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Facial flat warts are benign skin papillomas caused by human papillomavirus infections. They present as papules with hyperkeratotic surface, than can appear alone or in group. Though flat warts normally have spontaneous remission within 2 years, there is a large proportion of cases that can persist years despite treatment and cause significant psychological distress1,2 .

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.

BACKGROUND 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. METHODS 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. RESULTS 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

Background Ingenol mebutate (IngMeb) 0.015% or 0.05% is approved for actinic keratosis (AK) areas of 25 cm2 or less; some patients require treatment of larger fields. Objective To determine efficacy and safety of IngMeb 0.027% in areas of AK of up to 250 cm2 during an 8-week initial assessment period and extended 12-month follow-up. Methods 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 cm2) or chest (approximately 250 cm2). Patients received once-daily IngMeb or vehicle for 3 consecutive days on the full face, full balding scalp, or approximately 250 cm2 on the chest. The primary endpoint was complete AK clearance (AKCLEAR 100; week 8). Additional endpoints included partial AK clearance (AKCLEAR 75), recurrence, patient satisfaction, cosmetic outcome, and safety. Results IngMeb was superior to vehicle for complete AK clearance (21.4% vs 3.4%, P Limitations Localized skin responses hindered maintenance of double-blinding. Conclusions IngMeb 0.027% was superior to vehicle for treatment of AK areas of up to 250 cm2. The safety profile of IngMeb was as expected.

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.

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

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 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. Objectives 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. Patients and methods 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. Results 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. Conclusions Ingenol mebutate is effective for the treatment of AK in Asians, with tolerable safety profiles.

There are only a few anecdotal case reports about Bowen's disease (BD) treated with ingenol mebutate (IM) gel but no clinical study has been published yet. The aim of this study was to evaluate the effectiveness of IM gel in the treatment of BD and to observe the therapeutic efficacy of IM alone or IM with ablative fractional laser pretreatment. Nineteen patients with BD or squamous cell carcinoma in situ confirmed by skin biopsy were enrolled. IM was applied with 0.015% gel on facial lesions for 3 days consecutively and 0.05% gel on other sites for 2 days consecutively, with a 5-mm application margin around the visible lesion. Nine patients applied IM gel immediately following fractional CO2 laser treatment. Two patients were lost to follow up and a total of 17 patients were enrolled. Nine patients (9/17, 52.9%) had a clinically complete response at 2 months after treatment. Among the patients treated with the fractional CO2 laser before applying IM gel, eight (8/9, 88.9%) showed a complete response and one (1/9, 11.1%) showed partial response. Among the patients treated with IM gel alone, only one patient (1/8, 12.5%) showed a complete response, four (4/8, 50%) showed a partial response and three (3/8, 37.5%) did not respond to therapy. IM gel alone seems to have limited value for treatment of BD; however, a combination therapy with the ablative fractional laser can increase its therapeutic effectiveness.

BACKGROUND Anogenital warts (AGW) can cause physical discomfort and decreased quality of life. Recent case reports suggest that ingenol mebutate gel might be an effective treatment of AGW. OBJECTIVE To explore primarily the safety, and secondarily the efficacy of ingenol mebutate gel 0.05% in patients with AGW. METHODS This was an exploratory, open-label, 1-arm trial of ingenol mebutate gel 0.05% administered up to three times to patients with AGW. Safety was assessed by occurrence and severity of local skin reactions (LSRs) and treatment-related adverse events (AEs). Efficacy was assessed by complete clearance and reduction in AGW count 14 days after last treatment, and recurrence 12 weeks after clearance. RESULTS Of 41 patients enrolled, 40 received treatment and 26 completed the trial. Patients had a median AGW count of 11.0 and AGW duration of 3.0 years at baseline. All patients experienced transient LSRs following treatment with a maximum composite LSR score of 7.5 (on a scale from 0 to 18). A total of 93% of patients reported treatment-related AEs, most frequently pain (85%) and procedural complications (35%) due to smearing of the gel. 78% of patients took mild analgesics for the pain, typically for 1-2 days following treatment. The majority of AEs were of moderate-to-severe intensity. Seventeen of 39 patients (43.6%) had complete clearance 14 days after last treatment, and AGW count was reduced by 90.9%. There was a tendency towards lower clearance rate in patients with longer duration of AGW. Eight of 14 patients (57.1%) had AGW recurrence 12 weeks after clearance. CONCLUSION Ingenol mebutate gel was associated with a high number of AEs and withdrawals due to painful local and adjacent skin reactions. Furthermore, it showed promising efficacy in reducing AGW despite a difficult-to-treat population. Optimization of the formulation is warranted to improve the safety profile of the treatment.

Condylomata acuminata (CA), or anogenital warts, is the most common sexually transmitted infection. Treatments for CA generally have suboptimal recurrence rates, which results in a need for repeated treatments and adds to the already negative impact on the patients’ quality of life. CA can present at the urethral meatus, which is a particularly challenging anatomic location from a therapeutic perspective. We report two cases of CA at the urethral meatus successfully treated with topical application of high-dose ingenol mebutate gel.

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) 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 cmPhase I, multicenter, open-label, uncontrolled, non-randomized trial. Patients received ingenol mebutate gel for three consecutive days on approximately 250 cmOf 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

Cryosurgery is the most commonly used method to treat actinic keratosis (AK). Cryosurgical methods are not standardized. To examine differences in the spray techniques used for liquid nitrogen cryosurgery when treating AKs of the head, and the effect of these variations in technique on rates of complete clearance of AKs. Patients were those from the FIELD-1 study, who received cryosurgery as per the investigators' usual practice to all AKs. This was followed by topical treatment with either vehicle gel or ingenol mebutate gel, 0.015%, after 3 weeks. The investigator recorded the average duration of cryosurgery spray used, the number of freeze–thaw cycles, and the distance from the tip of the spray device to the AK. Clearance rates were determined at Week 11. Less-aggressive freezing techniques were used for AKs on the face than for those on the scalp. However, higher rates of complete clearance on the face and scalp were associated with more-aggressive freezing techniques. Patients with AKs on the face receive less-aggressive cryosurgery than do patients with AKs on the scalp.

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

Background Imiquimod 3.75% cream (Zyclara® Meda, Stockholm, Sweden) is a new field-directed therapy for actinic keratosis (AK). Objectives The aim is to evaluate efficacy and the morphologic dynamic changes induced by this treatment by means of dermatoscopy and reflectance confocal microscopy (RCM) of imiquimod 3.75% cream for the treatment of AKs of the face or scalp and to evaluate. Methods Thirty-two patients were treated with Imiquimod 3.75% cream. Demographic parameters, AK-FAS and AKASI scores and side-effects were collected. RCM and dermatoscopy on one target AKs were performed at each visit. We collected images at baseline (T0), after 1 week from the end of the first 2-week cycle (T1), after 1 week from the end of the entire treatment (T2) and 2 months after the end of treatment (T3). Results One target representative AK in the selected area of treatment of each patient was analysed. All dermoscopic and confocal parameters were reduced 2 months after the end of the therapy (T3) with a substantial reduction of AKASI and AK-FAS scores, and 17 cases (54.8%) were completely solved. Confocal microscopic analysis showed a reduction of keratinocytes disarray in 77.4% of cases; none showed crusts and parakeratosis. Inflammation was considerably decreased and was observed only in 12.9% of patients at the last visit. This improvement was not assessed on dermatoscopy because of inflammation and background erythema, which adversely influenced the assessments. LSRs were observed in almost all the patients during treatment being more severe after the first cycle of treatment (T1). Conclusions Imiquimod 3.75% cream is effective in treating clinical and subclinical AKs with an easy management of side-effects. Dermatoscopy and mostly RCM allow non-invasive monitoring of treatment response in vivo.

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

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.

We report three Bowen's disease (BD) cases treated with ingenol mebutate (IM), a novel topical chemotherapeutic agent approved for the treatment of actinic keratosis (AK) that is available in two doses: 0.015% and 0.05%. Three women diagnosed with BD exhibited a positive response after 2 or 3 day period of IM treatment, depending on lesion location. In the three cases, clinical resolution was observed 4 or 9 weeks posttreatment, and was confirmed with histopathology. Local skin reactions were common the first week after treatment but they resolved spontaneously. In our opinion these cases, along with another case reported in Germany, support the concept of commencing of clinical trials using IM on patients with BD.

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.

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.