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Elena Campione,1 Evelin Jasmine Paternò,2 Eleonora Candi,3,4 Mattia Falconi,5 Gaetana Costanza,2 Laura Diluvio,1 Alessandro Terrinoni,4 Luca Bianchi,1 Augusto Orlandi2,6,7 1Department of Dermatology, 2Department of Biomedicine and Prevention, 3Department of Experimental Medicine and Surgery, University of Rome “Tor Vergata”, 4Biochemistry Laboratory IDI-IRCCS, Faculty of Medicine, University of Rome “Tor Vergata”, 5Department of Biology, University of Rome “Tor Vergata”, 6Institute of Anatomic Pathology, University of Rome “Tor Vergata”, 7Tor Vergata University-Policlinic of Rome, Rome, Italy Abstract: Piroxicam (PXM), a nonsteroidal anti-inflammatory drug, is an enolic benzothiazine and a potent member of the oxicam series. The drug suppresses the synthesis of proinflammatory enzymes, such as cyclooxygenases-1 and -2 (COX-1 and 2), downregulates the production of prostaglandins (PGs) and tromboxanes, and inhibits polyamines production by blocking ornithine decarboxylase induction involved in nonmelanoma skin carcinogenesis. In addition, PXM is able to induce tumor cell apoptosis and suppresses metalloproteinase 2 activities. Skin carcinogenesis is a multistep process in which the accumulation of genetic events leads to a gradually dysplastic cellular expression, deregulation of cell growth, and carcinomatous progression. COX-1 upregulation plays a significant role in PG and vascular epidermal growth factor production supporting tumor growth. Increased level of PGs in premalignant and/or malignant cutaneous tumors is also favored by upregulation of COX-2 and downregulation of the tumor suppressor gene 15-hydroxy-prostaglandin dehydrogenase. Chemoprevention can be a hopeful approach to inhibit carcinoma occurrence before an invasive tumor develops. The chemopreventive effect of nonsteroidal anti-inflammatory drugs on nonmelanoma skin cancers has been established. In this study, we highlighted the different modalities of action of PXM on the pathogenesis of nonmelanoma skin cancer, analyzing and evaluating binding modes and energies between COX-1 or COX-2 and PXM by protein–ligand molecular docking. Our clinical experience about the local use of PXM on actinic keratoses and field cancerization is also reported, confirming its efficacy as target therapy. Keywords: COXs inhibitor, actinic keratosis, tumor progression, binding mode

Elena Campione,1 Evelin Jasmine Paternò,2 Gaetana Costanza,2,3 Laura Diluvio,1 Isabella Carboni,1 Daniele Marino,4 Cartesio Favalli,4 Sergio Chimenti,1 Luca Bianchi,1 Augusto Orlandi2,3 1Department of Dermatology, 2Department of Biomedicine and Prevention, 3Department of Anatomic Pathology, Policlinic Tor Vergata, 4Department of Microbiology, University of Rome Tor Vergata, Rome, Italy Background: Distal and lateral onychomycoses are the most frequent forms of onychomycosis, causing subungual hyperkeratosis that usually limits local penetration of antimycotic drugs. Tazarotene exerts anti-inflammatory and immune-modulating activities toward both infective agents and damaged keratinocytes. Given the well-documented efficacy of tazarotene on hyperkeratotic nail psoriasis, we investigated its therapeutic use in onychomycosis. Patients and methods: We designed a preliminary open clinical trial in patients affected by distal and lateral subungual onychomycosis of the toenails and verified the fungistatic activity of tazarotene in vitro. Fifteen patients were treated with topical tazarotene 0.1% gel once per day for 12 weeks. Mycological cultures and potassium hydroxide stains of nail samples were performed at the beginning and at the end of the study. Treatment was considered effective when clinical healing and negative mycological culture were obtained. Onycholysis, nail bed discoloration, and subungual hyperkeratosis were measured using standardized methodologies and analyzed by means of Mann–Whitney test and analysis of variance. Fungistatic activity of tazarotene was evaluated by disk diffusion assay. Results: Six patients (40%) reached a mycological cure on target nail samples already after 4 weeks of treatment. Complete clinical healing and negative cultures were reached in all patients at week 12, with a significant improvement of all clinical parameters of the infected nails. Disk diffusion assay after 48 hours of incubation with tazarotene solution showed a central area of inhibition in all examined fungal cultures. Conclusion: Our results documented a good clinical outcome using topical tazarotene 0.1% gel in distal and lateral subungual onychomycosis and its fungistatic activity of tazarotene in vitro. The majority of patients appeared cured at a 6-month follow-up. The efficacy and safety of tazarotene must be confirmed on a larger number of patients, although already documented in nail psoriasis patients often affected by onychomycosis. Keywords: antiproliferative agent, retinoids, fungistatic activity

The detoxifying enzyme glutathione-s-transferase pi (GST-π) is present in keratinocytes and melanocytes and exerts a protective role against tumour progression. Melanomas close to melanocytic naevus remnants occur less frequently on sun-exposed areas, whereas solar dermal elastosis, hallmark of chronic sun-damage, characterise melanomas on sun-exposed skin. We evaluated the expression of GST-π in 113 melanomas associated to melanocytic naevus remnants or to solar dermal elastosis, classified according to clinical characteristics, history of sun exposure, histological subtypes and AJCC staging. Chronically sun-damaged melanomas, identified by moderate-severe solar dermal elastosis, showed a lower nuclear GST-π expression and a higher thickness than those related to melanocytic naevus remnants (p < 0.03). Multivariate logistic regression analysis demonstrated that male gender and chronic sun-exposure are independent risk factors significantly associated to melanomas localised on the trunk (OR = 3.36, 95% CI: 1.31-8.65; OR = 5.97, 95% CI: 1.71-20.87). If confirmed on a larger series, lower expression of nuclear GST-π in melanoma cells could represent a possible marker of chronically sun-damaged melanoma pathogenesis.

Background: Hereditary syndromes frequently need the cooperation of different specialties to increase diagnostic competence. Multiple cutaneous and uterine leiomyomatosis syndrome is a rare autosomal dominant disorder caused by the mutations of the fumarate hydratase gene, demonstrated in 80 to 100 percent of affected individuals. This can be linked to an increased risk of renal cancer in both sexes. The skin involvement is described to highlight the diagnostic role of the cutaneous counterpart in identifying this rare syndrome., Case Presentation: A 37-year-old woman suffering from several uterine fibroids presented multiple, painful, papulo-nodules on her left subscapular side, both forearms and legs. The patient underwent surgery on six lesions: five were leiomyomas, whilst one was a dermatofibroma. Genetic sequencing did not evidence known fumarate hydratase gene mutations. Dermoscopy showed a brown delicate pigmented network and included leiomyomas among the non-melanocytic benign skin tumours featuring a dermatofibroma-like pattern. Abdominal computerized-tomography scan did not reveal renal cancer, but brain magnetic resonance imaging showed one asymptomatic cerebral cavernoma. The patient benefited from the surgical removal of the five larger cutaneous lesions and from gabapentin, which relieved her pain., Conclusions: This observation highlights the usefulness of dermoscopy in the diagnosis of cutaneous leiomyomas disclosing multiple cutaneous and uterine leiomyomatosis syndrome. Dermoscopy should be performed for non-melanocytic multiple lesions mimicking leiomyomas in a large number of patients, to establish a strict classification and identify false negative cases or evaluate them as dermatofibromas. In this case, the dermatologist recognized the risk of renal cancer and cerebral cavernomas.

Background: The cyclo-oxygenase enzymes 1 and 2 (COX-1 and COX-2) are both involved in skin tumorigenesis, causing inhibition of apoptosis, angiogenesis, invasiveness, recruitment of growth factors, immunosuppression, and production of carcinogens. Piroxicam is a nonselective nonsteroidal anti-inflammatory drug that blocks the activity of COX-1 and COX-2., Objective: To evaluate the efficacy and tolerability of piroxicam 1% gel in the treatment of actinic keratoses., Methods: Piroxicam 1% gel was applied twice daily for 12 weeks to 31 actinic keratoses. The lesions were evaluated clinically and by means of dermoscopy at an initial baseline visit, at intermediate visits, and after 90 days. Changes were evaluated using a new scoring system (AKESA), based on the clinical presence of erythema, scale, and atrophy on a target lesion. In our experience, the use of piroxicam 1% gel for 90 days induced complete regression in 48% of evaluated actinic keratoses, corresponding to keratotic and verrucous clinical variants. In these lesions, the AKESA score was markedly reduced after treatment. Adverse effects were pruritus, mild erythema, dry skin, and, rarely, rash. Our preliminary trial shows that piroxicam exerts anti-tumorigenic effects and may play a useful role in the chemoprevention of skin cancers.

Background: Bilateral T2 to T3 thoracoscopic sympathectomy and injection of botulinum toxin-A are presently the most effective modalities in the treatment of primary palmar hyperhidrosis. In this study we evaluated comparative merits of the two therapies., Methods: Patients suffering primary palmar hyperhidrosis were treated by either bilateral T2 to T3 thoracoscopic sympathectomy (n = 68) or by injection of botulinum toxin-A (n = 86). The groups were homogeneous for relevant demographic, physiologic, and clinical data. Quantification of sweat production was performed by Minor's iodine starch and glove tests. Subjective changes were assessed by quality of life questionnaires (Hyperhidrosis, Dermatology Life Quality Index, Short Form-36, Nottingham's Health Profile) and patient's satisfaction self-assessment. A cost comparison between groups was also carried out., Results: No operative mortality or major morbidity was recorded in either group. Minor's test showed a more significant reduction in the surgical group: +94% versus +63% at 6 months and +94% versus +30% at 12 months. Compensatory sweating was significantly greater and long-lasting in the surgical group. All subjective tests improved rapidly and significantly in both groups. After 6 months, results mildly worsened in the surgical group and more significantly in the botulinum group. Patient's satisfaction was initially greater in the botulinum group (p = 0.03), but after 6 months it significantly reversed (p = 0.04). Surgical treatment cost approximately as much as four botulinum treatments., Conclusions: Thoracoscopic sympathectomy is superior to botulinum toxin-A injection. The greater initial costs and discomfort are offset by a greater reduction in compensatory sweating.

Imiquimod is a 240.3-Da synthetic imidazoquinolinamine (C14H16N4), developed in 1983 and approved in 1997 by the US Food and Drug Administration for the topical treatment of external genital and perianal warts and, more recently, also for actinic keratosis and superficial basal cell carcinomas. We report five cases of patients affected by basal cell carcinomas localized in seborrhoeic areas of the face, successfully treated with topical imiquimod and characterized by the occurrence of eruptive epidermoid cysts at the end-point of therapy. The dermatoscopic evaluation disclosed the presence in all lesions of a common feature characterized by a hyperkeratotic yellow-withish area, resembling 'popcorn', excluding dermoscopic basal cell carcinoma features. Furthermore, histological proof confirmed the diagnosis of epidermoid cysts. As reported in the literature and as observed in our clinical experience, the occurrence of epidermoid cysts, after the topical treatment of basal cell carcinomas with imiquimod, may represent a local immune reaction that is drug-related and is a typical remission pattern in particular anatomical areas. We also emphasized the usefulness of dermoscopy in supporting the clinical diagnosis of epidermoid cysts, excluding the presence of tumoural residue or recurrence. In the future, it will be possible to follow-up the lesions after treatment avoiding the post-control biopsy punch.

The cases are reported of two women patients presenting asymptomatic solitary lesions: one in the anterior tibial region of the right leg, the other on the right arm. The first patient's lesion was 3 cm in diameter and had appeared 2 years earlier as a translucent oval atrophic patch with a definite border. The second patient presented a whitish area with a lilac ring, 2.5 cm in diameter, which had appeared nearly a year earlier. Both patients had no other similar cutaneous lesions, and their family histories for cutaneous disease were negative. The lesions underwent punch biopsy, and the histopathological findings confirmed the diagnosis of morphea. Laboratory investigations showed no abnormalities. Imiquimod 5% cream was prescribed for 5 consecutive days a week for 16 weeks. Clinical and dermoscopic assessment of the lesions was performed before treatment, during follow-up and at treatment end point. No local or systemic side effects were observed during treatment. Following treatment, both patients achieved complete clinical remission of the lesions, with a definitive improvement in the lesions' initial disfiguring features.

Case 1. A 54 year old woman affected by chronic asthmatic bronchitis from the age of 11 years and ulcerous recto-colitis from 15 years, presented several erythematous-violaceous macules from the trunk including abdominal region to all skin surface except the face. Case 2. A 17 year old woman presented a similar hyperpigmentation in the same areas. In both patients histology showed a thin epidermis with vacuolar changes of basal layer and apoptotic bodies and melanophages rich in melanosomes in the papillary dermis. Our diagnosis was Ashy dermatitis. Clinico-pathological correlations and treatment options are discussed.

Keratoacanthoma (KA), a cutaneous neoplasm histologically resembling squamous cell carcinoma, is characterized by rapid growth and common spontaneous regression. The regression depends on an individual's immune response. We are reporting a case of a 53-year-old man who presented with an ulcerated tumor, which had arisen as a nodular lesion 9 months earlier. This was localized on the the left thumb. The patient had undergone a kidney transplant after severe glomerulonephritis. Following the operation, he was treated with systemic immunosuppressive drugs and developed multiple non-melanoma skin cancers. The histology examination of biopsy specimens was consistent with keratoacanthoma and showed low-density chronic inflammatory cells. Our patient refused surgical excision, so we prescribed imiquimod 5 percent cream once daily for 5 days a week. After 6 weeks of treatment the lesion had regressed completely, yielding an excellent cosmetic result. Continued resolution was documented 3 years after treatment. The patient had no signs of graft rejection related to the imiquimod treatment.

Nail psoriasis occurs in 7% to 40% of children, with a similar pattern of clinical presentation to that of adults. In 0.6% to 2.3% of the patients nail changes appear as the only sign of the disease, preceding other skin and articular involvement. No pediatric clinical trials are available yet, but considering the successful use of tazarotene for nail dystrophy therapy in adults, we chose this drug to treat a child.