The tubulin polymerization and Src kinase signaling inhibitor tirbanibulin is being investigated as a topical treatment for actinic keratosis, a precursor of squamous-cell carcinoma.
In two ...identically designed double-blind trials, we randomly assigned, in a 1:1 ratio, adults with actinic keratoses on the face or scalp to receive either topical tirbanibulin or vehicle (placebo) ointment. The ointment was applied by the patients to a 25-cm
contiguous area containing four to eight lesions once daily for 5 consecutive days. The primary outcome was the percentage of patients with a complete (100%) reduction in the number of lesions in the application area at day 57. The secondary outcome was the percentage of patients with a partial (≥75%) reduction in the number of lesions within the application area at day 57. The incidence of recurrence was evaluated at 1 year. Local reactions were scored with the use of 4-point scale (ranging from 0 absent to 3 severe).
A total of 702 patients were enrolled in the two trials (351 patients per trial). Complete clearance in trial 1 occurred in 44% of the patients (77 of 175) in the tirbanibulin group and in 5% of those (8 of 176) in the vehicle group (difference, 40 percentage points; 95% confidence interval CI, 32 to 47; P<0.001); in trial 2, the percentages were 54% (97 of 178 patients) and 13% (22 of 173), respectively (difference, 42 percentage points; 95% CI, 33 to 51; P<0.001). The percentages of patients with partial clearance were significantly higher in the tirbanibulin groups than in the vehicle groups. At 1 year, the estimated percentage of patients with recurrent lesions was 47% among patients who had had a complete response to tirbanibulin. The most common local reactions to tirbanibulin were erythema in 91% of the patients and flaking or scaling in 82%. Adverse events with tirbanibulin were application-site pain in 10% of the patients and pruritus in 9%, all of which resolved.
In two identically designed trials, tirbanibulin 1% ointment applied once daily for 5 days was superior to vehicle for the treatment of actinic keratosis at 2 months but was associated with transient local reactions and recurrence of lesions at 1 year. Trials comparing tirbanibulin with conventional treatments and that have longer follow-up are needed to determine the effects of tirbanibulin therapy on actinic keratosis. (Funded by Athenex; ClinicalTrials.gov numbers, NCT03285477 and NCT03285490.).
Diagnosis and therapy of actinic keratosis Thamm, Janis Raphael; Welzel, Julia; Schuh, Sandra
Journal der Deutschen Dermatologischen Gesellschaft,
20/May , Letnik:
22, Številka:
5
Journal Article
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Summary
Actinic keratosis (AK) is considered a chronic and recurring in situ skin neoplasia, with a possible transformation into invasive squamous cell carcinoma (SCC). Among others, predominant risk ...factors for development of AK are UV‐light exposure and immunosuppression. Basal epidermal keratinocyte atypia (AK I) and proliferation (PRO score) seem to drive malignant transformation, rather than clinical appearance of AK (Olsen I–III). Due to the invasiveness of punch biopsy, those histological criteria are not regularly assessed. Non‐invasive imaging techniques, such as optical coherence tomography (OCT), reflectance confocal microscopy (RCM) and line‐field confocal OCT (LC‐OCT) are helpful to distinguish complex cases of AK, Bowen's disease, and SCC. Moreover, LC‐OCT can visualize the epidermis and the papillary dermis at cellular resolution, allowing real‐time PRO score assessment. The decision‐making for implementation of therapy is still based on clinical risk factors, ranging from lesion‐ to field‐targeted and ablative to non‐ablative regimens, but in approximately 85% of the cases a recurrence of AK can be observed after a 1‐year follow‐up. The possible beneficial use of imaging techniques for a non‐invasive follow‐up of AK to detect recurrence or invasive progression early on should be subject to critical evaluation in further studies.
Cutaneous beta human papillomavirus (HPV) types appear to be involved in the development of non-melanoma skin cancer (NMSC); however, it is not entirely clear whether they play a direct role. We have ...previously shown that E6 and E7 oncoproteins from the beta HPV type 38 display transforming activities in several experimental models. To evaluate the possible contribution of HPV38 in a proliferative tissue compartment during carcinogenesis, we generated a new transgenic mouse model (Tg) where HPV38 E6 and E7 are expressed in the undifferentiated basal layer of epithelia under the control of the Keratin 14 (K14) promoter. Viral oncogene expression led to increased cellular proliferation in the epidermis of the Tg animals in comparison to the wild-type littermates. Although no spontaneous formation of tumours was observed during the lifespan of the K14 HPV38 E6/E7-Tg mice, they were highly susceptible to 7,12-dimethylbenz(a)anthracene (DMBA)/12-0-tetradecanoylphorbol-13-acetate (TPA) two-stage chemical carcinogenesis. In addition, when animals were exposed to ultraviolet light (UV) irradiation, we observed that accumulation of p21(WAF1) and cell-cycle arrest were significantly alleviated in the skin of Tg mice as compared to wild-type controls. Most importantly, chronic UV irradiation of Tg mice induced the development of actinic keratosis-like lesions, which are considered in humans as precursors of squamous cell carcinomas (SCC), and subsequently of SCC in a significant proportion of the animals. In contrast, wild-type animals subjected to identical treatments did not develop any type of skin lesions. Thus, the oncoproteins E6 and E7 from beta HPV38 significantly contribute to SCC development in the skin rendering keratinocytes more susceptible to UV-induced carcinogenesis.
Background
Aminolevulinic acid photodynamic therapy (ALA‐PDT) is an effective treatment for multiple actinic keratosis (AK). However, PDT‐induced pain often discontinues the therapy to reduce its ...efficacy, limiting its application. If modified painless PDT schedule with shorter photosensitizer dressing and higher dose illumination could achieve good efficacy in AK, it is still unknown.
Objectives
To explore the efficacy and pain tolerance of the modified painless PDT (M‐PDT) in facial multiple AK.
Methods
A split‐face controlled clinical study including 14 patients with facial multiple AK was conducted. The patients received conventional PDT (C‐PDT) on the left and M‐PDT in the contralateral area. The left area (C‐PDT) was illuminated by a red light‐emitting diode light (144 J/cm2) after applying the 10% ALA cream for 3 h; the other had illumination for a total light dose of 288 J/cm2 after applying the 10% ALA cream for 0.5 h. The primary endpoint was the lesion clearance rate at 1‐month postthree sessions of PDT. Secondary endpoints included pain scores, the incidence of adverse events during treatment, and cosmetic outcomes.
Results
At 1 month following three treatments, the total lesion clearance rate was comparable between M‐PDT and C‐PDT (91.6% vs. 89.0%). While the lesion clearance rate of M‐PDT was higher than that of C‐PDT in the Grade III lesions (86.5% vs. 72.0%, respectively) (p < 0.05). M‐PDT achieved a 100% lesion clearance rate for Grade I lesions earlier than C‐PDT, with M‐PDT treated twice and C‐PDT treated thrice. Moreover, the pain score during illumination was significantly lower for M‐PDT than for C‐PDT (p < 0.01). Regarding photoaging, the Global Subjective Skin Aging Assessment score showed that the total and atrophy scores of C‐PDT and M‐PDT were significantly improved, and M‐PDT also reduced discoloration. There was no significant difference in adverse reactions between C‐PDT and M‐PDT.
Conclusions
M‐PDT is comparable to C‐PDT's efficacy for treating facial multiple AK, resulting in much lower pain scores.
Seborrheic keratosis (SK) is a common, benign tumor that can occur on everybody site and can be conservatively managed. Cosmetic concerns, especially when a lesion involves the facial area, are the ...most common reason for excision. SK shows male gender preponderance and increasing age is an independent association with the condition. Even though more prevalent in the elderly, it has also been reported in younger age groups like adolescents and young adults. Precise pathogenesis is still obscure, but ultra‐violet exposure represents a predisposing factor to SK by altering the biochemical concentration and expression of factors like Glutamine deaminases, endothelin, and stem cell factor. Moreover, the accumulation of amyloid‐associated protein has also been postulated. Involvement of genitalia has been associated with human papillomavirus infection. Recently, Merkel cell polyomavirus nucleic acid was also detected in SK. Several oncogenic mutations involving FGFR‐3 and FOXN1 have been identified. SKs are usually classified clinically and histologically. Dermatoscopy is a noninvasive alternative diagnostic technique widely used in differentiating SK from other benign and malignant tumors. In terms of treatment, topical agents, shave dissection, cryosurgery, electrodesiccation, laser application and curettage under local anesthesia are safe methods for eradication of SKs, mostly for cosmetic purposes. Though generally safe, the latter techniques may occasionally cause post‐procedure depigmentation, scarring, and recurrence. Nanosecond‐pulsed electric field technology is a promising new technique with fewer side‐effects.
Seborrheic keratosis, which is a benign tumor composed of epidermal keratinocytes, develops common in the elderly. Uric acid generated by upregulated guanine deaminase (
) has been identified to ...cause UV-induced keratinocyte senescence in seborrheic keratosis. Seborrheic keratosis is also frequently pigmented. Growing evidences indicate that hyperuricemia is a risk factor of acanthosis nigricans, an acquired skin hyperpigmentation. The objective of this study was to investigate role of
and its metabolic end product, uric acid, in hyperpigmentation of patients with seborrheic keratosis using their lesional and non-lesional skin specimen sets and cultured primary human epidermal keratinocytes with or without
overexpression or uric acid treatment.
-overexpressing keratinocytes or their conditioned media containing uric acid increased expression levels of MITF and tyrosinase in melanocytes. Uric acid released from keratinocytes was facilitated by ABCG2 transporter with the help of PDZK1 interaction. Released uric acid was taken by URAT1 transporter in melanocytes, stimulating melanogenesis through p38 MAPK activation. Overall,
upregulation in seborrheic keratosis plays a role in melanogenesis via its metabolic end product uric acid, suggesting that seborrheic keratosis as an example of hyperpigmentation associated with photoaging.
Actinic keratosis (AK) lesions are surrounded by field cancerization (areas of subclinical, non-visible sun damage). Existing AK grading tools rely on AK counts, which are not reproducible. An ...Actinic Keratosis Field Assessment Scale (AK-FAS) for grading the severity of AK/field was developed. Standardized photographs of patients representing the full range of AK severity were collected. Six investigators independently rated each photograph according to 3 criteria: AK area (total skin area affected by AK lesions), hyperkeratosis and sun damage. Inter-rater reproducibility was good for all 3 criteria. Validation of the AK-FAS showed good reproducibility for AK area and hyperkeratosis, even for dermatologists untrained on use of the scale. In conclusion, the AK-FAS is objective, easy to use and implement, and reproducible. It incorporates assessment of the entire field affected by AK instead of relying on lesion counts. Use of the AK-FAS may standardize AK diagnosis, making it relevant to routine clinical practice.
Field cancerization was first described in 1953 when pathologic atypia was identified in clinically normal tissue surrounding oropharyngeal carcinomas. The discovery of mutated fields surrounding ...primary tumors raised the question of whether the development of subsequent tumors within the field represented recurrences or additional primary tumors. Since this initial study, field cancerization has been applied to numerous other epithelial tissues, including the skin. Cutaneous field cancerization occurs in areas exposed to chronic ultraviolet radiation, which leads to clonal proliferations of p53-mutated fields and is characterized by multifocal actinic keratoses, squamous cell carcinomas in situ, and cutaneous squamous cell carcinomas. In the first article in this continuing medical education series, we define field cancerization, review the available grading systems, and discuss the epidemiology, risk factors, and outcomes associated with this disease.
Background
Seborrheic keratosis (SK) is one of the most common skin tumors seen by dermatologists. It should be differentiated with many diseases, especially skin tumors. Reflectance confocal ...microscopy (RCM) has been applied for evaluation of SK. There are a few studies that describe the RCM of SK. The aim of the study was to find the challenge of diagnosing seborrheic keratosis by reflectance confocal microscopy.
Methods
A total of 390 patients with a clinical suspicious diagnosis of seborrheic keratosis were enrolled in this study, and lesions from each patient were imaged with RCM. Thirty‐seven of these patients performed a biopsy in order to be given a histological diagnosis. We retrospectively analyzed the outcomes of RCM diagnosis and histological diagnosis, and then found the RCM characteristics of biopsy‐proven lesions.
Results
According to RCM images, 258 of 390 (66.2%) patients were diagnosed with SK, 97 of 390 (24.9%) patients could not be diagnosed by the dermatologist according to RCM. Of all 37 biopsied lesions, 23 were SK, 6 were actinic keratosis, 2 were basal cell carcinoma, and 2 were squamous cell carcinoma.
Conclusion
It is challenge to diagnose seborrheic keratosis by reflectance confocal microscopy. It may due to the variable clinical and RCM appearances of SK, and limited depth of RCM.
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