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Enrico Matteini,1,* Laura Diluvio,1,* Sara Lambiase,1 Arnaldo Cioni,1 Ruslana Gaeta Shumak,1 Gaetana Costanza,2 Caterina Lanna,1 Giacomo Caldarola,3,4 Luca Bianchi,1 Elena Campione1 1Dermatology Unit, Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy; 2Department of Experimental Medicine, University of Rome ”Tor Vergata”, Rome, Italy; 3UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli - IRCCS, Rome, Italy; 4Dermatologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy*These authors contributed equally to this workCorrespondence: Laura Diluvio, Dermatology Unit, Department of Systems Medicine, University of Rome “Tor Vergata”, Viale Oxford 81, Rome, 00133, Italy, Tel +39 06 20902743, Fax +39 06 20902742, Email lauradiluvio@yahoo.itAbstract: Alopecia areata represents an autoimmune disease that specifically damages growing hair follicles on the scalp and/or around the body. Janus kinase inhibitors have been identified as an effective therapy in adult patients and topical formulations, such as Brevilin-A, might represent a well-tolerated treatment for mild-moderate disease in children and adolescents. The mechanism of action of Brevilin-A, a sesquiterpene lactone isolated from Centipeda minima, could consist in blocking STAT3 and STAT1 signaling as well as the JAKs activity by inhibiting the JAKs tyrosine kinase domain JH1. We report our cases of successful application of Brevilin-A in pediatric patients, suggesting this treatment as a safe and effective therapeutic option also for recalcitrant alopecia areata in pediatric population.Keywords: alopecia areata, brevelin A, pediatric, topical JAK inhibitors

Elena Campione,1 Terenzio Cosio,1 Monia Di Prete,2 Caterina Lanna,1 Annunziata Dattola,1 Luca Bianchi1 1Dermatologic Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, 00133, Italy; 2Anatomic Pathology, University of Rome Tor Vergata, Rome, 00133, ItalyCorrespondence: Elena CampioneDermatologic Unit, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier,1, Rome, 00133, ItalyTel +39.06.20900252Email elena.campione@uniroma2.itAbstract: Psoriasis is a chronic, relapsing, immune-mediated systemic disease. Its pathogenesis is complex and not fully understood yet. Genetic and epigenetic factors interact with molecular pathways involving TNF-α, IL-23/IL-17 axis, and peculiar cytokines, as IL-36 or phosphodiesterase 4. This review discusses the mechanisms involved in the development of the disease, as well as the therapeutic options proposed following the investigation of the inflammatory psoriatic pathways. We performed a comprehensive search using the words “psoriasis” and the newest molecules currently under investigation and approval. From these data, a new scenario in psoriasis is occurring to personalize the therapies - especially systemic ones and those using small molecules – and avoid topical and injectable drugs. We reported the newest therapeutic opportunities, including the inhibitors of Janus kinase/tyrosine kinase 2, phosphodiesterase-4 and IL-36 receptor. Today, more than 20 molecules are under investigation for the treatment of cutaneous psoriasis. Most of them are constituted by small molecules or biologic therapies. This underlines how psoriasis needs systemic therapies, due to its complex pathogenesis and multisystemic involvement.Keywords: psoriasis, janus kinase inhibitors, tyrosine kinase 2 inhibitors, phosphodiesterase 4 inhibitors, IL-36 receptors inhibitors

Marco Ardigò,1 Chiara Franceschini,1 Elena Campione,2 Terenzio Cosio,2 Caterina Lanna,2 Luca Bianchi,2 Massimo Milani3 1Clinical Dermatology, San Gallicano Dermatological Institute, Rome, Italy; 2Dermatology Institute, Università Tor Vergata, Rome, Italy; 3Medical Department, Cantabria Labs Difa Cooper, Caronno Pertusella, VA, ItalyCorrespondence: Massimo MilaniMedical Department, Cantabria Labs Difa Cooper, Caronno Pertusella, ItalyEmail massimo.milani@difacooper.comPurpose: To investigate the efficacy of a cream containing purified omental lipids 10% and three anti-itching substances (polidocanol/stimutex/palmitoylethanolamine) in elderly subjects with chronic pruritus/prurigo nodularis (CP/CPN).Patients and Methods: Thirty-five subjects (6 men; mean age 67± 4 years) with CP/CPN were enrolled in a prospective, assessor-blinded, 4-week study. The cream was applied twice daily in the most affected body area. The primary endpoints were the evolution of the 10-cm visual analogue itch severity scale (VAS) and the 4-point verbal itching rating scale (VRS) (from 0 to 3). Secondary endpoints were the evolution of optical coherence tomography (OTC) of four skin parameters (acanthosis/hyperkeratosis/scale/dermal vascular pattern), assessed in a target lesioned area, and the transepidermal water loss (TEWL). Study endpoints were evaluated at baseline and after 2 and 4 weeks by an investigator unaware of the type of treatment.Results: All the enrolled subjects concluded the trial. At baseline, the mean±SD scores for VAS and VRS were 4.9± 2.2 and 1.7± 0.7, respectively. The treatment was associated with a significant reduction (p=0.0001) of VAS score of 60% at week 2 and of 86% at week 4. VRS score was significantly reduced by 49% after 2 weeks and by 81% after 4 weeks, in comparison with baseline. TEWL (expressed as g/m2/h) mean values were 18± 5.4 at baseline and 12.7± 4.4 at week 2 and 9.8± 4.7 at week 4 (P=0.0001 vs baseline). All the OCT parameters evaluated improved during active treatment; acanthosis grade was 0.22 mm at baseline, 0.19 mm at week 2 and 0.17 mm at week 4 (p=0.0005), representing a 23% reduction in comparison with baseline. The product was very well tolerated.Conclusion: This purified omental lipid with three anti-itching components cream reduces significantly itch intensity in subjects with chronic pruritus/prurigo nodularis, improving the skin barrier function and skin structure.Trial Number: ISRCTN869561669.Keywords: chronic pruritus, prurigo nodularis, purified omental lipids, itch, antipruritic

Caterina Lanna,* Gaia Maria Cesaroni,* Sara Mazzilli, Luca Bianchi, Elena Campione Dermatologic Unit, University of Rome Tor Vergata, Rome, Italy*These authors contributed equally to this workCorrespondence: Caterina LannaDermatologic Unit, Department of Systems Medicine, University of Rome Tor Vergata, Viale Oxford 81, Rome 00133, ItalyEmail caterinalanna.cl@gmail.comAbstract: Psoriasis is a common inflammatory skin condition frequently associated with cardiometabolic diseases such as diabetes. Indeed, the state of systemic inflammation typical of psoriasis leads to an increase in the level of IL-1, IL-6 and TNF-alpha which may cause a reduced sensitivity to insulin and, ultimately, can lead to type 2 diabetes mellitus. Particularly, the derangement of PDE4-cAMP signaling has a critical role in disordered glucose and lipid metabolism. Apremilast, as a selective inhibitor of PDE4-cAMP signalling, represents an innovative therapeutic strategy for psoriasis. Here, we report a case of a patient affected by psoriasis and diabetes, who – after using Apremilast – improved his glucose metabolism as well as his need of anti-diabetic drugs and his psoriasis. This suggests that, in addition to its role against psoriasis, Apremilast may even act as a metabolic modulator.Keywords: psoriasis, diabetes, PDE4-inhibitor

Elena Campione, Sara Mazzilli, Caterina Lanna, Terenzio Cosio, Vincenzo Palumbo, Gaia Cesaroni, Flavia Lozzi, Laura Diluvio, Luca Bianchi Dermatologic Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, ItalyCorrespondence: Elena CampioneDermatologic Unit, Department of Systems Medicine, University of Rome Tor Vergata, Viale Oxford 81, Rome 00133, ItalyTel +39 0620902743Email campioneelena@hotmail.comIntroduction: Seborrheic dermatitis is a common skin disease with clinical aspects similar to those of psoriasis, eczema or allergic reactions, appearing on the sebum-rich areas of the scalp, face, and trunk. Yeast like Malassezia species, immunologic abnormalities and activation of complement are recognized as a crucial pathogen for the onset of seborrheic dermatitis. Intermittent and active phases are characterized by burning, scaling and itching, then followed by inactive periods. The disease is sometimes severe up to the erythrodermia; thus, it has a great influence on the patient’s quality of life. In vitro and vivo studies have shown that the exogenous intake of glutathione-GSH-C4 and tocopherol inhibits lipid peroxidation and effectively fights and reduces oxidative stress in inflammatory disorders.Methods: We have carried out a study enrolling 20 patients affected by SD to evaluate the effectiveness and tolerability of a new topical formulation in cream (hereinafter SEB) containing GSH-C4 0.4% in hyaluronic acid 0.25% – a new synthetic glutathione derivate called INCI (butyroyl glutathione)-assigned by the Personal Care Council. Investigator Global Assessment score and Patient Global Assessment of Treatment scales were used to test the efficacy of this new formulation.Results: All patients showed a good clinical response to the treatment with topical SEB demonstrated by the gradual reduction in inflammatory skin lesions.Discussion: The results of our pilot study confirm the efficacy and tolerability of this new topical formulation in a real-life assessment and patients showed strong adherence to therapy. These promising results – still to be confirmed on a larger number of patients – emphasize the potential SEB has in controlling the chronic inflammation of seborrheic dermatitis.Keywords: seborrheic dermatitis, glutathione, pilot study

Laura Vollono1, Arianna Piccolo1, Caterina Lanna1, Maria Esposito2, Mauro Bavetta1, Elena Campione1, Luca Bianchi1, Laura Diluvio1 1Dermatology Department, University of Rome, Tor Vergata, Italy; 2Dermatology Department, University of L’Aquila, L’Aquila, ItalyCorrespondence: Laura VollonoDermatology Department, University of Rome Tor Vergata, Viale Oxford 81, Rome 00133, ItalyTel +39 06 2090 0252Email laura.vollono@gmail.comIntroduction: Omalizumab is a recombinant humanized anti-IgE monoclonal antibody, approved for patients affected by chronic spontaneous urticaria resistant to antihistamines. Although the clinical benefit of omalizumab has been established in several clinical trials, there are very little data about long-term treatment with this drug and real-life reports regarding its use in patients affected by comorbidities other than urticaria are lacking.Objectives: To assess omalizumab efficacy and safety in a heterogeneous population of patients affected by chronic spontaneous urticaria and several comorbidities in a real-world setting.Materials and methods: Patients affected by chronic spontaneous urticaria with weekly urticaria activity score >16 resistant to antihistamines were treated with omalizumab 300 mg injection as add-on to H1-antihistamines administered every 4 weeks for 6 months. Clinical assessment of weekly urticaria activity score, dermatology life quality index and blood tests were performed at baseline, 12, 24 and 52 weeks of treatment. Response was assessed based on reduction weekly urticaria activity score.Results: Thirty-two patients (22F; 10M) with a mean age of 52.4 years (range 27–72) affected by chronic spontaneous urticaria were enrolled. Comorbidities affecting our study population were divided into 6 categories: cardio-metabolic (77%), oncologic (19%), infectious (16%), allergic (45%) immunologic (41%) and others (18%). Omalizumab determined a satisfactory reduction of symptoms of chronic spontaneous urticaria and an amelioration of quality of life within our population. No relevant alterations regarding patients’ underlying conditions were encountered. This is the first study regarding the use of omalizumab for chronic spontaneous urticaria in a population of adult patients affected by several comorbidities, eg, cardio-metabolic, oncologic, infectious, allergic, immunologic and psychiatric diseases. Real-life data represent a valuable source of information about a drug’s safety and efficacy profile, especially in patients affected by different comorbidities that are widely diffused in Western countries.Keywords: chronic spontaneous urticaria, omalizumab, oncologic, cardiovascular, allergic and immunologic conditions, comorbidities

Mario Puviani,1 Elena Campione,2 Anna Maria Offidani,3 Roberta De Grandi,4 Luca Bianchi,2 Ivan Bobyr,3 Melania Giannoni,3 Anna Campanati,3 Marta Bottagisio,4 Alessandro Bidossi,4 Elena De Vecchi,4 Klaus Eisendle,5 Massimo Milani5,61Medica Plus Dermatology Outpatients Clinic, Modena, Italy; 2Dermatology Clinic, Tor Vergata University, Rome, Italy; 3Dermatology Clinic, Ospedali Riuniti Ancona University, Ancona, Italy; 4Laboratory of Clinical Chemistry and Microbiology, IRCCS Orthopedic Institute Galeazzi, Milan, Italy; 5Dermatology Clinic, Ospedale Centrale di Bolzano (BZ), Bolzano, BZ, Italy; 6Medical Department Cantabria Labs, Difa Cooper, Caronno Pertusella, VA, ItalyObjective: A new cream formulation containing hyaluronic acid 5%, complexed with a mix of a bacterial-wall-derived glycoprotein and peptide glycan complex (EDS), has been recently developed. We evaluated in a prospective, assessor-blinded, 6-week study the efficacy and tolerability of EDS in the treatment of facial seborrheic dermatitis (SD) and the effects on skin microbiota.Subjects and methods: Seventy-five subjects (mean age 46; 60 men) with moderate-severe SD of the face were enrolled. EDS cream was applied twice daily. The primary outcome was the evolution of the Investigator Global Assessment (IGA) score, evaluating erythema, scale/flaking, grade of seborrhea and itch. Superficial skin bacterial microbiome at baseline and after treatment was assessed, using the 16S rRNA gene methodology, in affected and non-affected face areas. Local tolerability was evaluated checking self-reported side effects at each visit.Results: Baseline IGA scores (mean±SD) was 10±3. The use of EDS reduced IGA score significantly by 70% at week 3 and by 88% at week 6. An increase in the abundance of Cutibacterium acnes genera associated with a significant drop of Staphylococcus genera presence was detected in affected areas. The ratio of relative abundance of genera Cutibacterium/Staphylococcus increased significantly after treatment in affected areas. The product was very well tolerated.Conclusion: Treatment with EDS applied twice daily for 6 consecutive weeks was associated with a reduction of the signs and symptoms of SD. Furthermore, after EDS cream treatment, a reequilibrating effect on facial skin microbiota was observed. The product was very well tolerated.Keywords: seborrheic dermatitis, skin microbiota, hyaluronic acid, assessor blinded trial

Virginia Garofalo, Maria Vittoria Cannizzaro, Sara Mazzilli, Luca Bianchi, Elena CampioneDivision of Dermatology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, ItalyBackground: Acne is a debilitating disorder that requires proper treatment depending on the clinical manifestations and pathogenetic factors, among which hyper-keratinization, seborrhea and bacterial proliferation. Combining active ingredients targeting the different mediators of acne pathogenesis may yield optimal outcomes.Purpose: The purpose of this study was to evaluate the clinical effectiveness, safety and tolerability of a new topical medical device in cream containing benzoylperoxide 4%, pure retinol 0.05%, palmitate retinol 0.5%, mandelic acid 1% and glycyrrhetic acid on patients with mild acne.Patients and methods: Twenty consecutive patients of both sexes with mild acne were included in the study. The topical treatment was self-applied twice a day for 12 weeks. Evaluations included: Global Acne Grading System (GAGS); inflammatory and non-inflammatory lesions count; reflectance confocal microscopy; seborrhea and hydration degree; photographic documentation; a questionnaire to assess tolerability.Results: The GAGS score showed a 39% reduction from T0 to T1 and 69.20% from T0 to T2. The count of comedonic lesions showed a 44% reduction from T0 to T1 and 65% from T0 to T2. The count of papular lesions diminished by 49.4% from T0 to T1 and by 62% from T0 to T2. The count of pustular lesions decreased by 43% from T0 to T1 and by 80% from T0 to T2. Improvement of hydration and a decrease of seborrhea degree were even observed. These clinical results were confirmed by reflectance confocal microscopy exam.Conclusion: The topical medical device has shown to be clinically effective and well tolerated for the treatment of mild acne. Side effects were mild, transient and well tolerated. The results of our study demonstrated a high tolerability of this new combination of benzoylperoxide 4% and retinol. Furthermore, our results suggested that the studied compound could be considered as a “maintenance treatment” after specific pharmacological treatment, even in more severe types of acne.Keywords: acne vulgaris, therapeutics, benzoyl peroxide, alpha hydroxide acid, vitamin A

Sara Mazzilli,1 Virginia Garofalo,1 Alessandra Ventura,1 Laura Diluvio,1 Massimo Milani,2 Luca Bianchi,1 Elena Campione1 1Department of Dermatology, University of Rome “Tor Vergata”, Rome, Italy; 2Medical Department, Cantabria Labs Difa Cooper, Caronno Pertusella, Italy 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. Keywords: actinic keratosis, piroxicam, thiazide diuretics, skin cancer

Roberta Gaziano,1,* Elena Campione,2,* Federico Iacovelli,3 Daniele Marino,1 Francesca Pica,1 Paolo Di Francesco,1 Stefano Aquaro,4 Francesco Menichini,4 Mattia Falconi,3 Luca Bianchi2 1Microbiology Section, Department of Experimental Medicine and Surgery, University of Rome ‘Tor Vergata’, Rome, Italy; 2Department of Systems Medicine, University of Rome ‘Tor Vergata’, Rome, Italy; 3Department of Biology, University of Rome ‘Tor Vergata’, Rome, Italy; 4Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy *These authors contributed equally to this work Introduction: Dermatophytosis is a superficial fungal infection limited to the stratum corneum of the epidermis, or to the hair and nails, and constitutes an important public health problem because of its high prevalence and associated morbidity. Dermatophyte fungi, especially 2 species, Trichophyton rubrum and Trichophyton mentagrophytes, are the predominant pathogens. Topical antifungal drugs, mainly azoles or allyamines, are currently used for the treatment of dermatophytoses, although in some cases, such as in nail and hair involvement, systemic treatment is required. However, therapeutic efficacy of current antifungal agents can be limited by their side effects, costs, and the emergence of drug resistance among fungi. Plant extracts represent a potential source of active antimicrobial agents, due to the presence of a variety of chemical bioactive compounds. In the present work, we evaluated in silico and in vitro the antifungal activity of an extract of the medicinal plant Cardiospermum halicacabum against T. rubrum suggesting a potential interaction with Hsp90 as playing an important role in both pathogenicity and drug susceptibility of T. rubrum. Methods: We investigated in vitro the effect of different concentrations of C. halicacabum (from 500 to 31.25 µg) against a clinical isolate of T. rubrum. Furthermore, using a computational assessment, the interaction between different C. halicacabum active compounds and the fungal Hsp90 was also investigated. Results: Our results indicate a clear-cut antifungal activity of the total plant extract at the highest concentrations (500 and 250 µg). Among all tested C. halicacabum compounds, the luteolin and rutin molecules have been identified in silico as the most important potential inhibitors of Hsp90. Based on these data, luteolin and rutin were also individually assessed for their antifungal activity. Results demonstrate that both substances display an antifungal effect, even if lower than that of the total plant extract. Conclusion: Our data indicate a strong fungistatic effect of C. halicacabum against T. rubrum, suggesting its potential therapeutic efficacy in the treatment of dermatophytoses. Additionally, C. halicacabum compounds, and particularly luteolin and rutin, are all possible Hsp90 interactors, explaining their fungistatic activity. Keywords: Trichophyton rubrum, dermatophytoses, Cardiospermum halicacabum, antifungal activity, Hsp90, molecular modeling, molecular docking, rutin, luteolin

Alessandra Ventura,1 Mauro Mazzeo,1 Roberta Gaziano,2 Marco Galluzzo,1 Luca Bianchi,1 Elena Campione1 1Department of Dermatology, University of Rome “Tor Vergata”, Rome, Italy; 2Department of Experimental Medicine and Surgery, Rome, Italy Abstract: Psoriasis is a chronic inflammatory disease affecting up to 3% of the general population. The prevalence of nail involvement in psoriasis patients varies between 15% and 79%. While the nails represent a small portion of the body surface area, psoriasis in these areas can have a disproportionate influence on a patient’s physical and psychosocial activities. Differential diagnosis between an onychomycosis and a psoriatic nail could be challenging; nevertheless, coexistence of onychomycosis and nail psoriasis also occurs and both are common disorders in the general population. Nail psoriasis can be difficult to treat. Treatment of nail psoriasis should consider the body surface area of skin disease, psoriatic arthritis, severity of nail disease, and the impairment in the quality of life. All patients should be tested for onychomycosis before starting a therapy. This recommendation is underlined by the fact that nail psoriasis is mostly treated by immunosuppressive drugs, like steroids, methotrexate, or biologics, which may aggravate mycotic nail infections. Conventional systemic therapy, such as use of steroids, cyclosporine, methotrexate, and retinoid in the long term, can cause organ toxicities. Currently, use of apremilast and tofacitinib favors an early healing of nail psoriasis because they act directly on the pathogenic targets, distressing the inflammatory signals associated with the initiation and maintenance of the disease activity, and as with several conventional synthetic disease modifying antirheumatic drugs, they are characterized by the convenience of oral administration. The number of treatment options has increased considerably in recent years; however, given the heterogeneity of the disease, the therapy should be personalized to individual cases. Keywords: nail, psoriasis, onychomycosis

Elena Campione,1 Monia Di Prete,1 Laura Diluvio,1 Luca Bianchi,1 Augusto Orlandi2 1Department of Dermatology, 2Department of Pathology, University of Rome Tor Vergata, Rome, Italy Abstract: Actinic keratosis (AK) is considered as superficial squamous cell carcinoma. Chronic sun exposure plays a central role in its pathogenesis. In particular, ultraviolet B radiation causes direct damage to the DNA, producing pyrimidine dimers that suppress the protective role of p53. Other risk factors include advanced age, male sex, and fair skin type. Even some drugs used for treating blood hypertension, such as thiazide diuretics, can increase the risk of developing AK. Their photosensitizing action seems to be connected with reactive oxygen species production. We report our experience on ten patients affected by multiple AK, in therapy with thiazide diuretics, treated by ingenol mebutate gel. AK was clinically and dermoscopically evaluated at baseline and after 30 days from the beginning of the treatment. Moreover, patients were screened for vitamin D3 values and reported a general hypovitaminosis status. To our knowledge, we report for the first time the efficacy of ingenol mebutate gel in this group of patients, particularly at risk of developing AK. Keywords: anticancer agents, antitumor activity, cancer cells, skin precancerous lesion

Elena Campione,1 Roberta Gaziano,2 Daniele Marino,2 Augusto Orlandi3 1Department of Dermatology, 2Department of Microbiology, 3Department of Anatomic Pathology, University of Rome Tor Vergata, Rome, Italy Purpose: Fungal infections are a major complication in hematologic and neoplastic patients causing severe morbidity and mortality. Aspergillus fumigatus and Candida albicans are among the most invasive opportunistic pathogens in immunocompromised patients, and classic antifungal drugs are frequently unsuccessful in these patients. Recent reports hypothesize that the antifungal efficacy of all-trans retinoic acid (ATRA) is mainly related to its strong capacity to stimulate monocyte-mediated immunity, but no consideration was given to its potential direct fungistatic activity. Moreover, ATRA offers the opportunity for systemic therapy. Methods and results: We investigated the efficacy of ATRA at different concentrations for its antifungal activity against opportunistic A. fumigatus and C. albicans obtained from clinical samples according to standard protocols. A fungistatic activity of ATRA on A. fumigatus and C. albicans at 0.5–1 mM concentration was documented up to 7 days. Conclusion: This is the first evidence of a direct and strong fungistatic activity of ATRA against A. fumigatus and C. albicans. The potential adjuvant therapeutic application of ATRA might be useful in the treatment and/or prevention of systemic mycoses in immunocompromised patients. The discovery of a direct fungistatic activity, in association with its reported immunomodulatory properties, makes ATRA an excellent candidate for new combined antifungal strategies for systemic mycoses in immunocompromised and cancer patients. Keywords: all-trans retinoic acid, fungistatic activity, fungal infections

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