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Background Anogenital warts (AGWs) are a common therapeutic challenge. All therapies are associated with burning, pain, and frustrating high rate of recurrence. The search for a new alternative continues. Recently, a diterpene ester extracted from the Euphorbia peplus plant (ingenol mebutate [IM]) has been shown to possess activity against AGWs. Objective This study aimed to compare and evaluate the therapeutic efficacy and safety of topical 0.05% ingenol gel with another herbal extract medication (topical 25% podophyllin solution) in treatment of AGWs. Methods This was a comparative single blinded nonrandomized, 2-arm trial of ingenol 0.05% gel versus podophyllin solution 25% administered up to 6 times to patients with AGWs. To evaluate the therapeutic efficacy, the complete clearance rate and recurrence rate were assessed 1 and 12 weeks after last treatment, respectively. Safety was assessed by occurrence and severity of pain and local skin reaction (LSR). Results Of 31 and 36 patients in the IM group and podophyllin group who completed the study, initial complete resolution was observed in 20 (64.5%) and 14 (38.9%) patients, respectively (P = 0.03). The initial clearance was faster in the IM group (2.00 ± 0.91 weeks) compared with the podophyllin group (4.21 ± 1.05 weeks, P = 0.00). After 3 months, recurrence was seen in 13 (65.0%) of 20 patients in the IM group and 6 (42.8%) of 14 in the podophyllin group (P = 0.20). The number of patients with complete resolution after 3 months was not different between the 2 groups (7/31 in the IM group and 8/36 in the podophyllin group, P = 0.97). The mean ± SD severity scores for LSR and pain in the IM group were 6.65 ± 1.76 and 6.13 ± 2.57, respectively, which was significantly higher than their scores (3.39 ± 1.57 and 2.58 ± 1.38) in the podophyllin group (P = 0.00). Conclusion Ingenol mebutate 0.05% gel is effective as podophyllin 25% solution in treating AGWs, with further benefit of being much more rapid. However, high recurrence rate, sever pain, and LSR limit its use.

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.

Introduction Actinic keratosis is a common skin disease that occurs in response to prolonged exposure to ultraviolet radiation. This problem affects up to 60% of the population over 40 years of age. Actinic keratosis is considered to be a precancerous lesion leading to squamous cell carcinoma (SCC). The new therapeutic option for the treatment of actinic keratosis is ingenol mebutate gel (0.015%, 0.05%). Aim Retrospective evaluation of response and potential side effects of ingenol mebutate treatment in clinical practice. Material and methods Eight patients with actinic keratosis lesions on the face or scalp self-applied a 0.015% gel for 3 consecutive days on the 25 cm2 marked area. They were assessed at baseline and on day 4, 7, 14 and 57. Results All patients on day 57 presented a complete absence of AK lesions in the area of ingenol mebutate application. No adverse events were observed. Conclusions Our study shows that ingenol mebutate is highly efficacious field treatment for actinic keratosis.

Background and importance Ingenol mebutate was granted a marketing authorisation from European Medicines Agency (EMA) to treat actinic keratosis. On 30 April 2020, due to an increased risk in provoking skin cancer in treated patients compared with imiquimod, the EMA withdrawn it after a safety data review. The final results of the 3 year safety study (NCT01926496) in 484 patients showed that, among skin malignancies, squamous cell carcinoma (SCC) had a higher incidence with ingenol mebutate gel compared with imiquimod (3.3% versus 0.4% of patients). Aim and objectives This study aimed to evaluate the safety issue (signal) of increased occurrence of skin malignancy (eg, SCC of the skin) during therapy with ingenol mebutate by mining of the FDA Adverse Event Reporting System (FAERS) database. Material and methods By querying the FAERS database, we searched for cases of SCC associated with ingenol mebutate using the following MedDRA preferred terms (PTs) ‘squamous cell carcinoma of skin’, ‘skin squamous cell carcinoma metastatic’ and ‘skin squamous cell carcinoma recurrent’. With a contingency table, we computed the PRR to evaluate the strength of association between SCC and ingenol mebutate. Results We found the following co-occurrence data: ingenol mebutate/SCC (DE)=90 reports, ingenol mebutate/other ADR (De)=5128, other drugs/SCC (dE)=2882 and other drugs/other ADR (de)=13 899 084 from 2012 to 2020. The two by two contingency table showed a value for PRR of 44.4105 (95% CI 33.332 to 59.1711, p 85 years (7.7%) and not specified (12.2%); 75.6% were men and 23.3% women. Conclusion and relevance Disproportionality analysis showed that the ingenol mebutate–SCC pair was reported more often than expected. Based on this statistical association, our data confirmed the safety signal evaluated by the EMA that led to the withdrawal of ingenol mebutate from the EU market. In addition, it raises the question of why the FDA has not revoked the marketing authorisation of the drug in the USA. References and/or acknowledgements https://clinicaltrials.gov/ct2/show/NCT01926496 https://www.ema.europa.eu/en/documents/referral/picato-article-20-referral-risks-picato-actinic-keratosis-outweigh-benefits_en.pdf Conflict of interest No conflict of interest

Patients' perspectives on actinic keratosis treatments may have an impact on treatment adherence and, therefore, therapeutic outcomes. We performed a systematic review to assess patients' perspectives of topical, field‐directed treatments for actinic keratoses. A literature search was conducted, and 14 studies were identified encompassing 4433 patients. Only four studies were focused on face and/or scalp, which are the locations that typically impact patients' quality of life. Four studies were clinical trials. One study utilized a validated patient‐reported outcomes (PRO) instrument specifically developed for actinic keratosis. In general, treatment adherence and patient satisfaction were better with shorter‐duration treatment regimens such as ingenol mebutate gel. Imiquimod improved quality of life in one study but not in another. No data was available on topical piroxicam. The findings underscore the need for effective and well‐tolerated, short‐duration topical treatment for actinic keratosis.

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.

Two round tables involving experts were organized in order to reach a consensus on the management of patients with actinic keratosis (AK). In the first, seven clinical questions were selected and analyzed by a systematic literature review, using a Population, Intervention, Control, and Outcomes framework; in the second, the experts discussed relevant evidences and a consensus statement for each question was developed. Consensus was reached among experts on how to best treat AK patients with respect to different clinical scenarios and special populations. Lesion-directed treatments are preferred in patients with few AKs. Patients with multiple AKs are challenging, with more than one treatment usually needed to achieve complete lesion clearance or a high lesion response rate, therapy should be personalized, based on previous treatments, patient, and lesion characteristics. Methyl aminolevulinate-PDT, DL (day light) PDT, and imiquimod cream were demonstrated to have the lowest percentage of new AKs after post treatment follow-up. For IMQ 5% and 3.75%, a higher intensity of skin reactions is associated with higher efficacy. Photodynamic therapy (PDT) is the most studied treatment for AKs on the arms. Regular sunscreen use helps preventing new AKs. Oral nicotinamide 500 mg twice daily, systemic retinoids and regular sunscreen use were demonstrated to reduce the number of new squamous cell carcinomas in patients with AKs. Limited evidence is available for the treatment of AKs in organ transplant recipients. There is no evidence in favor or against the use of any of the available treatments in patients suffering from hematological cancer.

Background: Mycosis Fungoides (MF) is the most frequent type of the primary cutaneous NK/T-cell lymphomas. Ingenol mebutate (IM) displays in vitro pro-apoptotic properties on neoplastic lymphocytes. Objectives: To evaluate the efficacy and safety of IM gel as topical treatment for MF. Materials and Methods: Ten male patients with longstanding classic type MF (n=9) and follicular MF (FMF; n=1), T2bN0M0B0, stage Ib, resistant to systemic methotrexate or acitretin therapies for at least 3 months, were included in this pilot study. In these patients, 11 target patch/plaque stage lesions with an area ≤ 25 cm2 were selected for IM therapy (0,05%, 2 weekly applications). The primary endpoint was the improvement of the CAILS scores. Biopsies were performed before and after treatment from 10 target lesions. Relapse rates were evaluated at 6 months. Results: The mean CAILS score of treated target lesions was reduced by 58.2%. The mean erythema, scaling and plaque elevation scores were improved by 73.6%, 93.9% and 97.9% (p Conclusion: IM gel warrants further investigation and development as a potential topical treatment for localized patch/plaque stage MF and FMF.

Actinic keratoses (AKs) develop as a consequence of chronic ultraviolet (UV) exposure and exist on a continuum with squamous cell carcinoma (SCC). As one of the most common conditions treated by dermatologists, AK places a significant burden on patients and the healthcare system. A range of treatments are used, including topical treatments that target the visible and subclinical lesions. The goal of such therapies is to achieve complete clearance of AKs and eliminate the risk of progression to SCC. Robust meta-analyses of trial data can provide valuable information for the optimal management of AK and cost-effectiveness evaluations of topical treatments, such as ingenol mebutate gel and diclofenac. These outcomes can facilitate prescribing physicians’ decisions and shape therapeutic guidelines. Peer-reviewed meta-analysis publications and treatment guidelines favoured ingenol mebutate efficacy over diclofenac and the relative cost-effectiveness of ingenol mebutate. We discuss and critique recent evidence, from a cost-effectiveness analysis of 3% diclofenac sodium and ingenol mebutate in the treatment of AK in Italy, which has challenged this view.

Elena Campione,1 Monia Di Prete,1 Laura Diluvio,1 Luca Bianchi,1 Augusto Orlandi2 1Department of Dermatology, 2Department of Pathology, University of Rome Tor Vergata, Rome, Italy Abstract: Actinic keratosis (AK) is considered as superficial squamous cell carcinoma. Chronic sun exposure plays a central role in its pathogenesis. In particular, ultraviolet B radiation causes direct damage to the DNA, producing pyrimidine dimers that suppress the protective role of p53. Other risk factors include advanced age, male sex, and fair skin type. Even some drugs used for treating blood hypertension, such as thiazide diuretics, can increase the risk of developing AK. Their photosensitizing action seems to be connected with reactive oxygen species production. We report our experience on ten patients affected by multiple AK, in therapy with thiazide diuretics, treated by ingenol mebutate gel. AK was clinically and dermoscopically evaluated at baseline and after 30 days from the beginning of the treatment. Moreover, patients were screened for vitamin D3 values and reported a general hypovitaminosis status. To our knowledge, we report for the first time the efficacy of ingenol mebutate gel in this group of patients, particularly at risk of developing AK. Keywords: anticancer agents, antitumor activity, cancer cells, skin precancerous lesion

The incidence of nonmelanoma skin cancer continues to increase. Surgical excision remains the best choice of treatment but the demand of patients is to have tissue-sparing approaches with good cosmetic results; these aims led to the development of novel therapeutic agents such as topical ingenol mebutate gel. We report the successful treatment with ingenol mebutate gel 0.05% of three pigmented basal cell carcinomas. Lesions were evaluated by dermoscopy and confocal microscopy before, during and after the treatment.

B ackground : Actinic keratosis (AK) represents a risk of progression to squamous cell carcinoma. Ingenol mebutate gel is a novel therapeutic option for field-directed treatment. O bjectives : 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. M ethods : 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. Results: 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. S tudy limitations : Calculation of composite local skin reaction score performed only on the fourth day. C onclusions : 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.

Background/Objective Ingenol mebutate gel is approved for actinic keratosis field therapy, but little has been published as a treatment of basal cell carcinoma (BCC). Our objective is to characterise the histopathological changes and the infiltrating cell populations to better understand its mechanism of action. Methods Sixteen patients with various BCC subtypes were prospectively evaluated and treated once daily for two consecutive days with ingenol mebutate gel 0.05% under occlusion. Patients were randomised to two arms: the first arm was biopsied between the third and the tenth day after treatment initiation ('early immune response'), and the second arm was biopsied at day 30 after treatment initiation ('late immune response'). The immunopathology was evaluated by immunohistochemistry: anti‐CD3, anti‐CD4, anti‐CD8, anti‐CD20, anti‐CD56, anti‐CD68, anti‐Bcl‐2, anti‐CASP3, anti‐FoxP3, anti‐GrzB and anti‐TIA‐1. Results Ten BCCs were in complete remission after 2 years of follow‐up. The early immune response was characterised by a quick recruitment of T lymphocytes, macrophages and natural killer cells. At later time‐points, T‐regulatory cells and some pro‐apoptotic markers were detected. Treatment‐related adverse events were described. Conclusion Ingenol mebutate gel produces a transient immuno‐inflammatory response and an important necrosis reaction in BCCs. Larger studies will be required to determine the maximum effective tolerated dose of ingenol mebutate gel for BCC. This was an investigator-initiated study funded by LEOPharma. The design of the study and analysis and inter-pretation of study results are exclusive responsibility ofinvestigators. Work was supported by IRBLleida Biobank (B.0000682) and PLATAFORMA BIOBANCOS (PT13/0010/0014). We would like to thank Lidia Rodriguez, Scien-tific Affairs LEO Pharma SA for support and medicalwriting

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.

Background 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. Objectives 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. Methods Patients with ≥5 Olsen II AKs in a 25 cm2 area of the scalp and face were enrolled and randomized to one of the treatment choices. Number of AKs and cumulative area were assessed before and after treatment. Dermoscopy and HFUS were performed on a single AK and surrounding photo-damaged skin in the treatment area. Results 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. Conclusions 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.

Miriam S Bettencourt1,2 1Advanced Dermatology and Cosmetic Surgery, Henderson, 2Department of Dermatology, University of Nevada, LasVegas,NV,USA Background: Basal cell carcinoma (BCC) is the most common cancer in Caucasians. Surgical approaches are the most widely used and effective treatment strategies for well-defined BCC. However, for patients with low-risk, superficial BCCs (sBCCs), medical therapy may be a treatment option. In this small case series, we describe our experience in using topical treatment with ingenol mebutate gel, 0.05%, for patients who refused surgical treatment for sBCC. Methods: We conducted a retrospective chart review of seven patients from our community dermatology practice for whom sBCC was treated with ingenol mebutate. The chart review extracted information on demography, dermatologic history, and prior treatment for actinic keratosis or skin cancer. Summary of the treatment outcome with ingenol mebutate included the size and location of the sBCCs, description of administration, local skin reactions, adverse events, and efficacy. Results: Histopathologic analysis of a shave biopsy sample of suspicious lesions on the trunk confirmed nine sBCCs: a single sBCC in five patients and two well-separated lesions in each of the other two patients. Patients were treated at 10 to 14 days after shave biopsy; biopsy sites were not required to be fully healed. Lesions were either occluded using a standard adhesive bandage (n=6) or not occluded (n=3). All patients experienced local skin reactions that began on day 1 or 2 of treatment, peaked on days 2 to 7, and were largely resolved at 2 weeks. All sBCCs were clinically resolved on short-term follow-up at 2 to 4 weeks. Repeat biopsy of six lesion sites in four patients at 3 or 4 months confirmed histologic clearance. There were no clinically suspicious lesions in any patients at subsequent follow-up evaluations at 3-month intervals. The longest follow-up to date has been 14 months. Conclusion: Ingenol mebutate gel, 0.05%, was efficacious and well tolerated for the treatment of biopsy-confirmed sBCCs on the trunk in seven patients. Keywords: superficial basal cell carcinoma, ingenol mebutate, nonsurgical treatment, local skin reaction

Introduction A relatively novel application for dermoscopy and reflectance confocal microscopy (RCM) is their use in the monitoring of topical treatment response for non-melanoma skin cancer. Actinic keratosis (AK) is the early phase of a multistep biologic continuum leading to invasive squamous cell carcinoma. A number of topical therapies are now available for the treatment of AK but their disadvantages include long treatment duration and prolonged local reactions. Ingenol mebutate is a newer therapy for AK which is only applied for 2 or 3 days. Case Report Dermoscopy and RCM findings in two patients with AK treated with ingenol mebutate confirm that it induces rapid lesion necrosis and specific neutrophil-mediated, antibody-dependent cellular cytotoxicity. Necrosis occurs via mitochondrial membrane disruption, with subsequent eradication of residual tumor cells via transient inflammation. Local skin reactions to ingenol mebutate should be considered part of the drug’s mechanism of action rather than an adverse effect. Conclusion Ingenol mebutate is a valuable therapy for the treatment of AK. This case report adds further evidence to the usefulness of dermoscopy and RCM in the assessment and monitoring of treatment outcome. Electronic supplementary material The online version of this article (doi:10.1007/s13555-016-0094-9) contains supplementary material, which is available to authorized users.

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.

Therapeutic options of anogenital warts (AGW) at the urethral meatus are limited and often require effortful and time-consuming procedures under general anesthesia. Here, we present two cases of AGW at the urethral meatus, which we have successfully treated with low-dose topical ingenol mebutate gel.

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.

Actinic keratosis (AK) is a clinical condition characterized by keratinocytic dysplastic lesions of the epidermis, affecting individuals chronically exposed to sunlight. Topical therapies allow the treatment of a whole area of affected skin and currently include diclofenac sodium gel, 5-fluorouracil cream, 5-fluorouracil and acetylsalicylic acid solution, imiquimod cream, and ingenol mebutate gel. Due to the comparable efficacy of 3% diclofenac, ingenol mebutate, and 3.75% imiquimod in treating AK multiple lesions, a pharmacoeconomic evaluation of cost-effectiveness of the three treatments was needed. A cost-efficacy analysis comparing 3% diclofenac sodium with ingenol mebutate and 3.75% imiquimod was performed. In this analysis, efficacy data were combined with quality-of-life measurement derived from previous studies as well as the costs associated with the management of these lesions in Italy. Patients’ demographics and clinical characteristics were assumed to reflect those from the clinical studies considered.

Background 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. Objective To investigate safety, efficacy and treatment satisfaction when treating separate areas simultaneously or sequentially with different concentrations of ingenol mebutate gel. Methods 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. Results 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. Conclusion 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.

**Background:** Currently available topical treatments for actinic keratosis (AK) adversely affect patients’ quality of life because of long treatment durations and long-lasting local skin reactions (LSRs), which may result in poor treatment adherence and patient outcomes. Ingenol mebutate gel, a recently introduced treatment for AK, is administered for 2 or 3 days, and LSR’s are predicable in onset and duration. **Objectives:** The objective of the study was to estimate the value of ingenol mebutate gel’s shorter treatment duration and tolerability profile to potential patients, versus existing topical treatments (imiquimod 3.75%, imiquimod 5% and diclofenac 3%) in the United States. **Methods:** The open-ended Contingent Valuation (CV) approach was used to estimate incremental willingness-to-pay (WTP) for ingenol mebutate gel rather than treatment with imiquimod 5%, imiquimod 3.75% and diclofenac 3%. Profiles for each therapy differed in regards to treatment duration, time-to-LSR resolution, and price. Subjects were asked to state their maximum out-of-pocket WTP to receive ingenol mebutate gel instead of each of the three alternatives. **Results:** 103 subjects provided usable answers. Between 48% and 63% of subjects were willing to pay extra to gain access to treatment with the ingenol mebutate gel profile instead of the comparators, and the mean incremental WTP ranged from $475 to $518. Subjects with experience of topical treatment stated higher WTP for accessing ingenol mebutate gel. Subjects whose most bothersome AK area was the full scalp or forehead also claimed higher WTP for ingenol mebutate gel. **Conclusions:** Patients diagnosed with AK indicated an unmet need for fast-acting topical treatment with shorter LSR resolution time.

Introduction Local skin responses (LSRs) are the most common adverse effects of topical actinic keratosis (AK) therapy. There is currently no method available that allows objective characterization of LSRs. Here, the authors describe a new scale developed to quantitatively and objectively assess the six most common LSRs resulting from topical AK therapy with ingenol mebutate. Methods The LSR grading scale was developed using a 0–4 numerical rating, with clinical descriptors and representative photographic images for each rating. Good inter-observer grading concordance was demonstrated in peer review during development of the tool. Data on the use of the scale are described from four phase III double-blind studies of ingenol mebutate (n = 1,005). Results LSRs peaked on days 4 (face/scalp) or 8 (trunk/extremities), with mean maximum composite LSR scores of 9.1 and 6.8, respectively, and a rapid return toward baseline by day 15 in most cases. Mean composite LSR score at day 57 was generally lower than at baseline. Conclusion The LSR grading scale is an objective tool allowing practicing dermatologists to characterize and compare LSRs to existing and, potentially, future AK therapies. Electronic supplementary material The online version of this article (doi:10.1007/s13555-014-0059-9) contains supplementary material, which is available to authorized users.

Ingenol mebutate gel, derived from the sap of the Euphorbia peplus plant, recently has been investigated as a potential topical treatment for actinic keratoses. The medication is proposed to have a dual mechanism of action: rapid lesion necrosis followed by lesion-specific, neutrophil-mediated, antibody-dependent cellular cytotoxicity. A literature review of the data from phase II and III clinical trials reveals that ingenol mebutate gel is an efficacious and safe therapy for actinic keratoses when used on areas of skin up to 25 cm2. Further research is needed to compare directly ingenol mebutate gel to other treatments available for actinic keratoses, as well as to establish safety and efficacy for application on larger areas of skin.

Shelbi C Jim On,1 Kim Mark Knudsen,2 Torsten Skov,2 Mark Lebwohl,1 1Department of Dermatology, Mount Sinai School of Medicine, New York, NY, USA; 2LEO Pharma A/S, Biostatistics, Ballerup, Denmark Background: Ingenol mebutate gel is a topical field treatment for actinic keratosis (AK). The treatment elicits application-site reactions in most patients. This analysis evaluated the relationship between the severity of reactions and the speed of their resolution. Methods: Patients in Phase III studies were treated for AKs on the face (n=218), scalp (n=56), and trunk and extremities (n=209). All of the patients were treated with either ingenol mebutate gel 0.015% once daily for three consecutive days (face/scalp) or ingenol mebutate gel 0.05% once daily for two consecutive days (trunk/extremities). Local skin reactions (LSRs) were assessed on a 5-point scale from 0 to 4 in six categories, yielding composite scores in the range of 0 to 24. Results: The composite LSR score on the day after the last application of ingenol mebutate gel was an important predictor of the speed of resolution of LSRs. The rate of resolution was greatest for AKs treated on the face, followed by the scalp, and then the trunk and extremities. All patients were expected to have minimal LSR scores for the face and scalp at 2 weeks, and for the trunk and extremities at 4 weeks. Conclusion: The absolute reduction in LSR scores was proportional to the composite LSR score on the day after the last application of ingenol mebutate gel treatment. The rate of resolution for LSRs was dependent on the anatomic site treated as well as the day 4 composite score. Keywords: ingenol mebutate, local skin reaction, actinic keratosis

Introduction Actinic keratosis (AK) is a cutaneous intraepithelial neoplasm appearing within areas referred as ‘fields of cancerization’. AK can progress to invasive squamous cell carcinoma. Treatments that target both clinically visible and subclinical AKs in cancerization fields are able to reduce the risk of malignant progression. Ingenol mebutate gel is a new effective topical therapy for AK, used once daily for 2 or 3 days depending on the location of lesions. Case description Three elderly patients with multiple non-hypertrophic AKs within a contiguous 25-cm2 treatment area on the face or scalp were treated with ingenol mebutate 0.015 % gel once daily for three consecutive days and followed up over a period of 57 days. Discussion and Evaluation Although individual local responses to treatment varied, all patients had total clearance of AK lesions without any sign of recurrence. In addition, all patients said that they were satisfied with the effectiveness of ingenol mebutate treatment and the aesthetic outcome, and would be prepared to use this agent again to treat AK in the future, if necessary. Conclusions These three cases demonstrate that ingenol mebutate 0.015 % gel is effective and well tolerated in a clinical setting, with effective clearance of AK lesions present on the face and scalp, and good patient acceptability.

Joanna Emilio,1 Michelle Schwartz,2–4 Eleanor Feldman,2–4 Amy Kalowitz Bieber,2–4 Amanda Bienenfeld,2–4 Min-Kyung Jung,1 Daniel M Siegel,2,3 Orit Markowitz2–4 1Department of Dermatology, NYIT College of Osteopathic Medicine, Old Westbury, 2Department of Dermatology, SUNY Downstate Medical Center, 3Department of Dermatology, NY Harbor Healthcare System, Brooklyn, 4Department of Dermatology, Mount Sinai Medical Center, New York, NY, USA Abstract: Actinic keratoses (AKs), especially on areas of the face, have a negative impact on a patient's quality of life (QoL). These lesions manifest on sun-damaged skin and have the potential to progress to squamous cell carcinoma. Field-directed therapy alone and in combination with lesion-directed treatment is effective in clearing both visible and nonvisible AK lesions. Topical treatments of AKs thus have the potential to improve a patient's well-being. However, evidence demonstrating improvements in patient QoL is limited, and is mostly based on observational or retrospective studies. Some prospective studies have reported unchanged or even worsening QoL despite excellent treatment outcomes. Our prospective, pilot study demonstrated a significant increase in QoL in 28 subjects with AKs of the face treated with ingenol mebutate gel 0.015%. QoL was assessed at days 0 and 60 using the Skindex-16 survey. Mean overall scores improved from 24.5% at baseline to 15.5% at day 60 (P=0.031). Improvements in QoL were consistent with an 80% reduction in AK lesion number at day 60. These improved QoL findings are in line with those from a recent retrospective study using ingenol mebutate 0.015% gel. This study therefore further demonstrates the potential for field therapy to improve both treatment outcomes and patient satisfaction. Keywords: actinic keratosis, squamous cell carcinoma, ingenol mebutate gel, local skin reaction, quality of life, Skindex-16

Background: Lentigo maligna (LM) is a melanoma in situ on sun-damaged skin, with a strong predilection to the head and neck area of the elderly. Many therapeutic modalities have been proposed in the treatment of this pathology, including surgery, cryotherapy, radiotherapy and topical imiquimod. Up to date surgical excision remains the treatment of choice with the lowest recurrence rate. Recently, a new topical treatment with ingenol mebutate has been described to be efficacious and well tolerated in the treatment of melanoma in situ. Objective: We sought to demonstrate that ingenol mebutate might be an efficacious and well-tolerated treatment in a patient suffering from LM on an aesthetically challenging location. Methods: Case report. Results: After therapeutic failure with imiquimod 5% cream, a new topical treatment with ingenol mebutate gel 0.015% once daily on 3 consecutive days was initiated. Despite visible inflammation, no macroscopic lesion clearance was observed. While the first follow-up using reflectance confocal microscopy (RCM) performed at 6 weeks after the completion of the therapy showed no signs of LM, the second follow-up examination at 12 weeks using RCM and biopsy confirmed recurrence of the lesion. Conclusion: Ingenol mebutate cannot be considered a standard treatment modality for all types of LM. Further studies are needed to evaluate the prerequisites that can ensure therapeutic success.

Ingenol mebutate (IM) was recently introduced for the treatment of actinic keratosis (AK). It is considered a safe and effective treatment in spite of local reactions frequently reported. These reactions may consist of erythema, flaking, crusting, swelling, vesicles and erosions, and would usually spontaneously recede within 20–30 days. We reported a case of a patient affected by multiple actinic keratosis of the scalp treated with IM. The patient reported a severe reaction that was not solved in two months. We decided to treat the reaction with photodynamic therapy and aminolevulinic acid. This treatment was demonstrated to be effective in solving this severe side effect.

not available. Disclosures: Study supported by LEO Pharma. Copyright SKIN 2018

Field therapy is a popular and important treatment for actinic keratosis. These agents have unique benefits as well as side effects. Dermatologists and others prescribing topical treatment for actinic keratosis should be aware of several important side effects. One of the most important side effects is the development of impetigo on the treated skin. We present a case of a patient who developed impetigo after applying ingenol mebutate gel for treatment of actinic keratosis. Impetigo is a not uncommon, but important complication of topical therapy for actinic keratosis. Prompt diagnosis and treatment can prevent unnecessary morbidity. Topical pharmacotherapy for treatment of actinic keratosis (AK) is an alternative preferred by some dermatologists over lesion-directed modalities because the former allows for coverage of subclinical AKs (so called “field treatment”). There are several options for dermatologists and patients considering field treatment with a topical agent. Traditionally 5-fluorouracil (5-FU) has been used, but this requires consistent daily to twice daily application for up to four weeks. In comparison, ingenol mebutate (IM) requires only once daily applications for two or three days. Such a schedule allows for enhanced patient adherence. Furthermore, a recent prospective randomized trial confirmed that the local skin reaction (LSR) of patients treated with IM is more short lived compared to those treated with 5-FU (1). Topical pharmacotherapy agents are generally well tolerated. Nearly all patients receiving topical pharmacotherapy for AKs notice erythema and discomfort at the site of treatment. In a multicenter, randomized, doubleblind study, pain and pruritus were found to be the most commonly reported adverse events with IM use (2). A 70-year-old Caucasian male with prior non-melanoma skin cancer history presented with three erythematous macules with adherent scale on the lip and forehead. These were clinically determined to be AKs and were treated with combination cryotherapy and field treatment of the face with IM 0.015% gel for three days. The patient returned four weeks later with bright erythema and honey-colored crust of the upper and lower lip (Figure 1). A bacterial culture was collected and at that time the patient was treated empirically with mupirocin and cephalexin. The bacterial culture subsequently revealed pan-sensitive staphylococcus aureus and the patient rapidly improved. Impetigo during treatment with 5-FU for AK is not uncommon and is presumably a result of a compromised skin barrier. Reasonably, the incidence of impetigo could be expected to be higher in patients receiving 5-FU compared to IM as the LSR is more persistent in the former (1). In a study of 162 patients receiving IM, only one patient developed impetigo (3). Prompt recognition and treatment of this condition is essential to prevent unnecessary morbidity. While IM has a preferable treatment schedule and duration of LSR, it nevertheless can result in the adverse effects like impetigo that are assumed to be more characteristic of 5-FU.

Harnessing neutrophils for the eradication of cancer cells remains an attractive but still controversial notion. In this study, we provide evidence that neutrophils are required to prevent relapse of skin tumors following topical treatment with a new anticancer agent, ingenol-3-angelate (PEP005). Topical PEP005 treatment induces primary necrosis of tumor cells, potently activates protein kinase C, and was associated with an acute T cell-independent inflammatory response characterized by a pronounced neutrophil infiltrate. In Foxn1nu mice depleted of neutrophils and in CD18-deficient mice (in which neutrophil extravasation is severely impaired) PEP005 treatment was associated with a >70% increase in tumor relapse rates. NK cell or monocyte/macrophage deficiency had no effect on relapse rates. Both in vitro and in mice, PEP005 induced MIP-2/IL-8, TNF-α, and IL-1β, all mediators of neutrophil recruitment and activation. In vitro, PEP005 activated human endothelial cells resulting in neutrophil adhesion and also induced human neutrophils to generate tumoricidal-reactive oxygen intermediates. Treatment of tumors with PEP005 significantly elevated the level of anticancer Abs, which were able to promote neutrophil-mediated Ab-dependent cellular cytotoxicity (ADCC) in vitro. PEP005 treatment of tumors grown in SCID mice was also associated with >70% increase in tumor relapse rates. Taken together, these data suggest a central role for neutrophil-mediated ADCC in preventing relapse. PEP005-mediated cure of tumors therefore appears to involve initial chemoablation followed by a neutrophil-dependent ADCC-mediated eradication of residual disease, illustrating that neutrophils can be induced to mediate important anticancer activity with specific chemotherapeutic agents.

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A novel, topically applied, short course therapy for actinic keratoses (AK) is now widely licensed following first approval in the USA in 2012. The active agent, ingenol mebutate, is a naturally occurring diterpenoid found in the plant Euphorbia peplus. AK, the most common premalignant dermatological pathology, is increasing in prevalence with increased UV radiation exposure and aging populations, and has the potential to progress to malignant disease. Various treatment modalities exist for AK and the choice for the clinician and patient is now extended with this novel treatment, which requires topical application for only 2 or 3 days, and has cosmetic and tissue-sparing advantages. Ingenol mebutate gel is used as a field-directed therapy, thereby potentially reducing perilesional subclinical AK.

Dear editor We read with interest the review by Uhlenhake on treatments for actinic keratosis (AK).1 The author presents a summary of the various AK treatment options used to reduce the risk of progression to invasive squamous cell carcinoma. The article includes a table (Table 1) comparing advantages and side effects of these options. Patient-administered topical treatments are an important strategy for treating confluent AKs and areas of sun-damaged skin that may contain subclinical AKs. Rates of complete and partial clearance are similar across the topical agents (fluorouracil, imiquimod, diclofenac, and ingenol mebutate). It is noteworthy that the uniquely brief regimen for ingenol mebutate, 2 to 3 days, produced clearance rates similar to those with the other agents, which have treatment regimens of several weeks.1 All of the topical agents are associated with common side effects that include localized erythema, flaking, scaling, and crusting; however, dyspigmentation and scarring occur infrequently. Ingenol mebutate gel is a new topical treatment for AK. Occurrence of dyspigmentation and scarring are rare as there was minimal change in pigmentation and minimal scarring in all groups of the Phase III studies.2 Neither dyspigmentation nor scarring are reported among adverse reactions in the Picato package insert.3 Localized changes in pigmentation and scarring have been reported with fluorouracil and imiquimod.4–6 Localized skin reactions persist during treatment.3–6 In my experience, some patients are unable to tolerate prolonged inflammatory skin reactions and may discontinue treatment early, thus failing to achieve the anticipated rates of clearance. The short treatment regimen of ingenol mebutate provides a valuable option for such patients.

Importance 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. Objective 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. Design and Setting The treatment area was observed for recurrence for 12 months after the original study. Patients were treated in an outpatient setting. Participants 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-cm 2 area at day 57 of their original trial. Main Outcome Measures 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. Conclusion and Relevance 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

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.