Ingenol Mebutate Gel Research Articles

Photodynamic Therapy for Field Cancerization in the Skin: Where Do We Stand?

Photodynamic therapy (PDT) with a photosensitizer is available for the treatment of multiple actinic keratoses (AKs) in a restricted skin area or, as it is established, for the field-cancerized skin. Our review aims to present the up-to-date literature on skin field cancerization using PDT employing different topical photosensitizers, modified light delivery protocols and combination treatments to obtain excellent efficacy and safety in everyday clinical practice. We sought PubMed, MEDLINE, Scopus, OVID, Embase, Science Direct, Cochrane Library, Research Gate and Google Scholar for [(aminolevulinic acid OR aminolevulinate) AND photodynamic therapy] with (field-directed OR field cancerization, (actinic keratosis), and (efficacy OR effectiveness OR pain OR tolerability) for studies published until February 2023. Advantages of PDT compared to the other field treatments, including imiquimod, 5-fluorouracil, ingenol mebutate gel and diclofenac, reported better cosmetic outcomes and greater patient satisfaction. On the other hand, some drawbacks of field PDT include pain and treatment duration. Alternate illumination methods have also been investigated, including daylight as a light source. Pretreating the affected area may enhance photosensitizer absorption leading to better therapeutic results, while combinational treatments have also been tested. Patients prefer daylight PDT to traditional light sources since it is more well-tolerated and equally effective. Even as a preventive treatment, field PDT yields promising outcomes, especially for high-risk individuals, including organ transplant recipients. This review provides a thorough display of the field of PDT on cancerized skin, which will facilitate physicians in applying PDT more efficiently and intuitively.

Topical Treatment of Actinic Keratosis and Metalloproteinase Expression: A Clinico-Pathological Retrospective Study.

Actinic keratosis is an intraepithelial proliferation of atypical keratinocytes that could progress into invasive squamous cell carcinoma. Most evidence suggests an important role of the dermal matrix metalloproteinases in the progression of atypical skin epithelial lesions. We evaluated the clinical efficacy of three different therapeutic modalities (a medical device containing 0.8% piroxicam cream and 50+ sunscreen, photodynamic therapy, and ingenol mebutate gel) to treat suspicious actinic keratoses, which were biopsied for histopathological examination and then analyzed for the expression of matrix metalloproteinases by immunohistochemistry. Clinical, dermoscopic, and reflectance confocal microscopy evaluations revealed a gradual decrease in all standard scores validated for actinic keratosis assessment at the end of the treatments. From a histopathological point of view, we documented the substantial restoration of normal skin architecture, while the immunohistochemical evaluation of matrix metalloproteinases showed a reduction in expression in the treated skin lesions compared to the baseline. As actinic keratoses are considered the precursors of squamous cell carcinoma, their treatment is crucial to prevent the development of a more aggressive disease. Our study monitored the evolution of actinic keratoses subjected to three different topical therapies, with the value of correlating clinical and histopathological findings. Moreover, as the matrix metalloproteinases are largely recognized factors involved in the pathogenesis and evolution of actinic keratosis to squamous cell carcinoma, the demonstration by immunohistochemistry of a reduction in their expression after the treatments adds new valuable concern to the field.

Tirbanibulin: A New Topical Therapy for Actinic Keratoses With a Novel Mechanism of Action and Improved Ease of Use.

Tirbanibulin: A New Topical Therapy for Actinic Keratoses With a Novel Mechanism of Action and Improved Ease of Use.

RF-Herpes Zoster Triggered by Ingenol Mebutate Gel: First European Case Report

RF-Herpes Zoster Triggered by Ingenol Mebutate Gel: First European Case Report

Patient-reported outcomes of topical therapies in actinic keratosis: A systematic review.

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.

The Effect of Four Approaches to Treat Actinic Keratosis on the Health-Related QOL, as Assessed by the Skindex-29 and Actinic Keratosis QOL

To evaluate the impact of actinic keratosis (AK) and the effect of four AK treatments on the health-related QOL (HRQOL), the Skindex-29 and AK QOL (AKQOL) questionnaires were completed by 624 patients with AK participating in a randomized controlled trial comparing 5% fluorouracil cream (Efudix, Meda Pharma B.V., Amstelveen, the Netherlands), 5% imiquimod cream (Aldara, Meda Pharma B.V., Solna, Sweden), methyl aminolevulinate (Metvix, Galderma SA, Penn Pharmaceutical Services, Gwent, UK) photodynamic therapy (MAL-PDT), and 0.015% ingenol mebutate gel (Picato, LEO Pharma A/S, Bellerup, Denmark) (Jansen et al., 2019).

FR -Aparición de herpes zoster secundario a la aplicación de ingenol mebutato en gel: comunicación del primer caso europeo

An 85-year-old Caucasian man was referred to our clinic due to lesions clinically compatible with actinic keratoses (AKs), so one course of ingenol mebutate (IM) 0.015% gel was prescribed. One week after the treatment, the patient developed multiple painful vesicular lesions predominantly on the left half of the neck, compatible with a herpes zoster (HZ). Due to the location and clear temporal sequence, HZ was attributed to IM. Adverse skin reactions to IM include erythema, post-inflammatory hyperpigmentation and scarring, all due to local inflammation. Otherwise erosive pustular dermatosis of the scalp, bullous reaction and squamous cell carcinoma secondary to IM application have been described. No case of HZ related to IM has ever been reported before. In August 2015, based on the notification of 20 cases of HZ during the post marketing experience in USA, FDA included HZ as an adverse effect in the American prescribing information for IM. However, until now, this side effect has not been introduced in the European information. To our knowledge, we report the first European case of reactivation of the HZ caused by IM gel in an immunocompetent patient.

16127 Efficacy of ingenol mebutate in patients with actinic keratosis on face and scalp: Subgroup analysis of a 12-month observational follow-up study according to age (

Objective: To assess 12-month, sustained, complete clearance of actinic keratoses (AKs) according to age after treatment with ingenol mebutate gel (IMB) 0.015% once daily for 3 consecutive days on face and scalp.

16258 Evaluation of different approaches in managing local skin reactions with the use of ingenol mebutate 0.015% and 0.05% during the treatment of actinic keratosis

Introduction: Treatments for actinic keratosis (AK) can elicit local skin reactions (LSRs). A previous study demonstrated treatment burden of ingenol mebutate (IMB) gel associated with LSRs is small, manageable and short lasting (Hanke et al, 2016). We summarized the literature regarding LSR management and approaches for managing LSRs during treatment of AK with IMB.

16224 Comparing chemical peeling and chemical peeling followed by ingenol mebutate gel for the treatment of actinic keratosis

Background: Actinic keratoses (AKs) are characterized by thick, scaly, or crusty areas on the skin caused by damage from exposure to ultraviolet radiation. Several treatment options exist. This study compared the efficacy and safety of chemical peeling vs combination of chemical peeling and ingenol mebutate in the treatment of widespread AKs.

P.576 The effect of cariprazine on agitation and hostility in patients with schizophrenia: post-hoc analysis

Actinic keratosis therapy can elicit unsightly and painful local skin responses; assessment of treatment satisfaction and health-related quality of life (QoL) is important. Ingenol mebutate gel is a novel topical field therapy for actinic keratosis.Post-hoc analyses were performed based on patient-reported outcomes from phase-III trials (n = 1005) to assess the effects of ingenol mebutate on QoL and the relationship between both QoL and treatment satisfaction, and degree of lesion clearance.Patients received ingenol mebutate or vehicle for self-application to a 25-cm2 contiguous area: 0.015% once daily for 3 consecutive days (face/scalp) or 0.05% once daily for 2 consecutive days (trunk/extremities). QoL (Skindex-16) and Treatment Satisfaction Questionnaire for Medication data were recorded.Significant, positive associations between Treatment Satisfaction Questionnaire for Medication score and degree of clearance were identified for patients in the face/scalp (effectiveness P < .0001 and global satisfaction P = .0002) and trunk/extremities (P < .0001 and P = .0014, respectively) groups. There was a significant association between Skindex-16 score and clearance for patients in the face/scalp group for change in symptoms (P = .0218), emotions (P = .0002), and overall Skindex-16 score (P = .0006) from baseline.Clinical trial population findings may not be generalizable to clinical practice.Ingenol mebutate significantly improved patients' QoL and treatment satisfaction. Improvements were associated with higher degrees of actinic keratosis lesion clearance.

Ingenol mebutate for the management of cryotherapy-resistant anogenital warts.

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

Efficacy of topical photodynamic therapy in the treatment of Erythroplasia of Queyrat.

Erythroplasia of Queyrat (EQ) is an intraepidermal carcinoma in situ presenting clinically as a sharply demarcated, slightly raised erythematosus plaque on the glans penis or the inner side of the foreskin. Various treatment modalities for EQ have been proposed, including electrocautery and curettage, topical 5-floururacil cream, imiquimod cream, isotretinoin, cryotherapy, laser therapy, radiotherapy, ingenol mebutate gel and Photodynamic Therapy (PDT). Most of these treatments are limited by low clearance rates and frequent relapses. Surgical treatment including local excision, Mohs micrographic surgery and partial or total penectomy, ensures adequate healing rates. However, discomfort consequent to surgical treatment might be unacceptable. Topical PDT using the methyl ester of 5- aminolaevulinic acid (MAL) is an established non-surgical treatment of cutaneous precancerous lesions and skin cancers. We present the case of a 60-year-old uncircumcised man affected by EQ of the penis successfully treated with MAL-PDT, performed five times, two weeks apart, with no recurrences after 6 years.

Identification of differentially expressed genes in actinic keratosis samples treated with ingenol mebutate gel.

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.

Ingenol mebutate treatment for actinic cheilitis: clinical, histopathological and p53 profile of 14 cases

Introduction Actinic cheilitis (AC) is part of a spectral disease of keratinocyte carcinomas considered by some authors an early stage of in situ squamous cell carcinoma. Treatment options for AC can be lesion and field-directed therapies. Ingenol mebutate (IM) induces rapid and direct cell death and immune responses being able to destruct dysplastic cells. Materials and methods This study enrolled patients with AC to receive IM gel 0.015% for self-application on the lower lip for 3 consecutive days. A biopsy was performed before and after treatment for histopathological and immunohistochemical evaluation. Local skin reactions (LSR) were evaluated. The level of significance considered was 5%. Results Fourteen patients were enrolled. All LSR had a complete resolution for up to 2 weeks. The most common adverse events were burning sensation, angular cheilitis, and pain. There was an improvement of more than 80% in patients’ subjective evaluation. There was no statistically significant histopathological response since all patients remained with mild dysplasia. No reduction in the P53 expression was observed in the current study. Conclusions Despite being a safe therapeutic method, the absence of histopathological or immunohistochemical response suggests that clinical improvement may not be accompanied by histopathological cure for AC treated with IM.

Characterisation of the inflammatory response triggered by topical ingenol mebutate 0.05% gel in basal cell carcinoma.

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. 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. Ten BCCs were in complete remission after 2years 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. 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.

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

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

Ingenol mebutate gel for the treatment of molluscum contagiosum: An open-label comparative pilot study

Ingenol mebutate gel for the treatment of molluscum contagiosum: An open-label comparative pilot study

Safety and efficacy of ingenol mebutate gel 0.015%, for treatment of actinic keratoses on the face in solid organ transplant recipients

Safety and efficacy of ingenol mebutate gel 0.015%, for treatment of actinic keratoses on the face in solid organ transplant recipients

Field cancerization therapy with ingenol mebutate contributes to restoring skin-metabolism to normal-state in patients with actinic keratosis: a metabolomic analysis

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.