Ingenol mebutate 500micrograms/g gel

Abstract Pyogenic granuloma (PG) is a benign vascular tumor removed surgically or by physical modalities, such as electrocautery and cryotherapy. Other treatment options may be warranted, especially in children, using nonsurgical approach. The study aims to determine the effectiveness and safety of topical treatments on PG in children in the clearance of lesions. Systematic literature search were done in February 2023 in the following database: PubMed, HERDIN, Cochrane Library, Hindawi, Directory of Open Access Journals, ScienceDirect, and Google Scholar. The search included studies involving PG treated with topical medications in the pediatric age group. Twenty-five studies (9 cohort studies, 6 case series, and 10 case reports) were included and utilized the following medications: timolol, propranolol, corticosteroids, common table salt, imiquimod, and ingenol mebutate. Among the medications, timolol was the most reported drug to provide partial to complete resolution in 62 out of 149 patients. All the reviewed topical medications provided partial to complete resolution with minimal adverse effects. Among them, topical timolol, propranolol, and table salt have demonstrated high response rates. Topical therapy in children with PG may be considered as a nonsurgical option. However, further clinical trials are warranted to determine its effectiveness.

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BACKGROUND: Recently the production and marketing of ingenol mebutate in the European Union (EU) and Canada was halted due to a possible increased risk of squamous cell carcinoma (SCC) in patients with actinic keratosis (AK). OBJECTIVE: To investigate the relationship between SCC and topical AK medications including ingenol mebutate in the FDA Adverse Event Reporting System (FAERS). METHODS: Case/non-case analyses were performed in FAERS using data from 2012 to 2020 to examine the reporting odds ratio (ROR) signal for SCC for ingenol mebutate and all classes of topical AK medications under multiple conditions: i. comparison to all other drugs in FAERs, ii. comparison to other topical AK medications, iii. comparison to all other topical AK medications where only a single agent was implicated, iv. comparison of ingenol mebutate vs. imiquimod. RESULTS: A statistically significant ROR for SCC was found for ingenol mebutate under all conditions (i. 31.57 (25.45, 39.16), ii. 50.35 (32.21, 78.82), iii 61.09 (35.36, 105.56), iv. 2.53 (1.27, 5.05). A significant but substantially smaller signal was observed for imiquimod (i. 12.38 (6.42, 32.84), ii. 5.18 (2.61, 10.26), iii 5.42 (2.49, 11.78), but not for fluorouracil or diclofenac. When compared to imiquimod directly, ingenol mebutate had a statistically significant ROR for SCC (2.53 (1.27, 5.05). CONCLUSION: Our findings support an association between SCC and ingenol mebutate. This association is maintained under controls to limit bias and falsely elevated signal including controlling for disease state and cases with multiple drug exposures and when compared to imiquimod as in Phase IV studies of ingenol mebutate.

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Basal cell carcinoma (BCC) is the most common type of skin cancer.1 Surgery is considered to be the gold standard for BCC treatment, although low-risk BCCs can be treated with non-surgical topical methods such as imiquimod, 5-fluorouracil (5-FU), and photodynamic therapy (PDT).2 The use of imiquimod and 5-FU can be limited, however, by the fact that patients have to treat themselves for several weeks, while the use of PDT is limited by the availability of the equipment. Therefore, there is a need to find additional topical treatments for BCC. Ingenol mebutate (IM, Picato®, LEO Pharma), a drug approved in 2012 by the FDA and EMA for short-term treatment of actinic keratosis (AK), at a concentration of 0.015% or 0.05% pending on location, could provide a faster and easier topical therapy for BCC. Data regarding BCC treatment with IM are limited, however.3, 4 We therefore conducted a prospective, exploratory, uncontrolled, single-site study in the Dermatology Department of Nice University Hospital to investigate the efficacy and safety of one or two courses of 0.05% IM in superficial and nodular BCC (‘PICABAS’ study). However, during the course of the study the European marketing authorization of IM was withdrawn in 2020 at the request of LEO Pharma after a review by the EMA that concluded that IM may increase the risk of cutaneous squamous cell carcinoma (SCC) in patients treated for AK.5 Eligible participants were 18 years of age or older, with at least one histologically verified primary superficial or nodular BCC on the trunk or limbs. Ingenol mebutate gel (0.05%) was applied once daily for two consecutive days. Basal cell carcinoma responses were assessed on day 90 after treatment. If the tumor was no longer clinically visible (clinical examination including dermoscopy analysis), a three-mm biopsy was made in order to confirm histological clearance. If the lesion was still clinically visible or if the biopsy revealed residual BCC, a second treatment course was performed under the same modalities. Local adverse events were assessed at each cycle based on the local skin reaction (LSR) score. The primary outcome was the proportion of complete responses, defined as complete clinical and histological clearance assessed 3 months after one or two cycles of IM treatment. We performed a modified Intent-To-Treat (mITT) analysis, defined as all BCCs which met the inclusion criteria, received at least one application of IM, and which underwent at least one post-treatment evaluation. We also did a Per-Protocol (PP) analysis, including all BCCs which met the inclusion criteria, received the full study treatment (one or two cycles if needed according to the study protocol), and which did not have any major deviation. The mITT and the PP population comprised 39 and 28 BCCs, respectively. Basal cell carcinomas were located on the trunk (52.6%), arm (28.9%), or leg (18.4%) The mean diameter of the BCCs was 1.1 cm (SD 0.38) and the median diameter was 1 cm (range 0.6–2.5). There were 20 sBCC (52.6%) and 18 nBCC (47.4%). The mean histological thickness was 0.67 mm (SD 0.61), and the median thickness was 0.4 mm (0.1–2.6). The complete response rate for sBCC was between 50% (11/20, mITT) and 62.5% (10/16, PP) (Figure 1). For nBCC, the complete response rate was between 5.6% (1/18, mITT) and 8.3% (1/12, PP). The multivariate analysis showed that superficial BCC histotype was a significant independent prognostic factor of complete response to IM (OR 14.89, p = 0.036). The median LSR score was 7.0 (range 1–13) for the first treatment course and 6.5 (range 0.0–15.0) for the second, as reported for AK treatment. Following the EMA review concluding the IM may increase the risk of cutaneous SCC in patients treated for AK, we conducted an additional safety follow-up 14 months after the last application of IM. No occurrence of SCC was noted in 27 BCC cases treated with IM. However this is not a long enough period to conclude about the safety of IM in patients treated for BCC. Complete response of a superficial basal cell carcinoma (BCC) of the trunk after two cycles of 0.05% ingenol mebutate. Dermoscopic and histological aspects before (a, b) and after (c, d) treatment In conclusion, ingenol mebutate does not appear to be a useful addition to the existing treatment options for low-risk superficial BCC, and cannot be recommended for the treatment of low risk nodular BCC. Philippe Bahadoran: Conceptualization (Equal); Investigation (Equal); Methodology (Equal); Supervision (Equal); Validation (Equal); Writing – original draft (Equal); Writing – review & editing (Equal). Marine Velin: Conceptualization (Equal); Investigation (Equal); Methodology (Equal); Validation (Equal); Writing – original draft (Equal). Nathalie Cardot-Leccia: Conceptualization (Equal); Investigation (Equal); Methodology (Equal); Validation (Equal); Writing – original draft (Equal). Anne-Claire Cathelineau: Conceptualization (Equal); Investigation (Equal); Methodology (Equal); Validation (Equal); Writing – original draft (Equal). Luc Duteil: Conceptualization (Equal); Investigation (Equal); Methodology (Equal); Validation (Equal); Writing – original draft (Equal). Catherine Queille-Roussel: Conceptualization (Equal); Investigation (Equal); Methodology (Equal); Validation (Equal); Writing – original draft (Equal). Thierry Passeron: Conceptualization (Equal); Investigation (Equal); Methodology (Equal); Validation (Equal); Writing – original draft (Equal). Leo Pharma. The study was supported by a research grant from Leo Pharma. However, Leo Pharm did not interfere with the independence of the authors in regard to the conduct of this study. Philippe Bahadoran received consulting fees from Leo Pharma. People Protection Committee of Ile-de-France VIII, N° 2017-004608-22. NCT03546166. Data available on request from the authors.

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Ingenol mebutate (Picato gel, LEO Pharma, Inc) is a topical diterpene ester that was approved for the treatment of actinic keratoses (AK) by the US Food and Drug Administration in 2012. In addition, it has been used off-label for anogenital warts.1 It is derived from the sap of the Euphorbia peplus plant and has historically had therapeutic use for a variety of skin conditions. The drug causes rapid necrosis in as little as 1 day after application by increasing intracellular and mitochondrial calcium, triggering cellular swelling and loss of membrane integrity.

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Anti-angiogenic therapies (AATs) exhibit limited efficacy, as most patients with cancer inevitably develop resistance to them. In this study, data generated using a nasopharyngeal carcinoma orthotopic mouse model, combined with clinical data, reveal compensatory vasculogenic mimicry (VM) formation during AAT treatment and the association of VM with poor prognosis in nasopharyngeal carcinoma. Additionally, data-independent acquisition mass spectrometry-based proteomics shows that upregulation of a disintegrin And metalloprotease 10 (ADAM10) contributes to VM. Mechanistically, epigenetic and high-resolution chromatin interaction landscape analyses demonstrate that although ADAM10 does not interact with either the proximal or distal enhancers, DEAD-box helicase 5 (DDX5), a transcription factor of ADAM10, is regulated by long-range looping enhancer-promoter interactions. Further analyses identify transcription factors binding to critical constituents of the DDX5 super-enhancer. Ingenol mebutate, which docks excellently with DDX5, reverses ADAM10-mediated gene expression changes, thereby effectively suppressing compensatory VM formation and metastasis and improving prognosis. Collectively, these findings provide insights into the clinical application of AATs.

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Objective: Epithelial-mesenchymal transition (EMT) is a tightly regulated and dynamic process occurring in both embryonic development and tumor progression. Our study aimed to comprehensively explore the molecular subtypes, immune landscape, and prognostic signature based on EMT-related genes in low-grade gliomas (LGG) in order to facilitate treatment decision-making and drug discovery. Methods: We curated EMT-related genes and performed molecular subtyping with consensus clustering algorithm to determine EMT expression patterns in LGG. The infiltration level of diverse immune cell subsets was evaluated by implementing the single-sample gene set enrichment analysis (ssGSEA) and ESTIMATE algorithms. The distinctions in clinical characteristics, mutation landscape, and immune tumor microenvironment (TME) among the subtypes were subjected to further investigation. Gene Set Variation Analysis (GSVA) was performed to explore the biological pathways that were involved in subtypes. The chemo drug sensitivity and immunotherapy of subtypes were estimated through GDSC database and NTP algorithm. To detect EMT subtype-related prognostic gene modules, the analysis of weighted gene co-expression network (WGCNA) was performed. The LASSO algorithm was utilized to construct a prognostic risk model, and its efficacy was verified through an independent CGGA dataset. Finally, the expression of the hub genes from the prognostic model was evaluated through the single-cell dataset and in-vitro experiment. Results: The TCGA-LGG dataset revealed the creation of two molecular subtypes that presented different prognoses, clinical implications, TME, mutation landscapes, chemotherapy, and immunotherapy. A three-gene signature (SLC39A1, CTSA and CLIC1) based on EMT expression pattern were established through WGCNA analysis. Low-risk patients showed a positive outlook, increased immune cell presence, and higher expression of immune checkpoint proteins. In addition, several promising drugs, including birinapant, fluvastatin, clofarabine, dasatinib, tanespimycin, TAK−733, GDC−0152, AZD8330, trametinib and ingenol-mebutate had great potential to the treatment of high risk patients. Finally, CTSA and CLIC1 were highly expressed in monocyte cell through single-cell RNA sequencing analysis. Conclusion: Our research revealed non-negligible role of EMT in the TME diversity and complexity of LGG. A prognostic signature may contribute to the personalized treatment and prognostic determination.

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