Ingenol mebutate in actinic keratosis: a clinical, videodermoscopic and immunohistochemical study

Bobyr, Ivan; Campanati, Anna; Consales, Veronica; Martina, Emanuela; Molinelli, Elisa; Diotallevi, Federico; Brisigotti, Valerio; Giangiacomi, Mirella; Ganzetti, Giulia; Giuliodori, Katia; Offidani, Annamaria

doi:10.1111/jdv.13831

Cited by 18 publications

(31 citation statements)

References 36 publications

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“…It directly stimulates B cells to produce specific antineoplastic antibodies, interacting both on dysplastic AK or NMSC cells and on neutrophils in the inflammatory infiltrate. 18 Anti-proliferative effects have been demonstrated also in a study by Bobyr et al, 29 showing a significant reduction in neoangiogenesis marker VEGF and proliferation marker Ki67 after treating AKs with ingenol mebutate, alongside reduction in expression of p63, which is reported by the authors a reliable marker of actinic damage. In addition, ingenol mebutate might act as potent agonist of protein kinase C delta, 25 leading to an anti-proliferative effect and a regulatory effect on immune cell activation.…”

Section: Discussionsupporting

confidence: 52%

Ingenol mebutate‐mediated reduction in p53‐positive keratinocytes in skin cancerization field directly correlates with clinical response in patients with multiple actinic keratoses

Grandi

Gennaro

Torrigiani

et al. 2019

Acad Dermatol Venereol

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Background UV radiation represents the main risk factor for non‐melanoma skin cancers. Chronic UV exposure induces ‘p53 patches’, i.e. clonal outgrowths of keratinocytes with high nuclear expression of mutated p53, which might progress to actinic keratosis (AK) and ultimately squamous cell carcinomas (SCCs). Aims Analysis of ingenol mebutate gel (150 and 500 mcg/g) effects in the reduction in ‘p53 patches’ inside skin cancerization field (CF) in patients with multiple AKs of face/scalp or trunk/extremities, in order to investigate whether the expected reduction in p53+ keratinocytes might have a direct role in the long‐term AK reduction in treated areas. Results We enrolled n = 10 patients, treated with ingenol mebutate and evaluated at 2 and 6 months after treatment. We observed clinical responses in the majority of patients (n = 7), with AK reduction or complete clearance (n = 6 and n = 1, respectively). Notably, two patients did not respond to the treatment, and in one patient, after initial partial response, new lesion was recorded. In untreated skin CF samples (n = 3), we observed numerous p53+ keratinocytes, similar to those observed in invasive SCC samples (53.56 ± 8.79 and 74.34 ± 22.05, respectively; P = 0.2). After treatment, we observed a variable p53+ keratinocyte reduction in CF samples at 2 months (24.67 ± 31.19; P = 0.19). Importantly, the amount of p53+ keratinocytes strongly and directly correlated with AK number (R2 = 0.81). Conclusion Untreated skin CF expresses high level of p53+ keratinocytes as invasive SCC. Ingenol mebutate is able to reduce p53+ keratinocytes with variable efficacy, this reduction degree directly correlating with clinical efficacy.

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Section: Discussionsupporting

confidence: 52%

Ingenol mebutate‐mediated reduction in p53‐positive keratinocytes in skin cancerization field directly correlates with clinical response in patients with multiple actinic keratoses

Grandi

Gennaro

Torrigiani

et al. 2019

Acad Dermatol Venereol

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“…We found that treatment of AK with IM induced a significant clinical improvement rate of 80% in Korean patients with AK. Previous studies have reported a clinical clearance rate of AK lesions 2 months after treatment with IM within the range of 49% to 100%, but there is no existing data in the Asian population. Treatment with IM showed the favorable treatment outcomes when compared with many other therapies used in the treatment of AK including cryotherapy (39–83%), 3.0% diclofenac gel (33–50%), imiquimod 5% cream (45.1%) and 5‐fluorouracil 0.5% cream (19.5–47.5%.)…”

Section: Discussionmentioning

confidence: 98%

“…We observed a histopathological clearance rate of AK lesions of 66.7% after IM treatment in Koreans. Until now, only two studies have examined the histopathological improvement after treatment with IM . Bobyr et al .…”

Section: Discussionmentioning

confidence: 99%

“…Until now, only two studies have examined the histopathological improvement after treatment with IM . Bobyr et al . stated that the rate of histopathological clearance was 70%, while Ulrich et al .…”

Section: Discussionmentioning

confidence: 99%

“…To date, the majority of efficacy studies on IM have focused on the clinical clearance of AK in the Caucasian population . Studies evaluating the histopathological changes after treatment of AK with IM are extremely rare, and there are no such studies in the Asian population.…”

Section: Introductionmentioning

confidence: 99%

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Effect of ingenol mebutate on actinic keratosis in a Korean population: A prospective clinical, dermoscopic and histopathological study from a single center

Kim

Woo

Kim

et al. 2018

The Journal of Dermatology

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

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

Righi

Tarentini

Mucci

et al. 2019

Sci Rep

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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.

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Ingenol mebutate in actinic keratosis: a clinical, videodermoscopic and immunohistochemical study

Abstract: The clinical efficacy of ingenol mebutate on AKs is confirmed by its effect on angiogenesis, stem cell activity and cell proliferation in vivo.

Cited by 18 publications

References 36 publications

Ingenol mebutate‐mediated reduction in p53‐positive keratinocytes in skin cancerization field directly correlates with clinical response in patients with multiple actinic keratoses

Ingenol mebutate‐mediated reduction in p53‐positive keratinocytes in skin cancerization field directly correlates with clinical response in patients with multiple actinic keratoses

Effect of ingenol mebutate on actinic keratosis in a Korean population: A prospective clinical, dermoscopic and histopathological study from a single center

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

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