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.

Overview of germline and somatic genetic alterations in basal and squamous cell carcinoma: a review of the current literature.

Non-melanoma skin cancers (NMSCs), including basal and squamous cell carcinomas, represent the most common malignancies among Caucasians. Over two million cases of NMSC occur each year in the US, with a progressive increase in incidence. There are well-known environmental risk factors, such as iatrogenic or ionizing radiation exposure, but the effect of chronic ultraviolet radiation, especially ultraviolet B radiation, is one of the main predisposing factors. Currently, based on our knowledge of the pathophysiology of most NMSCs, we have a better understanding of the associated genetic risk factors. The aim of this study was to evaluate the factors that contribute to the onset of NMSC through a comprehensive literature research.

Combination of Laser Therapy and Photodynamic Therapy with 5-Aminolevulinic Acid Patch for the Treatment of Actinic Cheilitis.

Background: Actinic cheilitis (AC) is a premalignant lesion of the lips that can evolve into squamous cell carcinoma. Among nonsurgical treatments, photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) patch might represent a new noninvasive therapeutic approach for AC. Objective: We sought to investigate the potential role of fractional CO2 laser pretreatment in boosting ALA penetration and distribution into AC treated with PDT. Methods: We report a case of a woman with AC on the lower lip, treated with ablative fractional CO2 laser to boost drug delivery of 5-ALA patch before PDT treatment. Reflectance confocal microscopy was performed to assess diagnosis and treatment response. Results: We detected a good clinical and cosmetic outcome after two applications of combined treatment. Erythema, crust, and edema were reported as side effects. Conclusions: This case report shows that ablative fractional CO2 laser-assisted PDT might be an effective therapeutic alternative for patients with AC who refuse or are contraindicated for surgical procedures.

The combined role of clinical, reflectance confocal microscopy and dermoscopy applied to chronic discoid cutaneous lupus and subacutus lupus erythematosus: A case series and literature review.

Main subtypes of cutaneous lupus erythematosus are represented by acute, subacute cutaneous, intermittent and chronic cutaneous lupus erythematosus. Discoid lupus erythematosus represents the most common phenotype of chronic cutaneous lupus erythematosus. The spectrum of clinical manifestations mirrors that of several and distinct histopathological features. Such variability among different CLE subtypes is also observed at dermoscopy. Dermoscopy is nowadays considered an additional valuable method for skin lesions assessment in general dermatology, following and completing the well-known clinical diagnostic steps, such as medical history and clinical examination. In vivo reflectance confocal microscopy (RCM) is a non-invasive imaging tool able to assess the epidermis and upper dermis producing high resolution (horizontal ∼1.25 µm, vertical ∼5 µm), en face tissue sections used for melanocytic and inflammatory evaluation. In this study, we reported dermoscopic and RCM features about 9 patients affected by subacute and chronic lupus erythematosus retrospectively analyzed.

Efficacy of certolizumab pegol in naïve versus multi-treated patients affected by psoriatic arthritis.

BACKGROUND: The efficacy and safety of certolizumab pegol over 52 weeks was compared in two groups of patients: Group 1 comprised patients naïve to biologic treatments; Group 2 comprised patients previously treated with one or more antitumor necrosis factor (TNF)-α and/or anti-interleukin (IL) agents. METHODS: We reported results in 50 patients affected by both mild psoriasis (PsO) and psoriatic arthritis (PsA). Primary endpoint was a reduction from baseline at week 52 of Disease Activity Score (DAS44-ESR) in both groups of patients. Secondary endpoints were a reduction from baseline at week 52 of Psoriasis Area Severity Index (PASI), Visual Analog Scale for Pain (PAIN VAS), ESR, CRP, and Dermatology Life Quality Index (DLQI). RESULTS: We observed a statistically significant improvement of both cutaneous and rheumatic disease in all patients, with a consistent reduction of DAS44-ESR, PASI, and PAIN VAS from baseline to week 52. DAS44-ESR decreased from 3.9 at BL to 1.5 at W52 (Group 1), and from 3.8 to 1.7 at W52 (Group 2). Mean PASI Score decreased from 3.2 at baseline (BL) to 0.4 at W52 (Group 1), and from 5.4 to 0.7 at W52 (Group 2). Mean PAIN-VAS decreased from a value of 73.5 at BL to 2.5 at W52 (Group 1), and from a value of 62.4 at BL to 9.2 at W52 (Group 2). We also found a reduction in ESR, CRP and DLQI values for each time point. CONCLUSIONS: Our results confirm that CZP can be administered safely and effectively to treat both psoriasis and psoriatic arthritis irrespective of previous treatments with biologic agents.

Reflectance Confocal Microscopy Applied to Linear (en Coup de Sabre) Morphea.

En coup de sabre morphea is a clinical variant of morphea, presenting as a linear depressed, atrophic area in the paramedian forehead or the frontoparietal scalp, resembling a stroke from a sword. It affects the skin and subcutaneous connective tissues, with possible extension to the underlying musculature, cartilage, and bone and variable association with neurologic symptoms. A 50-year-old woman presented to our clinic for evaluation of an atrophic lesion on her forehead and scalp appearing 1 year before, progressively extending over time. An alopecic atrophic area involving the skin and subcutaneous tissues of her right forehead and scalp arranged in a linear fashion with an "en coup de sabre" appearance was observed in relation with hair loss in the affected area. Reflectance confocal microscopy showed marked hyperreflective areas with severe eccrine gland atrophy. All sebaceous glands had disappeared, with sporadic follicular persistence reduction. Histopathological examination of a punch biopsy specimen taken from a central parietal alopecic area was consistent with a diagnosis of morphea. To our knowledge, this is the first report regarding the use of reflectance confocal microscopy as an ancillary diagnostic technique in linear localized morphea of the scalp and face. This noninvasive technique may represent a useful tool in distinguishing between early stages of the disease, with prevalence of inflammatory lymphocytic infiltrate, and late stages characterized by more prominent sclerosis with mild or absent signs of inflammation.

Reflectance Confocal Microscopy of Pigmented Bowen's Disease: A Case Series of Difficult to Diagnose Lesions.

Pigmented Bowen's disease is a rare variant of in situ squamous skin cell carcinoma. It mainly affects patients between 60 and 70 years of age. Its clinical features include well-demarcated, pigmented plaque arising in photo-exposed areas of the body. The best-characterized feature of the disease by histological examination is the presence of atypical keratinocytes, hyperpigmentation of the epidermis with trans-epidermal elimination of melanin and dermal melanophages. Precise diagnosis is often difficult, both clinically and dermoscopically, as Bowen's disease is often mistaken with keratinocyte tumors such as solar lentigines, seborrheic keratosis, Bowenoid papulosis, pigmented basal cell carcinoma, pigmented actinic keratosis; or even melanocytic lesions such as melanocytic nevus, pigmented epithelioid melanocytoma, and melanoma. Precise diagnosis often requires biopsy and histopathological examination of the tissue. Reflectance confocal microscopy is a noninvasive technique to diagnose pigmented skin lesions. To date, not much data are available regarding its use in the diagnosis of pigmented Bowen's disease. Herein, we report a well-represented case series of pigmented Bowen's disease imaged using dermoscopy and reflectance confocal microscopy.

Melanocytic lesion in children and adolescents: an Italian observational study.

Malignant melanoma is a rare neoplasm in the pediatric age group. One of the main risks factors is represented by the presence of a high number of melanocytic nevi. Sun exposure in pediatric age represents a predictor of melanocytic nevi number in the adult age and there is a direct correlation between the presence of melanocytic moles in early childhood and the development of many nevi in adults, suggesting that a high number of nevi in childhood should be considered as a predictor of melanoma development during adult life. The predominance of dermoscopic types of melanocytic nevi varies according to the individual's age and depends on endogenous or exogenous signaling, suggesting different pathways of nevogenesis. We evaluated the total amount of melanocytic nevi of pediatric patients and their prevalent dermoscopic pattern. We investigated the reasons for dermatological examination, pointing out the role of older parents' populations in the decision to refer to a dermatological consultant. We performed a prospective observational study on 295 pediatric outpatients consecutively enrolled from July 2018 to July 2019. Descriptive and inferential statistical analyses were performed using logistic and linear regression. 49% of children were characterized by less than 10 nevi, 45% of children by a number of nevi between 10 and 30, whilst 17 patients (5%) had a number of nevi between 30 and 50. The most prevalent dermoscopic pattern was the globular one. An older parenting age was correlated with an autonomous reason for referral and a later first visit. Our data agreed with previous suggestions demonstrating a strong influence of latitude, sun exposure and ethnic background in the development of the number of nevi. To our knowledge, this is the first study, which evaluated the reasons for dermatological examination and the role of older parents' populations in the decision to refer to a dermatological consultant.

Lichenoid Keratosis: A Clinical Trap without Secrets for Reflectance Confocal Microscopy.

Lichenoid keratosis, also defined as benign lichenoid keratosis, was reclassified as lichen planus-like keratosis by Shapiro and Ackerman. Clinical and dermoscopic features of lichen planus-like keratosis can vary, often not providing useful and necessary information to perform an accurate diagnosis without performing a biopsy or histological examination. We describe 2 difficult to detect lichen planus-like keratosis cases in which we performed reflectance confocal microscopy. We underline the usefulness of this noninvasive diagnostic tool in the unclear cases of lichen planus-like keratosis.

Dermoscopy and Reflectance Confocal Microscopy in the Diagnosis and Management of Nail Fold Squamous Cell Carcinoma.

The management and prognosis of squamous cell carcinoma largely depend on its invasiveness and grade of differentiation. Pigmented nail fold squamous cell carcinoma represents a therapeutic challenge, needing careful treatment to preserve nail function. Here, we report the use of dermoscopy and Reflectance Confocal Microscopy to monitor nail fold squamous cell carcinoma in situ and its response to treatment with topical imiquimod.

The Dark Side of Gefitinib: Reflectance Confocal Microscopy Applied to Hair Hyperpigmentation.

Gefitinib is a multi-target tyrosine kinase inhibitor used for the treatment of non-small cell lung cancer. Papulo-pustular and/or paronychia, abnormalities in hair growth, itching, and dryness due to epidermal growth factor inhibitors - i.e., PRIDE Complex - are a common effect of tyrosine kinase inhibitors. We report a case of hair and eyebrow hyperpigmentation after 7 months of treatment with gefitinib. In the literature, we found no data regarding rapid pigmentation of hair due to treatment with any multi-target tyrosine kinase inhibitors. To our knowledge, this is the first case reporting both hair and eyebrow hyperpigmentation. We hypothesize the role of different mechanisms linked to rapid hair hyperpigmentation.

New Insight in Noninvasive Rejuvenation: The Role of a Rhodamine-Intense Pulsed Light System.

Background: Rhodamine-intense pulsed light (r-IPL) is a noncoherent, noncollimated, polychromatic light energy optimized for a double-peak wavelength emission, ranging between 550-680 and 850-1200 nm. Traditional IPL works within visible and infrared spectra, targeting hemoglobin and melanin, are effective to treat rosacea and pigmentary disorders. r-IPL, a new technology in dermatology, emits high-intensity light with a wavelength peak similar to the one of the pulsed dye lasers, showing a good safety and efficacy profile in nonablative photorejuvenation. Objective: Assess efficacy and safety of r-IPL on photodamaged facial skin showing hyperpigmentation, telangiectasias, fine lines, and textural changes. Methods: Five sessions of r-IPL treatment (fluence ranged between 13.5 and 14 J/cm2) have been performed on one 75-year-old lady affected by facial photodamaged skin. Efficacy of treatment was evaluated using the Fitzpatrick Elastosis and Wrinkles Scale (FEWS) and the Global Aesthetic Improvement (GAI) Scale assessed by an investigator, compared with baseline. Treatment safety and tolerance were also evaluated using the Visual Analog Scale (VAS). Results: Photographic and multispectral evaluation demonstrated relevant improvement (vascular, pigment, and texture) of photodamaged facial skin. One month after the last treatment, significant improvement in facial wrinkle and texture was noted. FEWS scores decreased significantly from 7 to 2. According to the GAI scale, the patient had an improvement in skin texture. Immediate response included mild-to-moderate erythema and only trace-mild edema in the treatment area. Pain during the treatment was minimal with a mean VAS pain score of 3/10. No other adverse events were reported. No post-treatment downtime was recorded. Conclusions: r-IPL may represent a valid therapeutic approach in noninvasive photorejuvenation.

Investigational drugs currently in phase II clinical trials for actinic keratosis.

INTRODUCTION: Actinic keratoses (AKs) are limited areas of irregular epidermal growth on a background of excessive solar exposure. The entire sun-damaged skin is considered a field of cancerization with multiple visible and subclinical lesions. AK management requires field-directed therapies to block lesion relapse and prevent squamous cell carcinoma (SCC). AREAS COVERED: In this review, we focused on phase II clinical trials for AKs, involving well-known agents and newer molecules such as proapoptotic drugs (VDA-1102, SR-T100, oleogel-S10, ICVT, eflornithine), immunomodulants (isotretinoin, tretinoin) and chemopreventive agents (nicotinamide, perillyl alcohol, liposomal T4N5). We used the website 'ClinicalTrials.Gov' as main reference. We selected and discussed completed and ongoing trials and analysed chemical structure and mechanism of action of the investigated molecules. EXPERT OPINION: AK therapy should be tailored on the patient's profile considering first of all the age and site of the AKs, which are relevant parameters for local immune response. The new molecules could be combined to obtain a synergic effect blocking the different steps of skin tumorigenesis. Phase II trials highlight a new therapeutic opportunity to block selectively cell proliferation regulators and work both on the field of cancerization and on the AKs currently present.

Effects of topical piroxicam and sun filters in actinic keratosis evolution and field cancerization: a two-center, assessor-blinded, clinical, confocal microscopy and dermoscopy evaluation trial.

Background: Actinic keratosis (AK) is considered an "in situ" non-melanoma skin cancer induced by ultraviolet chronic exposure. Sunscreen and topical anti-inflammatory agents like diclofenac could improve the evolution of this kind of lesions. A topical product containing piroxicam 0.8% and sun filters (50 SPF) (ACTX) has been shown to be very effective in reducing AK lesions. So far, no data are available regarding the effects of this product on skin modifications evaluated by reflectance confocal microscopy (RCM) and dermoscopy at the lesion sites and on the skin around the lesions (field cancerization). Study aim: To evaluate in a two-center, assessor-blinded, prospective trial the effect of ACTX on AK number, RCM and dermoscopy parameter evolution of a target lesion in subjects with multiple AK lesions. Subjects and methods: A total of 54 subjects (42 men and 12 women; mean age 65 years) with AK lesions grade I-III located on the scalp (n = 36) or face (n = 18) were enrolled after their written informed consent. ACTX was applied twice daily on the face and scalp for six consecutive months. AK lesion count was performed at baseline and after 3 and 6 months. Lesion count was assessed in a blind fashion evaluating digital color high definition images performed at each visit and coded in a blinded fashion. RCM evaluations were performed at the same time-points. A dermoscopy evaluation was performed at baseline and after 6 months. RCM and dermoscopy were assessed on a pre-specified target lesion. The RCM severity score was used evaluating 11 items, examining stratum corneum, stratum granulosum, stratum spinous and dermal layers (maximum score 11 points). The dermoscopy score evaluated erythema, scaling and follicular plugs (from 0 to 4 for each item) and pigmentation (from 0 to 5). Results: Forty-nine subjects (90%) concluded the trial. At baseline, the mean (SD) number of AK lesions was 9.6 (5.2). AK lesions significantly decreased to 5.9 and to 5.6 after 3 and 6 months of ACTX treatment (p = .001; intention to treat analysis), representing a -42% reduction. A reduction of AK lesion numbers >50% in comparison with baseline was observed in 51% of subjects at month 6. New AK lesions appeared in five subjects (9%). The RCM mean (SD) severity score at baseline was 6.4 (2.0). ACTX treatment was associated with a progressive and significant (p = .002) reduction to 4.9 after 3 months and to 4.8 (2.3) at month 6 (a -25% reduction). The dermoscopy score at baseline was 5.5 (2) and it was reduced significantly (p = .007) to 4.5 (2) at the end of the study. The product was in general very well tolerated. Conclusion: A 6 month application of ACTX in subjects with AK lesions was associated with an improvement in AK lesion count and with a reduction in the RCM/dermoscopy severity scores of the target lesion. Trial registration number: ISRCTN22070974.

Efficacy of sinecatechins 10% as proactive sequential therapy of external genital warts after laser CO2 ablative therapy: The PACT study (post-ablation immunomodulator treatment of condylomata with sinecatechins): a randomized, masked outcome assessment, multicenter trial.

External genital warts (EGW) are the most common viral sexually transmitted infection. Ablative treatments like cryotherapy, curettage, and CO2 laser therapies offer rapid onset of effect, fast clearance, and reduction of virus load. However, these procedures are associated with high recurrence rates (RRs) ranging from 20% to 77% in the short and medium terms and do not provide sustained clearance. After laser therapy removal of EGW, an RR up to 77% has been reported. Topical sinecatechins (TS) 10% is a patient-applied regimen for the treatment of EGW with a low RR (<6.5%) at three months after completion of the therapy in the pivotal trials conducted so far. Sinecatechins can be considered a suitable proactive sequential therapy (PST) after ablative strategies to obtain a low RR. So far, no prospective data are available regarding the efficacy of sinecatechins 10% as PST. We evaluated the efficacy and tolerability of TS 10% ointment applied twice daily in subjects with "difficult to treat" EGW after CO2 laser ablative treatment in a prospective controlled trial. A total of 87 subjects (76 men and 11 women; mean age 42 years) were enrolled in this three-month masked outcome assessment parallel group trial with imbalanced randomization allocation (2:1). One week after a successful CO2 laser treatment, 60 subjects were randomized to TS 10% treatment and 27 subjects to no treatment (control group: ConTRol (CTR); no sequential therapy). All patients had a history of an average of 4.5 previous ablative treatments in the last 12 months due to recurrent EGW. Mean (standard deviation) baseline number of treated lesions was 6.5 (2.7). One subject in the TS arm dropped out due to burning sensation after the application of the product. Therefore, 86 subjects completed the study. After three months, in the TS group, three subjects presented new EGW lesions (RR: 5%) on treated sites. In the CTR group, eight subjects presented new EGW lesions (RR: 29%) on treated sites (p = 0.0024; odds ratio: 0.16; 95% confidence interval: 0.04-0.68). In the TS group, 34 subjects (56%) reported mild to moderate erythema or burning sensation at the application site. In this prospective multicenter trial, the use of TS 10% as PST after ablative treatment with CO2 laser was associated with a lower recurrence rate of new EGW lesions in the short term in comparison with the control group. Comparative larger trials are warranted to evaluate the role of this approach as PST (Trial Registration Number: ISRCTN44037479).

Effects of topical 0.8% piroxicam and 50+ sunscreen filters on actinic keratosis in hypertensive patients treated with or without photosensitizing diuretic drugs: an observational cohort study.

BACKGROUND: Photosensitizing diuretics use (especially thiazide compounds) is associated with a significantly higher risk of squamous cell carcinoma (SCC). Actinic keratosis (AK) is a precursor of SCC. STUDY AIM: To evaluate in a prospective cohort study the efficacy of topical piroxicam 0.8% and sunscreen 50+ (ACTX) in the treatment of AK in hypertensive subjects with or without TD treatment. SUBJECTS AND METHODS: A total of 119 hypertensive subjects with multiple AK (39 under chronic TD treatment; and 80 treated with other non-TD, non-photosensitizing antihypertensive drugs) were enrolled after their informed consent in a 6-month observational cohort study. All the subjects were treated with ACTX twice daily. The primary endpoint was the evolution of AK lesions at baseline, after 3 and 6 months. The secondary endpoint was the clearance of AK target lesions and field of cancerization by dermoscopic evaluation using a score evaluating erythema, scaling, pigmentation, and follicular plugs (ESPFP score; ranging from 0 to 20). An investigator, unaware of the type of antihypertensive treatments (TD or non-TD), performed all the clinical and dermoscopy evaluations. RESULTS: At baseline, AK mean (SD) lesion number in TD group was 14.1(4) and 14.6(4) in the non-TD group. ESPFP mean (SD) score at baseline was 5.8(1.2) in both groups. A significant reduction of AK lesions in comparison with baseline was observed in both groups. A statistically significant greater reduction was observed in TD in comparison with the non-TD group (-54% vs -32%). ESPFP score was reduced in a higher proportion in the TD group in comparison with the non-TD group (-60% vs -37%, respectively). ACTX treatment was very well tolerated. CONCLUSION: In hypertensive subjects with multiple AK, the topical use of ACTX is associated with a significant reduction of lesions count with an improvement in the field cancerization. The clinical efficacy is more pronounced in subjects under thiazide diuretics treatment.