significant difference in the proportion of dropouts was observed between groups. Both treatments demonstrated a suitable safety profile.. For treating AKs, the local skin reactions in the IMB group were more short-lived compared with those of 5-FU, but both treatments seemed to be safe and tolerable.

Topics: Administration, Topical; Diterpenes; Drug Tolerance; Facial Dermatoses; Fluorouracil; Follow-Up Studies; Gels; Humans; Immunosuppressive Agents; Keratosis, Actinic; Prospective Studies; Time Factors; Treatment Outcome

Actinic keratosis therapy can elicit unsightly and painful local skin responses; assessment of treatment satisfaction and health-related quality of life (QoL) is important. Ingenol mebutate gel is a novel topical field therapy for actinic keratosis.. Post-hoc analyses were performed based on patient-reported outcomes from phase-III trials (n = 1005) to assess the effects of ingenol mebutate on QoL and the relationship between both QoL and treatment satisfaction, and degree of lesion clearance.. Patients received ingenol mebutate or vehicle for self-application to a 25-cm(2) contiguous area: 0.015% once daily for 3 consecutive days (face/scalp) or 0.05% once daily for 2 consecutive days (trunk/extremities). QoL (Skindex-16) and Treatment Satisfaction Questionnaire for Medication data were recorded.. Significant, positive associations between Treatment Satisfaction Questionnaire for Medication score and degree of clearance were identified for patients in the face/scalp (effectiveness P < .0001 and global satisfaction P = .0002) and trunk/extremities (P < .0001 and P = .0014, respectively) groups. There was a significant association between Skindex-16 score and clearance for patients in the face/scalp group for change in symptoms (P = .0218), emotions (P = .0002), and overall Skindex-16 score (P = .0006) from baseline.. Clinical trial population findings may not be generalizable to clinical practice.. Ingenol mebutate significantly improved patients' QoL and treatment satisfaction. Improvements were associated with higher degrees of actinic keratosis lesion clearance.

Topics: Administration, Topical; Diterpenes; Drug Administration Schedule; Gels; Humans; Keratosis, Actinic; Patient Satisfaction; Pharmaceutical Vehicles; Quality of Life; Self Administration; Surveys and Questionnaires; Treatment Outcome

Actinic keratosis (AK) lesions are in situ squamous cell carcinoma. These lesions have a low risk of progressing to invasive disease but significant impact on patients' quality of life (QoL). The aim of this study was to assess QoL and side effects in patients with AK receiving treatment with ingenol mebutate.. This was a prospective, non-randomized pilot study carried out in Spain. The target population was adults with a clinical diagnosis of AK affecting any part of the body. Outcomes were assessed on the basis of a QoL questionnaire (Skindex-29), local skin response, the Treatment Satisfaction Questionnaire for Medication (TSQM 1.4), and clinical response.. A total of 19 patients were studied. Most of the participants were men (89.5%) and mean age was 76.2 years. After treatment with ingenol mebutate, significant improvement was observed in the Skindex-29 subscales relating to symptom severity (P=.041), the patients' emotional state (P=.026), and in the overall score (P=.014). Erythema, crusting, and flaking or scaling were the local skin responses with highest median score (2.0 in all 3 cases). Imiquimod 5% and ingenol mebutate achieved higher median scores for effectiveness and global satisfaction than any other previous treatments (as measured by TSQM 1.4). In the patients' assessment of convenience, ingenol mebutate had a higher median score than previous treatments. Over half of the patients (52.6%) had an improvement of at least 75% at month 3.. QoL in patients with AK improves after treatment with ingenol mebutate. The presence of side effects did not affect QoL or patient satisfaction with treatment.

Topics: Aged; Aged, 80 and over; Dermatologic Agents; Diterpenes; Drug Eruptions; Female; Humans; Keratosis, Actinic; Male; Patient Satisfaction; Pilot Projects; Prospective Studies; Quality of Life; Severity of Illness Index; Surveys and Questionnaires; Treatment Outcome

Actinic keratoses (AKs) are precursors to invasive squamous cell carcinoma and can progress if untreated. Limited data support the use of ingenol mebutate to treat AKs on more than one area of the body simultaneously.. To investigate safety, efficacy and treatment satisfaction when treating separate areas simultaneously or sequentially with different concentrations of ingenol mebutate gel.. In this phase IIIb study (NCT01787383), patients with clinically visible, non-hyperkeratotic AKs on two separate treatment areas (face/scalp and trunk/extremities) were randomized to simultaneous or sequential treatment with ingenol mebutate gel (0.015% and 0.05%). Endpoints included composite local skin response (LSR) score 3 days after first application, complete AK clearance and percentage reduction in AKs at week 8.. There were no statistically significant differences between simultaneous (n = 101) and sequential (n = 98) groups in composite LSR score (10.4 vs. 9.7), complete clearance (52.7% vs. 46.9%) or percentage reduction in AKs (83.4% vs. 79.1%). Mean composite LSR scores on face/scalp and trunk/extremities were similar for both groups. Adverse event (AE) incidence was comparable between groups, the most common treatment-related AEs being pruritus and pain at the application site.. Treating AKs with ingenol mebutate simultaneously or sequentially gave similar results in terms of tolerability (LSR score, AEs) and efficacy (complete clearance). Therefore, the physician and patient can select the most convenient treatment regimen, with confidence in achieving a similar outcome.

Topics: Aged; Antineoplastic Agents; Diterpenes; Extremities; Facial Dermatoses; Female; Gels; Humans; Keratosis, Actinic; Male; Patient Satisfaction; Scalp Dermatoses; Torso; Treatment Outcome

Cryosurgery is the most common treatment for actinic keratosis (AK) in the United States. Efficacy with cryosurgery is variable, and is a modality for treating individual, visible lesions while failing to treat subclinical lesions.. FIELD Study 1 (NCT01541553) is a phase 3, multicenter, randomized, double-blind study that evaluated the short- (11-week) and long- (12-month) term efficacy and safety of sequential AK treatment using cryosurgery with liquid nitrogen followed by ingenol mebutate gel, versus cryosurgery followed by vehicle.. Overall, 329 patients were randomized to ingenol mebutate 0.015% gel (n=167) or vehicle (n=162) 3 weeks after cryosurgery. Baseline characteristics were balanced across groups. At week 11, complete clearance rate (100%) in the treatment area was higher for ingenol mebutate gel compared with vehicle (60.5% vs 49.4%, respectively; P=.04). Mean percentage reduction in number of AKs versus baseline was also numerically higher for ingenol mebutate gel (82.7% vs 75.6%). A general reduction from baseline lesion count was observed 3 weeks after cryosurgery. Treatment after cryosurgery was well tolerated.. Short-term (11-week) AK clearance rates on the face or scalp with ingenol mebutate gel after cryosurgery were higher than with cryosurgery alone.

Topics: Administration, Cutaneous; Aged; Combined Modality Therapy; Cryosurgery; Dermatologic Agents; Diterpenes; Double-Blind Method; Face; Female; Follow-Up Studies; Gels; Humans; Keratosis, Actinic; Male; Scalp; Treatment Outcome

Recurrence rates of actinic keratosis (AK) lesions after cryosurgery are high, and this treatment does not address field cancerization. We investigated the efficacy and safety of field treatment of AKs with ingenol mebutate gel following cryosurgery.. In this phase 3, randomized, double-blind, vehicle-controlled study (NCT01541553), patients ≥18 years with four to eight clinically typical, visible, discrete AKs within a contiguous 25-cm2 treatment area on the face or scalp underwent cryosurgery followed 3 weeks later by once-daily ingenol mebutate 0.015% or vehicle gel for 3 consecutive days. Endpoints included complete clearance at week 11 and safety and efficacy over 12 months.. In 329 randomized patients, complete clearance rates were greater with ingenol mebutate than vehicle (week 11: 60.5% vs 49.4%; P=.04; month 12: 30.5% vs 18.5%; P=.01). Fewer patients experienced the emergence of new lesions with ingenol mebutate than with vehicle (38.9% vs 51.9%; P =.02). At month 12, mean percentage reduction of AKs was higher with ingenol mebutate than with vehicle (68.2% vs 54.1%; P =.002). The probability of remaining free of lesions was sustained longer with ingenol mebutate compared with vehicle gel: 78% vs 68% at 6 months; 64% vs 57% at 9 months; 55% vs 40% at month 12, respectively. Ingenol mebutate 0.015% gel was well tolerated and no unexpected adverse events occurred; all adverse events resolved within 2 weeks of starting treatment.. Field treatment with ingenol mebutate 0.015% gel following cryosurgery significantly enhanced clearance of baseline lesions, and was well tolerated. Furthermore, ingenol mebutate 0.015% gel following cryosurgery reduced development of new lesions in the treated field.

Topics: Adult; Aged; Aged, 80 and over; Combined Modality Therapy; Cryosurgery; Dermatologic Agents; Diterpenes; Double-Blind Method; Female; Follow-Up Studies; Gels; Humans; Keratosis, Actinic; Male; Middle Aged

This randomized, 3-group study compared the efficacy and tolerability of 3 treatment modalities for facial actinic keratoses.. Twenty-four healthy adult male and female subjects who had 4 to 8 clinically visible and discrete actinic keratoses on the face in a contiguous 25cm2 treatment area. Subjects were randomized into one of three treatment groups: 2 treatments with 5-aminolevulinic acid (ALA) and photodynamic therapy (PDT), 1 ALA-PDT treatment and 1 course of ingenol mebutate (ingenol mebutate) 0.015% gel daily for 3 consecutive days, or 1 course of ingenol mebutate gel alone. Actinic keratoses in the treatment field were counted at the baseline visit, and at the completion of the study (day 57 or day 71). At the site of application, local site reactions were graded at each visit.. Subjects in the two ALA-PDT treatment group had a 97.5% mean reduction (P<0.00001) from the number of baseline actinic keratosis; ALA-PDT plus ingenol mebutate gel group had an 86.7% mean reduction (P<0.00001); while subjects in the ingenol mebutate gel alone group had a 91.7% mean reduction from the number of baseline actinic keratoses. The peak composite LSR score was 4.625 for the ALA-PDT group, 10.375 for the ALA-PDT followed by ingenol mebutate gel group, and 12.625 for the ingenol mebutate gel alone group (P=0.0004 and 0.001, respectively).. ALA-PDT, ingenol mebutate gel, and a combination of the two treatment modalities are successful topical therapies for the reduction of actinic keratoses on the face. The group of subjects receiving 2 consecutive treatments with ALA-PDT, compared to treatment with ingenol mebutate gel alone or sequentially after one course of ALA-PDT had a significantly lower mean composite LSR score and a non-significant trend for greater efficacy.

Topics: Administration, Cutaneous; Adult; Aminolevulinic Acid; Dermatologic Agents; Diterpenes; Facial Dermatoses; Female; Follow-Up Studies; Gels; Humans; Keratosis, Actinic; Male; Photochemotherapy; Photosensitizing Agents; Treatment Outcome

Ingenol mebutate is the active agent (a macrocyclic diterpene ester) in the sap of the plant Euphorbia peplus. This herb has been used as a traditional remedy for several different skin lesions, including skin cancers.. To assess 12-month recurrence rates and safety associated with ingenol mebutate gel treatment in patients who previously had achieved complete clearance of actinic keratoses.. The treatment area was observed for recurrence for 12 months after the original study. Patients were treated in an outpatient setting.. Patients received ingenol mebutate gel, 0.015%, daily for 3 consecutive days for actinic keratoses on the face or scalp or ingenol mebutate gel, 0.05%, daily for 2 consecutive days for actinic keratoses on the trunk or extremities. Study participants had achieved complete clearance in a prespecified 25-cm2 area at day 57 of their original trial.. Recurrence rates and safety were assessed. RESULTS In total, 108 patients with complete clearance of face or scalp lesions in the original trial and 76 patients with complete clearance of trunk or extremity lesions in the original trial were enrolled in the 12-month observational follow-up study. Of these, 100 patients (face or scalp) and 71 patients (trunk or extremities) completed all 12 months. The sustained lesion reduction rates compared with baseline were 87.2% for the face or scalp and 86.8% for the trunk or extremities. The estimated median times to recurrence were 365 days (face or scalp) and 274 days (trunk or extremities). There were no safety concerns during the follow-up period.. Ingenol mebutate gel applied as field therapy for 2 or 3 consecutive days to treat actinic keratoses produced clinically relevant sustained clearance and long-term lesion reduction. TRIAL REGISTRATION clinicaltrials.gov Identifiers: NCT00953732, NCT00952783, and NCT00989313.

Topics: Administration, Cutaneous; Dermatologic Agents; Diterpenes; Female; Follow-Up Studies; Gels; Humans; Keratosis, Actinic; Male; Middle Aged; Outpatients; Secondary Prevention; Time Factors; Treatment Outcome

Actinic keratosis is a common precursor to sun-related squamous-cell carcinoma. Treating actinic keratoses and the surrounding skin area (i.e., field therapy) can eradicate clinical and subclinical actinic keratoses. Topical field therapy currently requires weeks or months of treatment. We investigated the efficacy and safety of a new topical field therapy for actinic keratosis, ingenol mebutate gel (0.015% for face and scalp and 0.05% for trunk and extremities).. In four multicenter, randomized, double-blind studies, we randomly assigned patients with actinic keratoses on the face or scalp or on the trunk or extremities to receive ingenol mebutate or placebo (vehicle), self-applied to a 25-cm(2) contiguous field once daily for 3 consecutive days for lesions on the face or scalp or for 2 consecutive days for the trunk or extremities. Complete clearance (primary outcome) was assessed at 57 days, and local reactions were quantitatively measured.. In a pooled analysis of the two trials involving the face and scalp, the rate of complete clearance was higher with ingenol mebutate than with placebo (42.2% vs. 3.7%, P<0.001). Local reactions peaked at day 4, with a mean maximum composite score of 9.1 on the local-skin-response scale (which ranges from 0 to 4 for six types of reaction, yielding a composite score of 0 to 24, with higher numbers indicating more severe reactions), rapidly decreased by day 8, and continued to decrease, approaching baseline scores by day 29. In a pooled analysis of the two trials involving the trunk and extremities, the rate of complete clearance was also higher with ingenol mebutate than with placebo (34.1% vs. 4.7%, P<0.001). Local skin reactions peaked between days 3 and 8 and declined rapidly, approaching baseline by day 29, with a mean maximum score of 6.8. Adverse events were generally mild to moderate in intensity and resolved without sequelae.. Ingenol mebutate gel applied topically for 2 to 3 days is effective for field treatment of actinic keratoses. (Funded by LEO Pharma; ClinicalTrials.gov numbers, NCT00742391, NCT00916006, NCT00915551, and NCT00942604.).

Topics: Aged; Dermatologic Agents; Diterpenes; Extremities; Facial Dermatoses; Female; Humans; Keratosis, Actinic; Male; Middle Aged; Scalp Dermatoses; Skin; Thorax; Treatment Outcome

The sap of the plant Euphorbia peplus is a traditional remedy for skin conditions, including actinic keratosis. The active constituent of the sap is ingenol mebutate (ingenol-3-angelate), formerly known as PEP005. This randomized, double-blind, vehicle-controlled, phase IIa study investigated the safety (and secondarily the efficacy) of two applications of ingenol mebutate gel in 58 patients with biopsy-confirmed actinic keratosis. Five preselected lesions were treated with ingenol mebutate gel, 0.0025%, 0.01% or 0.05%, or vehicle gel, on days 1 and 2 (Arm A) or days 1 and 8 (Arm B). There were no significant differences in tolerability or efficacy between Arms A and B. Treatment was well tolerated. The most common local skin responses were dose-related erythema, flaking/scaling/dryness and scabbing/crusting. Efficacy was greatest with ingenol mebutate gel, 0.05%, which resulted in complete clinical clearance of 71% of treated lesions (P < 0.0001 vs vehicle gel). In addition, 67% of patients treated with ingenol mebutate gel, 0.05% had clinical clearance of at least four of five treated lesions (P = 0.0185 vs vehicle gel). Ingenol mebutate gel is being developed as a short-course topical therapy for actinic keratosis and non-melanoma skin cancer.

Topics: Administration, Cutaneous; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Arm; Australia; Diterpenes; Double-Blind Method; Drug Administration Schedule; Esters; Face; Female; Gels; Humans; Keratosis, Actinic; Male; Middle Aged; Scalp; Treatment Outcome

There is a need for improved medical approaches to the treatment of actinic keratosis. Ingenol mebutate, a diterpene ester extracted and purified from the plant Euphorbia peplus, is being evaluated as a topical therapy for actinic keratosis.. Assess the efficacy and safety of ingenol mebutate (formerly PEP005) gel at 3 dosing regimens for the treatment of actinic keratosis.. Patients with non-facial actinic keratoses applied vehicle gel for 3 days, ingenol mebutate gel, 0.025% for 3 days, or ingenol mebutate gel, 0.05% for 2 or 3 days, with an 8-week follow-up period.. All 3 active treatments were significantly more effective than vehicle at clearing actinic keratosis lesions, with a dose response observed. The partial clearance rate (primary efficacy end point) for patients treated with ingenol mebutate gel ranged from 56.0% to 75.4% compared with 21.7% for vehicle gel (P = .0002 to P < .0001 vs vehicle). The complete clearance rate was also significantly higher (P < or = .0006) for patients in the ingenol mebutate gel treatment groups (range: 40.0% to 54.4%) compared with vehicle (11.7%), as was the baseline clearance rate (range: 42.0% to 57.9% for ingenol mebutate gel compared with 13.3% for vehicle, P < .0001 to .0007 vs vehicle). The median percentage reduction in baseline actinic keratosis lesions for patients treated with ingenol mebutate gel ranged from 75% to 100% compared with 0% for vehicle gel (P < .0001 vs vehicle). Active treatment was well tolerated at all dosages. The mechanism of action of this agent is the localized induction of necrosis followed by a transient inflammatory response, and this was manifested in most patients as transient local skin responses consisting primarily of erythema, flaking/scaling, and crusting. There was no evidence of treatment-related scarring.. Local skin responses may have suggested active treatment to investigators.. Short-course, field-directed therapy with ingenol mebutate gel for actinic keratoses on non-facial sites seems to be effective with a favorable safety profile and potential benefits over topical agents that require a more prolonged course of treatment.

Topics: Administration, Topical; Adult; Aged; Aged, 80 and over; Diterpenes; Double-Blind Method; Euphorbia; Gels; Humans; Keratosis, Actinic; Middle Aged; Pharmaceutical Vehicles; Plant Extracts; Treatment Outcome

Vitamin D (VD) serum levels, and keratinocytic basal expression of vitamin D receptor (VDR) before treatment of actinic keratoses (AK) have been previously reported as possible biomarkers of the response of AK to treatments. We intended to evaluate the association between these and other serum and immunohistochemical parameters with the response of AK to treatment with topical ingenol mebutate (IM). Twenty-five patients with AK on the head were treated with topical IM 0.015% gel once daily for 3 days. Biopsies were taken at baseline and 6 weeks after treatment. Immunohistochemical staining was performed for VDR, P53, Ki67, Aurora B, Survivin and β-catenin. Basal serum 25(OH)D levels were determined. IM was more effective for KIN I and II AKs than in KIN III, and histological responders showed significantly higher serum VD levels (30.278 [SD 8.839] ng/mL) than nonresponders (21.14 [SD 7.079] ng/mL, p = 0.023). In addition, mean basal expression of VDR (45.63 [SD 16.105] %) increased significantly (57.92 [SD 14.738] %, p = 0.003) after treatment with IM. A significant decrease after treatment in the expression of several markers of aggressiveness and progression to squamous cell carcinoma, namely P53, Ki-67, aurora B kinase and survivin, was also observed. Our results support a relationship between VD status and the response of AK to treatment with topical IM, suggesting that its previous correction to proper serum levels in VD-deficient patients could improve the response of AK to the treatment.

Topics: Diterpenes; Humans; Keratosis, Actinic; Survivin; Treatment Outcome; Tumor Suppressor Protein p53; Vitamin D

Ingenol mebutate (IM) is highly effective in the treatment of human papillomavirus (HPV)-induced anogenital warts (AGW) leading to fast ablation within hours. However, the exact mode of action is still largely unknown. We performed dermoscopy, in vivo confocal microscopy (CLM), histology, immunohistochemistry, and immunofluorescence to gain insights in mechanisms of IM treatment in AGW. In addition, we used in vitro assays (ELISA, HPV-transfection models) to further investigate in vivo findings. IM treatment leads to a strong recruitment of neutrophils with thrombosis of small skin vessels within 8 h, in a sense of immunothrombosis. In vivo and in vitro analyses showed that IM supports a prothrombotic environment by endothelial cell activation and von Willebrand factor (VWF) secretion, in addition to induction of neutrophil extracellular traps (NETosis). IM superinduces CXCL8/IL-8 expression in HPV-E6/E7 transfected HaCaT cells when compared to non-infected keratinocytes. Rapid ablation of warts after IM treatment can be well explained by the observed immunothrombosis. This new mechanism has so far only been observed in HPV-induced lesions and is completely different from the mechanisms we see in the treatment of transformed keratinocytes in actinic keratosis. Our initial findings indicate an HPV-specific effect, which could be also of interest for the treatment of other HPV-induced lesions. Larger studies are now needed to further investigate the potential of IM in different HPV tumors.

Topics: Condylomata Acuminata; Diterpenes; Humans; Keratosis, Actinic; Necrosis; Papillomaviridae; Papillomavirus Infections; Skin Abnormalities; Warts

Actinic cheilitis (AC) is part of a spectral disease of keratinocyte carcinomas considered by some authors an early stage of. This study enrolled patients with AC to receive IM gel 0.015% for self-application on the lower lip for 3 consecutive days. A biopsy was performed before and after treatment for histopathological and immunohistochemical evaluation. Local skin reactions (LSR) were evaluated. The level of significance considered was 5%.. Fourteen patients were enrolled. All LSR had a complete resolution for up to 2 weeks. The most common adverse events were burning sensation, angular cheilitis, and pain. There was an improvement of more than 80% in patients' subjective evaluation. There was no statistically significant histopathological response since all patients remained with mild dysplasia. No reduction in the P53 expression was observed in the current study.. Despite being a safe therapeutic method, the absence of histopathological or immunohistochemical response suggests that clinical improvement may not be accompanied by histopathological cure for AC treated with IM.

Topics: Cheilitis; Diterpenes; Genes, p53; Humans; Keratosis, Actinic; Treatment Outcome; Tumor Suppressor Protein p53

Actinic keratoses (AKs) are common skin lesions association with increased exposure to ultraviolet radiation; these lesions have the potential to transform into squamous cell carcinomas (SCCs).1.

Topics: Aminolevulinic Acid; Carcinoma, Squamous Cell; Clinical Trials as Topic; Diterpenes; Fluorouracil; Humans; Imiquimod; Incidence; Keratosis, Actinic; Patient Preference; Photochemotherapy; Photosensitizing Agents; Risk Assessment; Skin Neoplasms; Treatment Outcome

Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Dermatology; Diterpenes; Female; Humans; Keratosis, Actinic; Male; Reproducibility of Results; Skin; Telemedicine; Treatment Outcome

Topics: Administration, Topical; Case-Control Studies; Diterpenes; Humans; Immunologic Factors; Keratosis, Actinic; Mesenchymal Stem Cells

Topics: Antineoplastic Agents; Diterpenes; Face; Gels; Humans; Keratosis, Actinic; Treatment Outcome

Topics: Aminolevulinic Acid; Cost-Benefit Analysis; Diterpenes; Fluorouracil; Humans; Imiquimod; Keratosis, Actinic; Netherlands; Photochemotherapy

Actinic keratosis is a common skin disease that may progress to invasive squamous cell carcinoma if left untreated. Ingenol mebutate has demonstrated efficacy in field treatment of actinic keratosis. However, molecular mechanisms on ingenol mebutate response are not yet fully understood. In this study, we evaluated the gene expression profiles of actinic keratosis lesions before and after treatment with ingenol mebutate using microarray technology. Actinic keratoses on face/scalp of 15 immunocompetent patients were identified and evaluated after treatment with topical ingenol mebutate gel 0.015%, applied once daily for 3 consecutive days. Diagnostic and clearance of lesions was determined by clinical, dermoscopic, and reflectance confocal microscopy criteria. Lesional and non-lesional skin biopsies were subjected to gene expression analysis profiled by Affymetrix microarray. Differentially expressed genes were identified, and enrichment analyses were performed using STRING database. At 8 weeks post-treatment, 60% of patients responded to ingenol mebutate therapy, achieving complete clearance in 40% of cases. A total of 128 differentially expressed genes were identified following treatment, and downregulated genes (114 of 128) revealed changes in pathways important to epidermal development, keratinocyte differentiation and cornification. In responder patients, 388 downregulated genes (of 450 differentially expressed genes) were also involved in development/differentiation of the epidermis, and immune system-related pathways, such as cytokine and interleukin signaling. Cluster analysis revealed two relevant clusters showing upregulated profile patterns in pre-treatment actinic keratoses of responders, as compared to non-responders. Again, differentially expressed genes were mainly associated with cornification, keratinization and keratinocyte differentiation. Overall, the present study provides insight into the gene expression profile of actinic keratoses after treatment with ingenol mebutate, as well as identification of genetic signatures that could predict treatment response.

Topics: Aged; Aged, 80 and over; Diterpenes; Gels; Gene Expression Regulation; Humans; Keratosis, Actinic; Male; Oligonucleotide Array Sequence Analysis

Topics: Dermatologists; Diterpenes; Humans; Keratosis, Actinic; Marketing

Topics: Adult; Aminolevulinic Acid; Diterpenes; Fluorouracil; Humans; Imiquimod; Keratosis, Actinic; Photochemotherapy; Scalp Dermatoses

Ingenol mebutate (IM), as an active compound, is derived from the sap of the Euphorbia peplus, which is an FDA-approved plant for the treatment of actinic keratosis. Some reports have demonstrated that the IM gel 0.05% is safe and effective in the treatment of external anogenital warts (AGWs) but the efficacy of the drug on the recalcitrant AGWs is not clear. This article assesses the efficacy and safety of the IM gel 0.05% for cryotherapy -resistant AGWs. Totally, 15 cryotherapy-resistant patients with AGWs (including 8 men and 7 women) and a mean age of 34 years old (age range of 23-50 years old) were enrolled in this study. IM gel 0.05% was applied carefully on the AGWs every two weeks for a maximum of three cycles. The complete clearance rate and recurrence rate were assessed 1 week and 3 months after the last treatment, respectively. Safety was assessed by the occurrence of local skin reaction and the severity of pain was evaluated using the 10-point Visual Analogue Scale. Initially, the AGWs were cleared completely in 10 (66%) patients while 4 (40%) and all of (100%) the patients experienced a recurrence in the 3- and 12-months follow-ups, respectively. All the 15 patients experienced some degrees of pain and local adverse reactions. The mean score of the reported pain was equal to 5.87 ± 2.39. The use of IM gel 0.05% in the treatment of the difficult-to-treat cases of AGWs is associated with a high recurrence rate despite the initial rapid and effective clearance of the lesions. Also, the high level of local adverse reactions and severe pain are other prohibitive factors in the treatment of recalcitrant AGWs with the IM.

Topics: Adult; Cryotherapy; Diterpenes; Female; Gels; Humans; Keratosis, Actinic; Male; Middle Aged; Neoplasm Recurrence, Local; Treatment Outcome; Young Adult

Topics: Carcinoma, Squamous Cell; Diterpenes; Humans; Keratosis, Actinic; Retrospective Studies; United States; United States Food and Drug Administration

Background: Real-world data for actinic keratosis treatment in the United States is lacking. Objectives: To understand real-world treatment patterns for actinic keratosis by type and modality, and compare effectiveness and safety of therapies, either alone or in combination. Methods: Medical charts of 429 patients were identified; clinical and outcome data were analyzed. Results: The first treatment after the index diagnosis was most frequently a procedure, followed by a topical agent. Treatment with 5-fluorouracil, ingenol mebutate, imiquimod, cryotherapy, or cryotherapy plus one topical (CRYO+One Topical) reduced actinic keratoses by 66.0%, 69.3%, 72.5%, 72.9%, and 73.0%, respectively; ≥75% clearance (AKCLEAR 75) was achieved in 57.1%, 72.7%, 57.1%, 62.4%, and 62.0% of those patients. Treatment effectiveness was positively correlated with the number of baseline actinic keratoses for topical and for procedural plus topical combination treatments, but not for procedural treatments alone. Adverse reactions (ARs) were more common with cryotherapy (9.7%); local skin responses (LSRs) were more common with field-directed (18.5%-43.1%) and CRYO+One Topical therapy (21.3%). Limitations: This was a retrospective study of limited duration and population size. Conclusions: The most commonly used treatments for patients with 6 or more actinic keratoses were topicals and a procedure plus topical combination, which also achieved higher rates of complete clearance than a procedure alone. ARs and LSRs were few in frequency and type.

Topics: Administration, Cutaneous; Aged; Antineoplastic Agents; Combined Modality Therapy; Cryotherapy; Diterpenes; Female; Fluorouracil; Humans; Imiquimod; Keratosis, Actinic; Male; Middle Aged; Retrospective Studies; Severity of Illness Index; Skin; Treatment Outcome; United States

Actinic keratosis (AK) is a skin premalignant lesion, which progresses into squamous cell carcinoma (SCC) if left untreated. Ingenol mebutate gel is approved for local treatment of non-hyperkeratotic, non-hypertrophic AK; it also has the potential to act as a field cancerization therapy to prevent the progression of AK to SCC. To gain better insights into the mechanisms of ingenol mebutate beyond the mere clinical assessment, we investigated, for the first time, the metabolome of skin tissues from patients with AK, before and after ingenol mebutate treatment, with high-resolution magic angle spinning nuclear magnetic resonance spectroscopy. The metabolomic profiles were compared with those of tissues from healthy volunteers. Overall, we identified a number of metabolites, the homeostasis of which became altered during the process of tumorigenesis from healthy skin to AK, and was restored, at least partially, by ingenol mebutate therapy. These metabolites may help to attain a better understanding of keratinocyte metabolism and to unmask the metabolic pathways related to cell proliferation. These results provide helpful information to identify biomarkers with prognostic and therapeutic significance in AK, and suggest that field cancerization therapy with ingenol mebutate may contribute to restore skin metabolism to a normal state in patients with AK.

Topics: Biomarkers, Tumor; Case-Control Studies; Diterpenes; Humans; Keratosis, Actinic; Metabolomics; Proton Magnetic Resonance Spectroscopy; Skin

Topics: Aged, 80 and over; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Diterpenes; Humans; Keratosis, Actinic; Male; Scalp; Skin Neoplasms

Actinic keratoses (AK) are common precancerous lesions of the skin due to cumulative sun exposure. A variety of interventions are available for the treatment; however, the majority of randomised controlled trials (RCTs) and meta-analyses focus on short-term efficacy outcomes. This network meta-analysis aims to investigate the long-term (> 12 months) efficacy of interventions for AK.. To identify relevant studies, we will perform a systematic literature research in MEDLINE, Embase, and CENTRAL and hand-search pertinent trial registers. Two authors will independently screen titles and abstracts for eligibility. We will include RCTs with an inter-individual (parallel arm) design. The study population includes patients with a clinical or histopathologic diagnosis of AK. Eligibility will be restricted to the following interventions: surgical approaches, cryosurgery, ablative laser treatment, topical drug treatment with 5-fluorouracil, imiquimod, ingenol mebutate, diclofenac, or photodynamic therapy. As outcomes, we will consider the following endpoints: (1) the participant complete clearance rate, (2) the participant partial clearance rate, (3) the lesion-specific clearance, (4) the mean lesion reduction per patient, and (5) the number of withdrawals due to adverse events after at least 12 months after the end of treatment. Monotherapy or placebo will serve as a comparison. Estimates of effects from individual studies will be pooled using a random-effects model. Heterogeneity will be evaluated based on I. The potential of interventions to achieve a sustained clearance of AK has not been assessed to date. To investigate the long-term efficacy of interventions is important as the natural disease course is highly variable and relapses occur frequently even after initial lesion clearance. This review will help to set a framework for clinical decision making in patients with AK.. CRD42018095903 (PROSPERO).

Topics: Adjuvants, Immunologic; Disease Progression; Diterpenes; Europe; Humans; Imiquimod; Keratosis, Actinic; Meta-Analysis as Topic; Network Meta-Analysis; Photochemotherapy; Randomized Controlled Trials as Topic; Systematic Reviews as Topic

The cost of topical treatments for actinic keratosis (AK) has historically been evaluated in relation to the number of lesions requiring treatment or simply by the price of a single tube/sachet of the drug used.. To demonstrate a new method of costing topical treatments in AK, which takes into account the actual cancerization area treated.. In order to evaluate the actual cost of each treatment, the official approval status of the drug was used to estimate the amount of cream needed per one cm. Areas which could be treated with a single tube/sachet of Metvix. Changing treatment costing strategy in the management of multiple AKs towards costing per cancerization area instead of costing per lesion is a much more accurate representation of the 'real world cost' for AK.

Topics: Administration, Topical; Aminolevulinic Acid; Cohort Studies; Cost of Illness; Diclofenac; Diterpenes; Drug Administration Schedule; Female; Fluorouracil; Health Care Costs; Humans; Imiquimod; Italy; Keratosis, Actinic; Male; Photochemotherapy; Precancerous Conditions; Retrospective Studies; Risk Assessment; Severity of Illness Index; Treatment Outcome

Topics: Administration, Cutaneous; Adult; Aged; Aged, 80 and over; Diterpenes; Drug Administration Schedule; Face; Female; Follow-Up Studies; Humans; Keratosis, Actinic; Male; Middle Aged; Patient Reported Outcome Measures; Patient Satisfaction; Quality of Life; Treatment Outcome

Actinic keratosis (AK) corresponds to the earliest stage of in situ squamous cell carcinoma and arises on chronically sun-exposed skin. Around the clinically evident AKs, the apparently healthy epidermis may contain different grades of atypia that can be detected by noninvasive imaging techniques such as reflectance confocal microscopy (RCM) and optical coherence tomography (OCT). Subclinical actinic keratosis (sAK) has captured increasing interest as a potential target of field therapies. The aim of this study was to evaluate in vivo the changes in the field cancerization undergoing treatment with topical ingenol mebutate by combining RCM and OCT. Twenty patients with field cancerization of the face and scalp were treated with ingenol mebutate gel (150 mcg/g) for three consecutive days on an area of 25 cm

Topics: Administration, Topical; Aged; Aged, 80 and over; Diterpenes; Dose-Response Relationship, Drug; Face; Female; Humans; Keratosis, Actinic; Male; Microscopy, Confocal; Scalp; Tomography, Optical Coherence

Topics: Croton; Croton Oil; Diterpenes; Humans; Keratosis, Actinic

Topics: Croton; Croton Oil; Diterpenes; Humans; Keratosis, Actinic

UV radiation represents the main risk factor for non-melanoma skin cancers. Chronic UV exposure induces 'p53 patches', i.e. clonal outgrowths of keratinocytes with high nuclear expression of mutated p53, which might progress to actinic keratosis (AK) and ultimately squamous cell carcinomas (SCCs).. Analysis of ingenol mebutate gel (150 and 500 mcg/g) effects in the reduction in 'p53 patches' inside skin cancerization field (CF) in patients with multiple AKs of face/scalp or trunk/extremities, in order to investigate whether the expected reduction in p53. Untreated skin CF expresses high level of p53

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Biopsy; Cell Nucleus; Diterpenes; Gels; Humans; Immunohistochemistry; Keratinocytes; Keratosis, Actinic; Male; Skin; Tumor Suppressor Protein p53

Dermatologists have many therapeutic options for the management of actinic keratoses (AK), in order to treat individual lesions or wider areas. Field cancerization is an area of sun-damaged skin, where visible and subclinical lesions co-exist, and is prone to the development of further AK lesions and sun-related skin cancers (SC). Treatments available are instrumental or medical. Resistance to treatment or atypical symptoms must lead to a biopsy for histological exam. Cryotherapy is the most frequently used method to destroy small or isolated AK, whereas photodynamic therapy (PDT), 5-fluoro-uracil (5-FU), imiquimod, ingenol mebutate and diclofenac are required for large, multiple lesions, and for the treatment of field cancerization. Side-effects of these therapies are essentially local, including pain, irritation, erythema, edema and scars. There is no randomized comparative study reviewing all these treatments, therefore physicians must also consider clinical characteristics, patient's compliance, side-effects and cost when treating AK. Medicoeconomic data of these treatments have been analyzed in several countries, and annual costs are estimated between 250 € and 2 000 €, with an uncertain cost-effective relation. Finally, beyond treatment of AK lesions, patients with AK are at high risk of developing SC, and must therefore have regular full-body examination, in order to be detected and treated precociously. © 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.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Cost-Benefit Analysis; Cryotherapy; Dermatologic Agents; Diclofenac; Diterpenes; Electrocoagulation; Fluorouracil; Humans; Imiquimod; Keratosis, Actinic; Laser Therapy; Photochemotherapy

Field-directed therapy, such as daylight-photodynamic therapy (DL-PDT) or ingenol mebutate (IM), is indicated for multiple actinic keratosis (AK) lesions located on contiguous areas of skin with significant sun damage.. To compare the efficacy of sequential DL-PDT and IM treatment with that of 2 sessions of DL-PDT in AK patients.. For this observational, multicenter, prospective study we recruited patients for whom DL-PDT was indicated for the treatment of AK lesions (grades I and II) located on the head. After 1 month of follow-up those who did not achieve a satisfactory clinical response received either a second session of DL-PDT or were treated with IM. Epidemiological and clinical data were collected and analyzed.. Forty-three patients were enrolled (39 male, 4 female). The mean (standard deviation, SD) age was 78 (7.84) years, and the mean (SD) number of AK lesions per patient was 9.58 (1.16). After the first session of DL-PDT, 27 patients (62.8%) required further treatment: 13 (48.1%) received a second session of DL-PDT and 14 (51.9%) were treated with IM. After 1 year of follow-up, lesion clearance rates were higher in patients who received 2 sessions of DL-PDT than those treated with sequential DL-PDT plus IM (75.2%vs 54.6%, p = 0.0013). Local skin reactions were more frequent in the DL-PDT plus IM group than the group treated with 2 sessions of DL-PDT (p = 0.0245).. The combination of DL-PDT plus IM appears to have no synergistic effect in the treatment of field cancerization, and offers no benefits over 2 sessions of DL-PDT monotherapy, although both combinations produced high lesion clearance rates, a good safety profile, excellent cosmetic outcome, and good patient satisfaction.

Topics: Aged; Aged, 80 and over; Aminolevulinic Acid; Diterpenes; Drug Therapy, Combination; Female; Humans; Keratosis, Actinic; Male; Patient Satisfaction; Photochemotherapy; Photosensitizing Agents; Pilot Projects; Prospective Studies; Sunlight

Actinic keratosis (AK) represents one of the most common diagnoses in our dermatology practices. The incidence of AK lesions continues to rise, along with that of non-melanoma skin cancers. Numerous risk factors have now been implicated, including chronic sun exposure, history of sunburns, fair skin, advanced age, male gender, and immunosuppression. Although an individual lesion’s likelihood of progression to malignancy remains very low, AKs seldom occur in isolation. Indeed, the condition can most accurately be described as a “field disease”, with a mix of clinical and subclinical lesions present in the same region. Studies have shown that the majority of squamous cell carcinomas arise in sites of pre-existing AKs, highlighting the importance of diagnosis and appropriate management.

Topics: Dermatologic Agents; Disease Progression; Diterpenes; Fluorouracil; Humans; Imiquimod; Keratosis, Actinic; Photochemotherapy

Actinic keratosis (AK) represents a risk of progression to squamous cell carcinoma. Ingenol mebutate gel is a novel therapeutic option for field-directed treatment.. To evaluate the safety, tolerability and patients' perspectives, related to the therapeutic success of managing AKs on the face and scalp with ingenol mebutate gel in Brazilian individuals.. This was an observational, retrospective and descriptive study of 68 areas of actinic keratosis on the face and scalp treated with Ingenol mebutate gel involving a total of 37 patients. The drug was applied for three consecutive days on an area of of 25 cm2 and documentation was performed on baseline and days 4, 8, 15, 60 and 180. On day 4, the composite local skin reaction score was calculated. At the end, a questionnaire was applied to evaluate patients' perspectives about the treatment.. Adherence was 100%, no serious adverse events were recorded and the mean composite local skin reaction score (standard deviation) was 8.61±4.22. The treatment was considered optimum by 75.68% of the patients.. Calculation of composite local skin reaction score performed only on the fourth day.. Treatment with ingenol mebutate gel was considered safe and tolerable in Brazilian subjects. Patients had a maximum adherence rate and a great improvement in self-esteem. The results of this research reproduce the findings of the literature.

Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Brazil; Dermatologic Agents; Diterpenes; Facial Dermatoses; Female; Gels; Humans; Keratosis, Actinic; Male; Middle Aged; Retrospective Studies; Scalp Dermatoses; Surveys and Questionnaires; Treatment Outcome

Topical treatments in dermatology can be long, complex and lead to nonadherence and nonpersistence to prescribed treatment. Clinical efficacy observed in randomized clinical trials (RCT) may therefore be reduced in real-world clinical practice. The objective of this study was to analyze patient-reported treatment adherence, treatment satisfaction and health-related quality of life (HRQoL) with topical treatments of actinic keratosis (AK) in routine clinical practice in Denmark and Sweden. Adult patients prescribed field-directed topical AK treatments with diclofenac gel, imiquimod or ingenol mebutate per routine clinical practice were eligible for the observational RAPID-ACT study. Data were collected through physician and patient questionnaires that included validated instruments to measure treatment satisfaction (TSQM-9), treatment adherence (MMAS) and HRQoL (EQ-5D-5L, EQ-VAS, AKQoL). In total, 446 patients from Denmark and Sweden were included. Ingenol mebutate patients reported a higher satisfaction with treatment effectiveness compared to patients treated with diclofenac (p = .006) while no other differences in treatment satisfaction could be determined. Treatment adherence was generally high, but higher for ingenol mebutate compared to both diclofenac (p < .001) and imiquimod (p = .007), possibly due to shorter treatment duration. No differences in improved HRQoL were found. More research is needed about the link between treatment adherence and real-world effectiveness.

Topics: Administration, Topical; Aged; Aminoquinolines; Denmark; Diclofenac; Diterpenes; Drug Administration Schedule; Female; Humans; Imiquimod; Keratosis, Actinic; Male; Middle Aged; Patient Reported Outcome Measures; Patient Satisfaction; Quality of Life; Surveys and Questionnaires; Sweden

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Body Surface Area; Diterpenes; Facial Dermatoses; Gels; Health Care Surveys; Humans; Keratosis, Actinic; Middle Aged; Nurse's Role; Patient Satisfaction

Topics: Aged; Dermatologic Agents; Diterpenes; Humans; Keratosis, Actinic; Male; Scalp Dermatoses; Skin Diseases, Vesiculobullous

The aim of the study was to evaluate the results on effectiveness and safety of topical treatment for actinic keratosis (AK) with ingenol mebutate gel (IMG) in real-life conditions and to perform an analysis of the factors that may influence the treatment outcomes.. Retrospective study of patients with non-hyperkeratotic AK lesions prescribed with IMG in Spain according to clinical practice. Dermatologists reported the characteristics of patients and AK at baseline, and the findings observed up to 60 d after treatment.. A total of 260 treatments in 246 patients with a mean (SD) age 70.6 (10.4) years were reviewed. The number of clinically visible AK in the treated area decreased from 6.16 (3.02) to 1.22 (2.02) (p < .001) lesions with an average reduction of 84%. Univariate analysis showed higher reduction rates when IMG was applied in the face/scalp (p = .026), in women (p = .041), and in patients under 70 years of age (p = .033). According to multivariate analysis, advanced age was associated with worse clearance rates (p = .038). However, besides statistical significance, we can conclude that gender (female) and age (under 70 years-old) show a tendency to have better efficacy outcomes but without clinical relevance. Topical IMG was generally well tolerated and had positive cosmetic results after 60 d. Age influences on IMG effectiveness for AK and LSRs were correlated with higher effectiveness ratios.

Topics: Administration, Topical; Adult; Age Factors; Aged; Aged, 80 and over; Diterpenes; Face; Female; Gels; Humans; Keratosis, Actinic; Male; Middle Aged; Multivariate Analysis; Patient Satisfaction; Retrospective Studies; Scalp; Treatment Outcome

Topics: Diclofenac; Diterpenes; Humans; Keratosis, Actinic; Scalp

Topics: Diclofenac; Diterpenes; Humans; Keratosis, Actinic; Scalp

Ingenol mebutate (IngMeb) 0.015% gel is an approved field treatment option for non-hyperkeratotic non-hypertrophic actinic keratosis (AK) of face and scalp. Efficacy of IngMeb has been assessed only on a clinical ground, in the majority of studies. Dermoscopy is a pivotal tool for the diagnosis of AK, while its role in evaluating the response to non-surgical therapies for AK has not been fully defined.. Our study aims to determine whether some dermoscopic features of AK of the face and scalp areas may independently predict the response to IngMeb therapy.. Clinical and dermoscopic responses, 1 month after 0.015% IngMeb therapy, were retrospectively evaluated using a per-patient and per-lesion approach. Safety was evaluated through local skin reaction composite score calculation. Demographic, clinical and dermoscopic factors were then evaluated via univariate and multivariate logistic regression analysis to assess independent predictors of response.. Fifty-five patients with 245 AKs were enrolled. Clinically, per-patient response evaluation identified 25 (45.4%) poor/partial and 30 (54.5%) complete responders, corresponding on a per-lesion approach to 66 (26.9%) and 179 (73.1%) AKs, respectively. Dermoscopy reclassified 14 patients in the per-patient and 48 AKs in the per-lesion analysis from complete to poor/partial responders. Multivariate logistic regression analysis showed that AKs dermoscopically characterized by red pseudonetwork and located on the face were independently associated with a complete dermoscopic response to 0.015% IngMeb therapy, while microerosions were negative predictors.. Specific dermoscopic features of AK may predict the response to 0.015% IngMeb therapy, together with the location on the face.

Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Antineoplastic Agents; Dermoscopy; Diterpenes; Erythema; Facial Dermatoses; Female; Gels; Humans; Keratosis, Actinic; Male; Predictive Value of Tests; Retrospective Studies; Scalp Dermatoses; Treatment Outcome

Topics: Diclofenac; Diterpenes; Follow-Up Studies; Humans; Keratosis, Actinic; Scalp

Topics: Aged; Carcinoma, Squamous Cell; Dermatologic Agents; Diterpenes; Female; Humans; Keratosis, Actinic; Male; Skin Neoplasms

Ingenol mebutate is an actinic keratosis treatment, which has a dual action mechanism. It allows a rapid cellular death and a severe inflammation.. We report the case of a 75 years old patient with a rapidly growing tumor 5 weeks after application of ingenol mebutate on typical actinic keratosis. Histological analysis after surgical excision showed an invasive squamous cell carcinoma (SCC); with aggressiveness signs: perineural infiltration and vascular permeation.. Ingenol mebutate's common side effects are benign and regressive within 2 to 4 weeks. There are erythema, edema, crusts, and ulcerations/erosions. Squamous cell carcinoma development was rarely reported. We have tried to collect other cases in the literature and in pharmacovigilance centres: three similar cases were recently published in the literature, 21 cases were notified to the European Medicines Agency and we asked French pharmacovigilance centres and found 5 cases of SCC after ingenol mebutate application. The role of the molecule in SCC development is currently unknown. Induced inflammation could take part in the development of these tumors. We compare this case with other situations of inflammation, such skin graft donor site or surgical incision, complicated of rapidly growing SCC. Our case, literature's and pharmacovigilance's cases encourage us to follow ingenol mebutate's side effects. Careful follow-up and registration of such cases are important to gain further insight on this topic.

Topics: Administration, Cutaneous; Aged; Carcinoma, Squamous Cell; Dermatologic Agents; Disease Progression; Diterpenes; Humans; Inflammation; Irritants; Keratosis, Actinic; Male; Neoplasm Invasiveness; Skin Neoplasms

Sequential treatment of actinic keratosis (AK) and cancerization field with cryotherapy and ingenol mebutate (IM) is widely used in clinical practice, however, the order of application of sequential treatment has not been examined yet.. To compare different sequential treatments of IM and cryotherapy in AK and to monitor cure rates and local skin reactions (LSR) through reflectance confocal microscopy (RCM).. Patients with AK were treated with IM and cryotherapy. Group A received treatment with IM before cryotherapy, and group B patients were firstly treated with cryotherapy and secondly IM. RCM evaluation of epidermal dysplasia and LSR was performed prior to the first treatment (Week 0), before the second treatment (Week 2), and one month and two months after initial assessment.. The study included 26 patients - 14 patients in group A and 12 patients in group B. In both groups, significant improvement in epidermal dysplasia RCM parameters between the first and last visit was observed. Regarding LSR parameters, group A presented fewer LSR parameters than group B on the second visit. This difference was present even if comparison was made between the third visit of group A and the second visit of group B.. Both sequences of treatment are effective, but IM treatment before cryotherapy is recommended because of the lower LSR. This probably decreases patient discomfort and improves compliance.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Apoptosis; Combined Modality Therapy; Cryotherapy; Dermatitis; Diterpenes; Edema; Female; Humans; Keratosis, Actinic; Male; Microscopy, Confocal; Middle Aged; Prospective Studies

Actinic keratosis (AK) is an in situ squamous cell carcinoma which is mostly found on sun-damaged skin, and it is prevalent among Caucasians. However, there is a lack of research on evaluating the treatment efficacy of ingenol mebutate (IM) on AK in Asians. This study was intended to analyze the treatment outcomes of IM on AK in Korean patients with regards to clinical, dermoscopic and histopathological aspects. A prospective study on 46 Korean patients who were diagnosed with AK and treated with IM was conducted. Clinically, 80% (24/30) of the patients showed an improvement at 8 weeks. Twenty out of the 30 (66.7%) patients were found to have achieved histopathological clearance. All local skin responses had disappeared at T4 in all patients. Patients with Fitzpatrick skin type III were proven to exhibit better treatment outcomes, both clinically (P = 0.001) and histopathologically (P = 0.001), than those with Fitzpatrick skin type IV. The clinical and histopathological clearance rate of AK with IM in Korean patients was 80% and 66.7%, respectively. The patients with Fitzpatrick skin type IV showed a tendency to have residual AK, histopathologically after treatment with IM. In conclusion, IM could be an effective and safe treatment option on AK in Korean patients. In addition, it would be helpful to carry out a cautious check-up when treating AK with IM in patients with a darker skin color.

Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma in Situ; Carcinoma, Squamous Cell; Dermoscopy; Diterpenes; Female; Humans; Keratosis, Actinic; Male; Middle Aged; Prospective Studies; Republic of Korea; Skin; Skin Neoplasms; Treatment Outcome

Ingenol mebutat (IM)-gel is effective for the topical treatment of epithelial tumors, including actinic keratoses (AKs) or anogenital warts (AGW). AK patients treated with IM develop intensified inflammatory reactions on sights of prior clinical visible or palpable AKs as compared to the surrounding actinically damaged skin, suggesting the induction of a tumor cell-directed inflammation. AGW patients treated with IM develop even stronger inflammatory reactions with large erosions, suggesting a directed inflammatory response against HPV-infected keratinocytes. Of note, even widespread erosions heal very fast without any superinfections. Here, we set out to elucidate underlying molecular and cellular mechanisms of these clinical observations.. The effects of IM (10. Ingenol mebutat significantly and dose-dependently induced the expression of proinflammatory chemokines (CXCL8, CCL2) and AMP (RNase7, HBD3) in HEK and epithelial cancer cell lines. A significantly stronger induction of CXCL8 and CCL2 was observed in our tested tumor cells as compared to HEK. We did not observe any significant effect of IM on HEK migration, respectively wound healing responses in vitro for any tested concentration (10. Our data suggest that tumor cells are more susceptible to IM as compared to differentiated HEK. This is evident by a stronger IM-mediated induction of proinflammatory chemokines in tumor cells, which may result in a tumor cell-directed inflammatory response and rapid tumor destruction. In addition, IM induces AMP in keratinocytes and seems not to severely interfere with keratinocyte migration, which contributes to a fast and uncomplicated wound healing. Surprising is a selective inhibition of keratinocyte migration by IM at the concentration of 10

Topics: Administration, Topical; Antimicrobial Cationic Peptides; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemokines; Condylomata Acuminata; Diterpenes; Gene Expression Regulation; HEK293 Cells; Humans; Inflammation; Keratinocytes; Keratosis, Actinic; Neoplasms; Papillomaviridae; Wound Healing

Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Collagen Type I; Diterpenes; Female; Gels; Humans; Keratosis, Actinic; Male; Matrix Metalloproteinase 1; Middle Aged; Rejuvenation; RNA, Messenger; Skin; Skin Aging; Transforming Growth Factor beta; Treatment Outcome

Actinic keratosis (AK) is the most common cutaneous premalignant neoplasm precursor of malignant skin tumors. The aberrant apoptotic pathway is thought to be associated with pathogenesis of AK. Ingenol mebutate has been shown to be effective and safe for treatment of AK. However, the effect of ingenol mebutate on apoptosis-related molecules using human skin samples has not been studied well. Erythroid differentiation regulator 1 (Erdr1) was recently reported to play a crucial role in malignant skin cancers like malignant melanoma. The role of Erdr1 in premalignant actinic keratosis (AK) has not been explored. The purpose of this study was to investigate whether the expression of apoptosis-associated molecules such as Erdr1, p53 and bcl-2 was affected by the treatment of ingenol mebutate in AK. Nine patients with AK underwent skin biopsy at baseline and 8 weeks after treatment with ingenol mebutate for immunohistochemical evaluation with Erdr1, p53 and bcl-2. In addition, skin samples from five control subjects were retrieved. Upregulation of Erdr1 and a significant decrease in expression of p53 and bcl-2 were observed after treatment with ingenol mebutate. Ingenol mebutate treatment for AK resulted in the modulation of apoptosis-associated molecules with an increase in the expression of Erdr1 and a decrease in the expression of p53 and bcl-2.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Apoptosis; Diterpenes; Down-Regulation; Humans; Keratinocytes; Keratosis, Actinic; Membrane Proteins; Proto-Oncogene Proteins c-bcl-2; Retrospective Studies; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Up-Regulation

The present study aimed to perform a cost-effectiveness analysis of ingenol mebutate (IM) versus other topical alternatives for the treatment of actinic keratosis (AK).. The analysis used a decision tree to calculate the clinical effects and costs of AK first-line treatments, IM (2-3 days), diclofenac 3% (for 8 or 12 weeks), imiquimod 5% (for 4 or 8 weeks), during a 24-month horizon, using discrete intervals of 6 months. A hypothetical cohort of immunocompetent adult patients with clinically confirmed AK on the face and scalp or trunk and extremities was considered. Clinical data on the relative efficacy were obtained from a network meta-analysis. Inputs concerning resource use derived from an expert panel. All costs were calculated from a Greek third-party payer perspective.. IM 0.015% and 0.05% were both cost-effective compared with diclofenac and below a willingness-to-pay threshold of €30,000 per quality-adjusted life-year (QALY) (€199 and €167 per QALY, respectively). Comparing IM on the face and scalp AK lesions for 3 days versus imiquimod for 4 weeks resulted in an incremental cost-effectiveness ratio of €10,868 per QALY. IM was dominant during the 8-week imiquimod period. IM use on the trunk and extremities compared with diclofenac (8 or 12 weeks) led to incremental cost-effectiveness ratios estimated at €1584 and €1316 per QALY accordingly. Results remained robust to deterministic and probabilistic sensitivity analyses.. From a social insurance perspective in Greece, IM 0.015% and IM 0.05% could be the most cost-effective first-line topical field treatment options in all cases for AK treatment.

Topics: Aminoquinolines; Cost-Benefit Analysis; Diclofenac; Diterpenes; Greece; Humans; Imiquimod; Keratosis, Actinic; Quality-Adjusted Life Years

Background: Ingenol mebutate gel 0.015% provides high clearance rates for actinic keratosis (AK) on the face and scalp but causes transient local skin responses (LSRs).

Objective: This study sought to determine whether the application of 1% dimethicone would decrease ingenol mebutate-associated LSRs and/or affect efficacy during the treatment of multiple AKs on the face.

Methods: Ingenol mebutate gel 0.015% was applied for 3 days to two 25 cm2 areas, each containing 3 to 8 AKs on the face of each subject, followed by application of 1% dimethicone lotion in an investigator-blinded manner to one randomly selected AK-containing area until LSRs were no longer present.

Results: In total, 20 subjects were enrolled and completed the study. Topical 1% dimethicone lotion applied during and after treatment of facial AK with ingenol mebutate gel 0.015% reduced mean total LSR scores at days 8 and 15 compared with ingenol mebutate gel only, although the difference was not statistically significant. Efficacy was equivalent between the two treatment arms.

Limitations: The study evaluated a relatively small number of subjects, all of whom were white.

Conclusions: The application of 1% dimethicone following ingenol mebutate gel 0.015% produced a trend toward lower severity of some LSRs, with no difference in efficacy.

J Drugs Dermatol. 2017;16(5):432-436.

Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Dermatologic Agents; Dimethylpolysiloxanes; Diterpenes; Drug Compounding; Drug Therapy, Combination; Face; Female; Gels; Humans; Keratosis, Actinic; Male; Middle Aged; Skin Cream; Treatment Outcome

Topics: Aged; Aged, 80 and over; Dermatologic Agents; Diterpenes; Humans; Keratosis, Actinic; Male; Scalp Dermatoses; Skin Diseases, Vesiculobullous

Non-melanoma skin cancer is the most frequently occurring cancer in Caucasians today. Incidence rates in Europe have increased steadily since the 1960s and more than tripled over the last 50 years. Despite primary preventative efforts, incidences of non-melanoma skin cancer continue to rise and development of effective chemopreventative strategies is needed. In 2013, ingenol mebutate was approved in Denmark as a new topical drug for field-directed treatment for actinic keratoses. Ingenol mebutate has a dual mechanism of action, causing initial cell death, followed by an immune activation. The treatment induces an acute inflammation, manifesting as local skin responses, often accompanied by pain and pruritus. The severity of local skin responses for a given patient is unpredictable, and some individuals may develop insufferable inflammation. The overall aim of the thesis was to investigate if ingenol mebutate could be used as a chemopreventive agent to prevent development of non-melanoma skin cancer with minimal side effects. Specific aims included: Determine if ingenol mebutate can prevent progression of histological photodamage and squamous cell carcinoma (murine). Determine if ingenol mebutate can reverse clinical actinic damage in patients with multiple actinic keratoses and fieldcancerized skin (clinical). Determine if a topical glucocorticoid (clobetasol propionate) can reduce ingenol mebutate-induced local skin responses, pain, and pruritus without compromising the treatment efficacy (murine clinical). In two in vivo murine studies, ingenol mebutate's effect on photodamage and squamous cell carcinoma formation was investigated. Mice were irradiated with solar simulated ultraviolet radiation. During the first 20 weeks, 5 single applications with ingenol mebutate were given at four-week intervals with and without concurrent application of clobetasol propionate. Prophylactic treatments with ingenol mebutate prevented progression of histological photodamage of all investigated characteristics, including keratosis grade, epidermal hypertrophy, dysplasia, and dermal actinic damage. In addition, tumor formation was postponed by 3 weeks. In the clinical trial, patients with multiple actinic keratoses and field-cancerized skin were treated with ingenol mebutate, according to label, with and without sequential application of clobetasol propionate. Ingenol mebutate treatments were found to clear overall 86% of all actinic keratoses, exerting a therapeutic effe

Topics: Administration, Cutaneous; Animals; Carcinoma, Squamous Cell; Denmark; Dermatologic Agents; Diterpenes; Glucocorticoids; Humans; Keratosis, Actinic; Mice; Pain; Pruritus; Skin Neoplasms; Treatment Outcome; Ultraviolet Rays

Actinic keratoses are cutaneous lesions that appear as the result of the proliferation of atypical keratinocytes. These lesions are considered pre-malignant and they can progress to squamous cell carcinoma. Ingenol mebutate has been approved as an effective treatment for AK on the face and trunk. We studied the local skin reactions to this therapy. Data about local skin reactions were collected in a series of 5 patients with photographic documentation, a visual analog scale, and a ranking of satisfaction of the patient. Moderate to severe reactions were reported in most of patients, but only one stopped treatment early. The short duration of treatment contributes to high adherence to the therapy.

Topics: Administration, Cutaneous; Antineoplastic Agents; Diterpenes; Drug Eruptions; Facial Dermatoses; Humans; Keratosis, Actinic; Scalp Dermatoses

Topics: Administration, Cutaneous; Dermatologic Agents; Diterpenes; Drug Delivery Systems; Female; Humans; Keratosis, Actinic; Leg; Middle Aged; Needles; Skin Neoplasms

Topics: Dermatologic Agents; Diterpenes; Facial Dermatoses; Gels; Humans; Keratosis, Actinic; Microscopy, Confocal; Middle Aged; Prospective Studies; Scalp Dermatoses

Ingenol mebutate gel, a topical field treatment for actinic keratosis (AK), elicits inflammatory application-site reactions in most patients. This analysis explored the relationship between the intensity of local skin reactions (LSRs) and AK clearance, measured by the reduction in AK count from baseline in 218 patients who were treated for AK on the face in the pivotal Phase 3 studies. The analysis modeled the AK count at week 8, adjusted for baseline count, with the composite LSR score at 1 day after the last treatment application for each patient as a predictor to estimate the mean and 90% prediction interval for the percent reduction in AK count. The predicted mean percent reduction in AK count was higher in patients with higher composite LSR scores. Lower composite scores demonstrated a variable, less predictive percentage reduction in efficacy. Therefore, a large inflammatory reaction from ingenol mebutate gives a more reliable prognosis for improved AK clearance.

J Drugs Dermatol. 2017;16(2):112-114.

Topics: Administration, Cutaneous; Clinical Trials, Phase III as Topic; Diterpenes; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Facial Dermatoses; Gels; Humans; Keratosis, Actinic; Prognosis; Randomized Controlled Trials as Topic; Regression Analysis

Topics: Administration, Topical; Aged; Aged, 80 and over; Disease Management; Diterpenes; Erythema; Female; Follow-Up Studies; Humans; Keratosis, Actinic; Male; Skin

Topics: Diterpenes; Humans; Keratosis, Actinic; Laser Therapy; Male; Scalp; Treatment Outcome

Actinic keratosis (AK) is a UV-induced, pre-malignant skin condition that is common in adults over 60 years of age with fair skin in Scotland. The most commonly prescribed first-line treatment for AK in Scotland is currently diclofenac gel (3 %). Ingenol mebutate gel is a recently developed topical therapy available in two strengths for the treatment of AK lesions on the face and scalp (150 mcg/g once daily for 3 consecutive days) or trunk and extremities (500 mcg/g once daily for 2 consecutive days).. To compare the cost-effectiveness of two strengths of ingenol mebutate gel developed to treat AK lesions on the face and scalp (150 mcg/g once daily for 3 consecutive days) or trunk and extremities (500 mcg/g once daily for 2 consecutive days) with other first-line AK therapies including diclofenac gel, 5-FU, 5-FU/salicylic acid, and cryotherapy for the first-line treatment of AK in adult patients, from the perspective of the National Health Service (NHS) in Scotland.. A cost-utility analysis was conducted using a decision-tree approach to calculate the costs and benefits of different treatment strategies for AK on the face and scalp or trunk and limbs over a 12-month time horizon. Data on the relative efficacy of treatments were obtained from a systematic literature review and meta-analysis. Utility scores and resource-use data were obtained from published sources.. Over 12 months, ingenol mebutate 150 mcg/g gel and 500 mcg/g gel were cost-effective compared with the most commonly used topical therapy in Scotland, diclofenac (3 %) gel, at a willingness-to-pay threshold of £20,000 per QALY, with a minimal additional cost of £43 and £105, respectively per QALY gained.. Ingenol mebutate gel is a cost-effective therapy for the first-line treatment of AK from a Scottish NHS perspective.

Topics: Cost-Benefit Analysis; Cryotherapy; Diclofenac; Diterpenes; Dose-Response Relationship, Drug; Fluorouracil; Humans; Keratolytic Agents; Keratosis, Actinic; Models, Econometric; Quality-Adjusted Life Years; Recurrence; Salicylic Acid; Scotland; Treatment Outcome

The efficacy and safety of ingenol mebutate versus placebo have been proven in four randomized controlled trials (RCTs), although there is a lack of real-life studies corroborating such promises in routine clinical practices. In our study, we sought to describe real-life effectiveness, safety and regimen adherence among patients with multiple AKs on the face treated with ingenol mebutate and evaluate correlates of clinical outcomes in this population.. We reviewed the clinical charts of adult patients with multiple (≥3) AK grade I and II of the face and scalp, treated with ingenol mebutate from April 2014 to April 2015. All subjects received the medication according to ingenol mebutate standard of care.. We enrolled 88 patients during the study period and carried out 122 treatment cycles. The unadjusted lesion clearance rate per treated field was 81.3% and the average local skin reactions score at day 4 was 6.0 ± 2.8 (range: 0-18).. We observed an excellent rate (>99%) of adherence to ingenol mebutate. This was mirrored by the fact that our clinical outcomes broadly confirmed results obtained in RTCs. Our study showed that the efficacy and safety of ingenol mebutate observed in RCTs can be reliably translated in real-world practice.

Topics: Administration, Cutaneous; Adult; Diterpenes; Face; Female; Humans; Keratosis, Actinic; Male; Retrospective Studies; Scalp; Treatment Outcome

Actinic keratosis (AK) represents an emerging issue in the area of skin diseases which undergo high risk for developing squamous cell carcinoma (SCC). Recently, evidence has been accumulated that 3% diclofenac sodium and ingenol mubetate may efficiently counteract the development of progressive AK even if the pharmacoeconomic impact of such a treatment remains poorly defined. With the objective of assessing the efficacy of 3% diclofenac sodium versus ingenol mebutate, a comparative cost-efficacy analysis was performed between both pharmacological treatments. In the present analysis, data of efficacy of clinical studies were combined with information on the quality of life associated with AK lesions based on available literature data. Furthermore, the cost associated with the management of these lesions in Italy has been taken into account. To this purpose, we carried out a literature survey on the clinical and economic data among clinical reports available in Italy based on the assessment of related expenditure of public resources and their relationship with the subsequent health benefits.

Topics: Cost-Benefit Analysis; Diclofenac; Diterpenes; Humans; Italy; Keratosis, Actinic; Quality of Life; Treatment Outcome

Granuloma faciale (GF) is a rare chronic inflammatory dermatosis of unknown etiology, characterized by leukocitoclastic vasculitis usually occurring on the face. We report a case of 60-years-old man with 3 year history of multiple actinic keratoses (AK) and persistent asymptomatic erythematous papules and plaques located over his left temporal region and the cheek: histopathology was consistent with GF. Herein we describe the successful treatment of the lesion with ingenol mebutate 0.015% gel focusing on the clinical, dermoscopic and histopathological findings of GF both before and after treatment.

Topics: Administration, Cutaneous; Biopsy; Dermatologic Agents; Dermoscopy; Diterpenes; Facial Dermatoses; Gels; Granuloma; Humans; Keratosis, Actinic; Male; Middle Aged; Remission Induction; Skin; Treatment Outcome

Ingenol mebutate is a recently approved topical agent for the treatment of actinic keratosis. Its most common adverse effects are transient local skin reactions. We report a 63-year-old white man who presented with a red-brownish crusted plaque involving the dorsum of his nose and an eroded area on his lower lip, which appeared soon after topical application of ingenol mebutate gel. Clinical, histological and immunopathological features were consistent with a diagnosis of pemphigus vulgaris (PV). To our knowledge, this is the first report of relapse of PV after topical application of ingenol mebutate gel. The temporal relationship between the application of the drug and the outbreak of PV supports the involvement of this agent in triggering the disease. It is plausible that ingenol mebutate may have induced the disease by its action on the production of proinflammatory cytokines.

Topics: Administration, Topical; Cytokines; Desmoglein 1; Diterpenes; Genetic Predisposition to Disease; Humans; Keratinocytes; Keratosis, Actinic; Male; Middle Aged; Pemphigus; Recurrence; Treatment Outcome

We present the case of a 73-year-old male patient who had received a first renal transplant at 36 years and a second one at the age of 55 years. He is currently under immunosuppression with everolimus 2.5 mg/day and prednisone 5 mg/day. The patient presented with multiple actinic keratoses on both cheeks and the forehead and received treatment by ingenol mebutate 150 µg/g gel daily on 3 consecutive days on his right cheek and methyl aminolevulinate (MAL) photodynamic therapy activated by daylight (MAL-dPDT) on the forehead and the left cheek. MAL-dPDT treatment proved a feasible, repeatable, physician-directed method of treating field cancerization with limited morbidity for a period of 6 days. Treatment with ingenol mebutate gel was a feasible, possibly self-directed method of treating field cancerization with limited morbidity for 10 days in this immunosuppressed patient. Both treatments showed similar efficacy. At the time of treatment, the MAL daylight PDT ran at 3 times the cost of ingenol mebutate gel.

Topics: Aged; Aminolevulinic Acid; Antineoplastic Agents; Carcinogenesis; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Diterpenes; Face; Humans; Keratosis, Actinic; Kidney Transplantation; Male; Photochemotherapy; Photosensitizing Agents; Skin Neoplasms; Transplant Recipients

Ingenol mebutate induces strong inflammation after a single application already. This must be taken into account when prescribing the drug, as mistakes in the application may results in severe side effects. Here, we report the case of a 72-year-old woman who applied ingenol mebutate on the cheekbones and developed a pronounced conjunctivitis, needing topical corticosteroids. The treatment was intended for the actinic keratosis she had on the chest, and the regimen of 2 consecutive once daily applications of ingenol mebutate at 500 µg/g had been prescribed as registered. The inadvertent application on the thin skin of the cheekbones led to a pronounced inflammation. With topical steroids followed by fusidic acid, both conjunctivitis and skin inflammation resolved within a few days. The skin showed erythema for a few weeks, but after 3 months, the patient presented a perfectly smooth skin and was very happy with the cosmetic outcome. This suggests that the cheekbones are a sensitive site for ingenol mebutate, but that intense inflammation should not scare physician or patient, as clinical remission with excellent healing can still be expected.

Topics: Administration, Topical; Aged; Anti-Bacterial Agents; Antineoplastic Agents; Cheek; Conjunctivitis; Dermatologic Agents; Diterpenes; Female; Glucocorticoids; Humans; Keratosis, Actinic

Patients suffering from chronic lymphocytic leukemia often develop actinic keratosis (AK) and squamous cell carcinoma in sun-exposed areas. In these particular patients, who have a suboptimal immune function, AK treatment can be particularly challenging. We report the case of a patient who failed to respond to most AK treatments, including 5-FU, imiquimod and photodynamic therapy, but responded to ingenol mebutate. We started with 3 applications of 150 μg/g (registered treatment of the scalp) and also 2 applications of 500 μg/g (registered in for trunk and extremities). Both treatments were well tolerated, but only the latter led to significant clinical success. This suggests that 500 μg/g of ingenol mebutate may represent an interesting therapeutic option in patients with mild immunosuppression.

Topics: Aged; Antineoplastic Agents; Carcinogenesis; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Diterpenes; Humans; Keratosis, Actinic; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Scalp; Skin Neoplasms

Ingenol mebutate (IM) is a topical pharmacotherapy approved in Switzerland since 2012 for treating non-hypertrophic, non-hyperkeratotic actinic keratosis (AK). We report 2 cases with off-label use of IM. The first case of bowenoid AK was treated with 150 μg IM for 3 consecutive days with an almost complete clinical remission of the lesion. The second case of Bowen's disease was treated with 500 μg IM for 2 consecutive days leading to complete clinical remission.

Topics: Administration, Cutaneous; Aged; Antineoplastic Agents; Bowen's Disease; Diterpenes; Eyelids; Female; Gels; Hand; Humans; Keratosis, Actinic; Male; Skin Neoplasms

The rapid and strong clinical efficacy of the first-in-class, ingenol mebutate, against actinic keratosis (AK) has resulted in its recent approval. We conducted the first comprehensive analysis of the cellular and molecular mode of action of topical ingenol mebutate 0.05% gel in both AK and uninvolved skin of 26 patients in a phase I, single-center, open-label, within-patient comparison. As early as 1 day after application, ingenol mebutate induced profound epidermal cell death, along with a strong infiltrate of CD4+ and CD8+ T-cells, neutrophils, and macrophages. Endothelial ICAM-1 activation became evident after 2 days. The reaction pattern was significantly more pronounced in AK compared with uninvolved skin, suggesting a tumor-preferential mode of action. Extensive molecular analyses and transcriptomic profiling of mRNAs and microRNAs demonstrated alterations in gene clusters functionally associated with epidermal development, inflammation, innate immunity, and response to wounding. Ingenol mebutate reveals a unique mode of action linking directly to anti-tumoral effects.. ClinicalTrials.gov NCT01387711.

Topics: Administration, Topical; Adult; Biomarkers; Cell Death; Cluster Analysis; Diterpenes; Epidermis; Gene Expression; Gene Expression Profiling; Humans; Immunity, Innate; Keratosis, Actinic; Leukocytes; MicroRNAs; RNA, Messenger

Ingenol mebutate (IngMeb) is an effective treatment for actinic keratosis. In this study, we hypothesized that repeated treatments with IngMeb may prevent progression of UV-induced photodamage, and that concurrent application of a corticosteroid may reduce IngMeb-induced local skin responses (LSR).. Hairless mice (n = 60; 3 groups of 20 mice) were irradiated with solar simulated ultraviolet radiation (UVR) throughout the study. Five single treatments with IngMeb were given at 4-week intervals (Days 21, 49, 77, 105, and 133). Clobetasol propionate (CP) was applied once daily for 5 days prior to each IngMeb application, as well as 6 h and 1 day post treatment. One week after IngMeb treatment No. 1, 3, and 5 (Days 28, 84, and 140), biopsies from four mice in each group were collected for histological evaluation of UV-damage on a standardized UV-damage scale (0-12). LSR (0-24) were assessed once daily (Days 1-7) after each IngMeb treatment.. IngMeb prevented progression of photodamage in terms of keratosis grade, epidermal hypertrophy, dysplasia, and dermal actinic damage with a lower composite UV-damage score on day 140 (UVR 10.25 vs. UVR+IngMeb 6.00, p = 0.002) compared to UVR alone. IngMeb induced LSR, including erythema, flaking, crusting, bleeding, vesiculation, and ulceration. Concurrent CP increased LSR (max LSR Tx 1-5: UVR+IngMeb+CP 3.6-5.5 vs. UVR+IngMeb 2.6-4.3) and provided better prevention of photodamage compared to IngMeb alone (Day 140: UVR+IngMeb 6.00 vs. UVR+IngMeb+CP 3.00 p < 0.001).. Repeated field-directed treatments with IngMeb prevent progression of cutaneous photodamage in hairless mice, while CP cannot be used to alleviate IngMeb-induced LSR. The findings suggest that IngMeb may potentially serve as a prophylactic treatment for UV-induced tumors.

Topics: Animals; Clobetasol; Disease Progression; Diterpenes; Female; Keratosis, Actinic; Mice, Hairless; Ultraviolet Rays

Topics: Administration, Cutaneous; Dermatologic Agents; Diterpenes; Female; Humans; Keratosis, Actinic; Male; Microscopy, Confocal; Tomography, Optical Coherence

Actinic keratosis, which is a potential precursor of squamous cell carcinoma, is a common skin condition in fair-skinned adults worldwide. Actinic keratosis may be treated with 'lesion-directed' approaches and/or 'field-directed' therapies, the latter of which include imiquimod, diclofenac and 5-fluorouracil. The topical formulation of ingenol mebutate, which is a protein kinase C inhibitor derived from the sap of the plant Euphorbia peplus, is the newest addition to the existing arsenal of field-directed treatments. Its mechanism of action primarily involves the induction of primary necrosis and initiation of an inflammatory response characterized by the migration of neutrophils to the treated area. The gel is available in two strengths: 150 micrograms/g to be applied to lesions on the face and scalp once daily for 3 consecutive days and 500 micrograms/g for application to lesions on the trunk and extremities for 2 consecutive days. Clinical studies have supported claims of the convenience of its application and efficacy; however, the literature provides scant information on comparative efficacy rates and side-effect profiles.

Topics: Administration, Topical; Antineoplastic Agents; Diterpenes; Humans; Keratosis, Actinic; Plant Extracts; Protein Kinase Inhibitors

Cumulative exposure of the skin to ultraviolet radiation promotes mutation in keratinocytes and their abnormal growth led to the formation of scaly lesions, called actinic keratoses (AKs). Its incidence is growing at an emerging rate, becoming a worldwide problem especially for occupational ultraviolet (UV) rays exposure. Detectable lesions are often associated with field changes, where the surrounding skin is altered and subclinical lesions may be present. Thus, a field-directed therapy, such as topical treatment, should be preferred for the prevention of invasive cancer development. A retrospective analysis was made, evaluating the efficacy of ingenol-mebutate gel, using a novel device the 3D in vivo optical skin Imaging (Antera 3D, Miravex, Ireland).. We included all patients with multiple non-hypertrophic Aks, to whom it was prescribed ingenol-mebutate gel, applied at the dosages of 0.015 for lesions in the scalp/face (for 3 consecutive days) and at the dosage of 0.05% for lesions in the trunk and/or extremities (for 2 consecutive days).. A reduction of the lesions and of median hemoglobin levels, after a follow-up of 60 days, was observed in 100% of patients.. Ingenol mebutate gel, the last topical molecule appeared in the Italian market showed its efficacy using Antera 3D also in terms of hemoglobin reduction. Therefore, this camera could be considered an useful tool for the identification of the area to be treated and for therapeutic follow-up.

Topics: Administration, Topical; Adult; Aged; Diterpenes; Female; Humans; Imaging, Three-Dimensional; Keratosis, Actinic; Male; Middle Aged; Retrospective Studies; Treatment Outcome

Ingenol mebutate gel is a topical field treatment of actinic keratosis (AK). One of several proposed mechanisms of action for ingenol mebutate is induction of cell death in proliferating keratinocytes, suggesting a preferential action on AKs rather than healthy skin. Local skin reactions (LSRs) during 2 sequential 4-week cycles of AK treatment with ingenol mebutate gel 0.015% on the face or scalp were evaluated to test the hypothesis that reapplication of the study product would produce lower LSR scores than during the first treatment cycle. In this unblinded study, 20 participants with AKs on the face or scalp were treated with ingenol mebutate gel 0.015% once daily for 3 days in 2 sequential 4-week cycles. Composite LSR scores were evaluated during both cycles. The composite LSR score during the second cycle was found to be significantly lower than the first cycle (P=.0002). The proportion of participants who experienced LSRs in the second treatment cycle was less than the first cycle. Ingenol mebutate gel 0.015% may cumulatively reduce the burden of sun-damaged skin over 2 treatment cycles by targeting and removing transformed keratinocytes.

Topics: Administration, Topical; Aged; Aged, 80 and over; Diterpenes; Female; Gels; Humans; Keratosis, Actinic; Male; Middle Aged; Treatment Outcome

Topically applied ingenol mebutate (IngMeb) is approved for field-treatment of actinic keratosis and is currently being investigated for treatment of non-melanoma skin cancer (NMSC). Ablative fractional lasers (AFXLs) generate microscopic ablation zones (MAZs) in the skin, which may help induce a deep penetration needed for effective treatment of NMSC. Using Franz diffusion cells, uptake and bio-distribution were investigated over 21 h in intact (n = 9) and AFXL-exposed porcine skin (n = 58). A 2940-nm fractional Er:YAG laser generated intraepidermal (11.2 mJ/MAZ; 66 μm deep, 177 μm wide) and intradermal (128 mJ/MAZ; 570 μm deep, 262 wide) MAZ's with 16, 97, and 195 MAZs/cm(2). Surface ablation densities corresponded to 0.5, 2.5, and 5 % for intraepidermal MAZs, and corresponded to 1, 5, and 10.5 % for intradermal MAZs. Liquid-chromatography-mass-spectrometry quantified deposition of IngMeb in stratum corneum, epidermis, dermis, and receiver chamber. In intact skin, IngMeb readily penetrated to the epidermal layer (1,314 ng, 41 % of the applied IngMeb), while dermal deposition was limited (508 ng, 16 %). In AFXL-exposed skin, a profound dermal deposition of IngMeb was achieved, while less accumulated in SC and epidermis. Uptake depended entirely on laser density; increasing coverage from 0 % to 0.5 %, 1 %, 2.5 %, 5 %, and 10.5 % enhanced dermal uptake 1.6-, 2.1-, 3.1-, 3.4-, and 3.9-fold, respectively (p < 0.0001). Channel depth did not influence drug uptake; at 5 % density, dermal deposition with intraepidermal and intradermal MAZs was analogous (1801 vs. 1744; p = 0.447). In conclusion, IngMeb readily distributes to superficial layers of intact skin, whereas dermal uptake is limited. Independent of channel depth, AFXL enhances dermal drug deposition, providing for customized topical delivery and potential use of IngMeb for treatment of NMSC.

Topics: Administration, Cutaneous; Animals; Chromatography, Liquid; Diterpenes; Drug Delivery Systems; Humans; Keratosis, Actinic; Laser Therapy; Lasers, Solid-State; Mass Spectrometry; Skin; Skin Absorption; Swine; Tissue Distribution

Cost-utility assessment of first-line actinic keratosis (AK) treatments for max 25 cm2 AK field.. A probabilistic, 2-year decision tree model was used to assess costs, quality-adjusted life-years (QALY), incremental cost-effectiveness ratio (ICER), cost-effectiveness efficiency frontier, cost-effectiveness acceptability frontier (CEAF), and expected value of perfect information (EVPI) of AK treatments from the Finnish health care payer perspective with 3% discounting per annum. In the model, the first-line AK treatment resulted in complete clearance (CC) or non-CC with or without local skin responses (LSR), or AK recurrence. Non-CC AK was treated with methyl aminolevulinate+photodynamic therapy (MAL+PDT), and AK recurrence was retreated with the previous effective treatment. Costs included primary and secondary health care, outpatient drugs, and LSR management. QALYs were assessed with the EuroQol (EQ-5D-3L). Result robustness was assessed with sensitivity analyses.. The mean simulated per patient QALYs (costs) were 1.526 (€982) for MAL+PDT, 1.524 (€794) for ingenol mebutate gel (IngMeb) 0.015% (3 days), 1.522 (€869) for IngMeb 0.05% (2 days), 1.520 (€1062) for diclofenac 3% (12 weeks), 1.518 (€885) for imiquimod 3.75% (6 weeks), 1.517 (€781) for imiquimod 5% (4/8 weeks), and 1.514 (€1114) for cryosurgery when treating AK affecting any body part. IngMeb 0.015% was less costly and more effective (dominating) than other AK treatments indicated for face and scalp area with the exception of imiquimod 5% for which the ICER was estimated at €1933/QALY gained and MAL+PDT, which had an ICER of €82,607/QALY gained against IngMeb 0.015%. With willingness-to-pay €2526-18,809/QALY gained, IngMeb 0.015% had >50% probability for cost-effectiveness on the CEAF. IngMeb 0.05% dominated AK treatments indicated for trunk and extremities. EVPIs for face and scalp (trunk and extremities) analyses were €26 (€0), €86 (€58), and €250 (€169) per patient with the willingness-to-pay of €0, €15,000, and €30,000 per QALY gained, respectively.. IngMebs were cost-effective AK treatments in Finland.. LEO Pharma.

Topics: Cost-Benefit Analysis; Dermatologic Agents; Diterpenes; Finland; Health Care Costs; Humans; Keratosis, Actinic; Quality-Adjusted Life Years; Treatment Outcome

Cryotherapy is the most common treatment for actinic keratosis, but its effect is limited to individual lesions. Several topical drugs, however, are available that, in addition to treating individual actinic keratoses, target field cancerization and thereby act on subclinical lesions. Examples are 5-fluorouracil, imiquimod, diclofenac, and ingenol mebutate. We report on 17 patients with actinic keratoses treated with ingenol mebutate and describe our findings on treatment effectiveness, adherence, and tolerance. Complete and partial response rates were 35% and 53%, respectively. Ninety-four percent of patients fully adhered to treatment and 18% developed severe local reactions. Ingenol mebutate is an effective treatment for actinic keratosis. Although it has a similar rate of local reactions to other treatments available for actinic keratosis, its short treatment regimen favors better adherence.

Topics: Aged; Aged, 80 and over; Combined Modality Therapy; Cryotherapy; Diterpenes; Drug Eruptions; Drug Evaluation; Facial Dermatoses; Female; Humans; Keratosis, Actinic; Male; Medication Adherence; Middle Aged; Remission Induction; Retrospective Studies; Scalp Dermatoses; Treatment Outcome

Actinic keratoses (AKs) are defined as cutaneous areas of atypical squamous transformation that are regarded as an early step in the continuum of alterations leading from normal skin to invasive and metastatic squamous cell carcinoma (SCC). AKs are classified as precancerous lesions by some authors and in situ SCC by others. The rate of evolution of a given AK to an invasive SCC has been estimated as 0·075-0·096% per lesion per year. These rates are similar to those estimated for gynaecological intraepithelial neoplasia. We describe two cases of SCC with rapid onset that developed after the application of ingenol mebutate gel for the treatment of AKs.

Topics: Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Dermatologic Agents; Diterpenes; Drug Eruptions; Facial Dermatoses; Facial Neoplasms; Female; Head and Neck Neoplasms; Humans; Keratosis, Actinic; Skin Neoplasms

Actinic keratoses (AKs) are premalignant skin lesions caused by cumulative ultraviolet-light exposure that may progress to invasive squamous cell carcinoma (SCC). As the clinical presentation of AKs varies widely, only a histopathologic analysis of a biopsied sample can eliminate or confirm a diagnosis of invasive SCC. Reducing the burden of AK with a combination of lesion-directed and field-directed treatments may help to identify persistent, suspicious lesions that require further evaluation. We present 10 cases of SCC that were identified and histologically confirmed in 7 patients after complete or substantial clearance of AKs by sequential treatment of sun-damaged skin with cryosurgery and ingenol mebutate.

Topics: Aged; Antineoplastic Agents; Biopsy; Carcinoma, Squamous Cell; Combined Modality Therapy; Cryosurgery; Diterpenes; Facial Neoplasms; Female; Gels; Humans; Keratosis, Actinic; Male; Middle Aged; Scalp; Skin; Skin Neoplasms

Topics: Aminoquinolines; Antineoplastic Agents; Combined Modality Therapy; Cryotherapy; Curettage; Cyclooxygenase Inhibitors; Diclofenac; Diterpenes; Evidence-Based Medicine; Fluorouracil; Humans; Imiquimod; Keratosis, Actinic; Laser Therapy; Lasers, Gas; Photochemotherapy

Topics: Aged, 80 and over; Antineoplastic Agents; Diterpenes; Gels; Humans; Keratosis, Actinic; Male; Scalp Dermatoses; Skin Aging

Topics: Administration, Topical; Diterpenes; Humans; Keratosis, Actinic

Ingenol 3-benzoates were investigated with respect to chemical stability, pro-inflammatory effects, cell death induction and PKCδ activation. A correlation between structure, chemical stability and biological activity was found and compared to ingenol mebutate (ingenol 3-angelate) used for field treatment of actinic keratosis. We also provided further support for involvement of PKCδ for induction of oxidative burst and cytokine release. Molecular modeling and dynamics calculations corroborated the essential interactions between key compounds and C1 domain of PKCδ.

Topics: Antineoplastic Agents; Benzoates; Cell Death; Cytokines; Diterpenes; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Keratosis, Actinic; Models, Molecular; Molecular Docking Simulation; Molecular Structure; Protein Kinase C-delta; Protein Kinase Inhibitors; Skin Neoplasms; Structure-Activity Relationship

Ingenol mebutate gel is a topical field treatment for actinic keratosis (AK) approved for a 2- or 3-day duration of application.. This chart review examined the efficacy and safety of ingenol mebutate gel for treatment of AK in patients from a community dermatology practice.. A retrospective chart review was conducted for all patients with AK treated with ingenol mebutate gel.. A total of 135 patients with a prolonged history of AK were treated from April 2012 to January 2013. The majority received cryosurgery to all visible lesions, followed 2 weeks later by ingenol mebutate; areas treated with ingenol mebutate were typically >25 cm² in size. Local skin reactions, consisting of mild to moderate erythema and flaking/scaling, were significantly improved by 1 week after peak inflammation and were not treated in most patients. At 1 to 4 months after treatment of AKs on the face, nearly all patients (99%) achieved ≥75% clearance of baseline and emergent AKs. After treatment of AKs on the scalp or forearm and/or hand, >80% of patients demonstrated ≥75% clearance.. This was a retrospective chart review of patients from a single practice.. Ingenol mebutate is an effective, well-tolerated topical treatment for AK in sun-damaged skin.

Topics: Administration, Cutaneous; Adult; Aged; Aged, 80 and over; Combined Modality Therapy; Cryosurgery; Dermatologic Agents; Diterpenes; Female; Gels; Humans; Keratosis, Actinic; Male; Middle Aged; Retrospective Studies; Time Factors; Treatment Outcome

Ingenol mebutate is the active ingredient in Picato® a new drug for the treatment of actinic keratosis. A number of derivatives related to ingenol mebutate were prepared by chemical synthesis from ingenol with the purpose of investigating the SAR and potency in assays relating to pro-inflammatory effects (induction of PMN oxidative burst and keratinocyte cytokine release), the potential of cell death induction, as well as the chemical stability. By modifications of the ingenol scaffold several prerequisites for activity were identified. The chemical stability of the compounds could be linked to an acyl migration mechanism. We were able to find analogues of ingenol mebutate with comparable in vitro properties. Some key features for potent and more stable ingenol derivatives have been identified.

Topics: Antineoplastic Agents; Apoptosis; Cell Line; Diterpenes; Humans; Interleukin-8; Keratinocytes; Keratosis, Actinic; Leukocytes, Mononuclear; Melanoma; Oxidative Stress; Reactive Oxygen Species; Skin Neoplasms; Structure-Activity Relationship; Tumor Necrosis Factor-alpha

Topics: Aminoquinolines; Carcinoma, Squamous Cell; Case Management; Clinical Trials as Topic; Cryosurgery; Diagnosis, Differential; Diclofenac; Disease Management; Disease Progression; Diterpenes; Fluorouracil; Humans; Imiquimod; Italy; Keratosis, Actinic; Laser Therapy; Neoplasms, Radiation-Induced; Photochemotherapy; Practice Guidelines as Topic; Skin Neoplasms; Sunscreening Agents; United Kingdom; United States; Watchful Waiting

Topics: Diterpenes; Drug Approval; Euphorbia; History, 18th Century; History, 21st Century; Humans; Keratosis, Actinic; Medicine, Traditional; Plant Extracts; United States; United States Food and Drug Administration

Picato (ingenol mebutate) was recently marketed for local treatment of actinic keratosis (AK). Compared to alternative creams and gels, Picato is a quick and efficient treatment, which is applied for only two to three days. A patient developed a bullous reaction to the gel after a single application. Picato 150 microg/g was applied in the evening to AK in the patient's forehead. The patient experienced a headache during the night, and the next morning big, thin-walled bullae had developed in the treated area.

Topics: Administration, Cutaneous; Aged; Dermatologic Agents; Diterpenes; Female; Forehead; Gels; Humans; Keratosis, Actinic; Skin Diseases, Vesiculobullous

Topics: Carcinoma, Squamous Cell; Diterpenes; Humans; Keratosis, Actinic; Ultraviolet Rays

Actinic keratosis (AK) is a common ultraviolet light-induced skin lesion found on sun-exposed skin areas generally in older, fair-skinned people. It is part of a disease continuum observed in photodamaged skin that may lead to invasive squamous cell carcinoma. The presence of AK is associated with an increased risk of all skin cancers, as it is visible evidence of the carcinogenic effects of cumulative ultraviolet exposure. AKs are treated with lesion- and field-directed methods. Field-directed methods treat both the visible and subclinical lesions present in photodamaged skin, but treatment regimens are often lengthy and associated with poor tolerability because of vigorous local inflammatory reactions. Ingenol mebutate gel was recently approved by the Food and Drug Administration for topical treatment of AK. It induces cell death preferentially in transformed keratinocytes and promotes an inflammatory response that kills remaining tumor cells. In human studies, ingenol mebutate achieved high clearance rates of AK on the trunk or extremities and face or scalp after once-daily application for 2 or 3 consecutive daily treatments, when measured by complete or partial clearance of lesions. The localized inflammatory skin responses were generally mild to moderate and resolved in approximately 2 weeks on the face or scalp and 4 weeks on the trunk or extremities.

Topics: Aged; Clinical Trials as Topic; Diterpenes; Female; Humans; Keratinocytes; Keratosis, Actinic; Male; Skin; Skin Neoplasms

Skin cancer is the most prevalent cancer worldwide and is primarily caused by chronic UV exposure. Here, we describe the topical field-directed treatment of SKH1/hr mice with UVB-damaged skin with ingenol mebutate, a new topical drug shown to be effective for the treatment of actinic keratosis (AK). Application of 0.05% ingenol mebutate gel to photo-damaged skin resulted in a ≈70% reduction in the number of skin lesions that subsequently emerged compared with placebo treatment. Ingenol mebutate treatment also reduced the number of mutant p53 keratinocyte patches by ≈70%. The treatment resulted in epidermal cell death, acute inflammation, recruitment of neutrophils, hemorrhage, and eschar formation, all of which resolved over several weeks. Ingenol mebutate field-directed treatment might thus find utility in the removal of subclinical precancerous cells from UV-damaged skin. Field-directed treatment may be particularly suitable for patients who have AKs surrounded by UV-damaged skin.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Disease Models, Animal; Diterpenes; Dose-Response Relationship, Drug; Keratinocytes; Keratosis, Actinic; Male; Mice; Mice, Hairless; Mutation; Neoplasms, Radiation-Induced; Precancerous Conditions; Skin; Skin Neoplasms; Tumor Suppressor Protein p53; Ultraviolet Rays

The incidence of nonmelanoma skin cancer continues to increase. While surgical excision remains the mainstay of treatment, growing demand from patients for effective, tissue-sparing approaches with good cosmetic results has led to the development of novel therapeutic agents. Several studies have reported on the safety and efficacy of topical ingenol mebutate gel, a derivative of the plant Euphorbia peplus, in the treatment of actinic keratosis and superficial basal cell carcinoma. An understanding of the history, mechanism of action, and recent trial evidence for this emerging therapy can assist physicians in counseling patients on available treatment options and in selecting appropriate therapy.

Topics: Administration, Cutaneous; Antineoplastic Agents, Phytogenic; Carcinoma, Basal Cell; Diterpenes; Euphorbia; Humans; Keratosis, Actinic; Skin Neoplasms

Topics: Administration, Cutaneous; Diterpenes; Euphorbia; Gels; Humans; Keratosis, Actinic

Ingenol mebutate is a diterpene ester derived from the plant Euphorbia peplus and is FDA approved for the topical treatment of actinic keratoses (AK). Shown to be efficacious with as little as a 3-day trial, this compound is being further tested for the topical treatment of other nonmelanoma skin cancers with promising preclinical data. In an effort to elucidate the molecular mechanism of this novel drug, Stahlhut et al. (2012) suggest a role for calcium and apoptosis. Further studies are needed to evaluate the intracellular mechanisms of ingenol mebutate-mediated cytotoxicity. Additionally, studies such as this not only shed light on the mechanism of ingenol mebutate and its derivatives, but also pave the way for evaluating the involvement of the immune system in eliminating drug-treated cells and tissues. This has important implications for the development of novel topical immune modulatory products and the field of topical immunotherapy.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Diterpenes; Humans; Immunologic Factors; Keratosis, Actinic; Signal Transduction; Skin Neoplasms

Topics: Aminoquinolines; Antineoplastic Agents; Carcinoma, Squamous Cell; Cryotherapy; Diterpenes; Humans; Imiquimod; Keratosis, Actinic; Photochemotherapy; Skin Neoplasms