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Epidermolytic PalmoPlantar keratoderma (EPPK) Vörner-type is an autosomal dominantly inherited skin disease, characterized by severe thickening of the palms and soles, caused by mutations in the keratin K9 (KRT9) gene. To date, a number of KRT9 mutations have been detected, most of which affect the highly conserved 1A region of the central alpha-helical domain, important for keratin heterodimerization. The most common mutation is the substitution of the arginine in position 163 with a tryptophan (R163W), which has been reported in North American, European, and Japanese populations. In a small number of cases, EPPK is associated with knuckle pad keratosis, but no correlation between this additional phenotype and a specific mutation has been found. Moreover, K9 is not normally expressed in knuckle skin, raising the question of the pathogenic mechanism leading to this additional phenotype. Here we show that in a family affected by EPPK and knuckle pad keratosis, carrying the R163W substitution, wild type (wt) and mutated K9 are strongly expressed in knuckle pads. These results suggest that the knuckle pad phenotype is due to ectopical expression of K9.

Background: Multimarker reverse transcriptase-polymerase chain reaction (RT-PCR) was originally reported to reveal melanoma-associated mRNAs (MAMs) in melanoma cells but not in the peripheral blood of healthy individuals., Objectives: To evaluate the expression of MAMs in the peripheral blood of melanoma patients at different American Joint Committee on Cancer (AJCC) stages, and to correlate their presence with early and/or advanced stages of the disease., Materials and Methods: One hundred blood samples of melanoma patients (AJCC I-IV) were analysed using multimarker RT-PCR to assess the co-expression of Tyr-OH, MART-1, MAGE-3, MUC-18/MCAM and p97. Patients were stratified into two disease categories: early and advanced stages. The former includes in situ and melanoma stages AJCC I-II, the latter AJCC III-IV. chi(2) and Fisher's exact tests were used to statistically evaluate the association between each MAM and disease categories. The recognized significant associations were subsequently resubmitted to univariate logistic regression. Furthermore, sensitivity and specificity were established., Results: At least one MAM could be detected in 24% of our series. Tyr-OH was the most common marker (14%), followed by MUC-18 (12%), MART-1 (5%), MAGE-3 (4%) and p97 (3%). No significant association among Tyr-OH, MART-1, MAGE-3, p97 and disease stages were evidenced. Only MUC-18 was statistically associated (P < 0.009) with advanced stages alone or co-expressed with other MAMs. According to logistic regression univariate analysis, MUC-18 increases the probability (odds ratio: 33) being in advanced stages and the incidence of recurrences (95% CI 2.9-374)., Conclusions: MUC-18 RT-PCR assay could be proposed as an adjunctive molecular method in the management of melanoma patients and is useful in the monitoring of study protocols.

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.

Background: Animal-type melanoma (ATM) is a rare variant of the tumor showing diffuse, heavily pigmented neoplastic cells in the dermis. Despite the high mean thickness of the lesions, reports seem to indicate a less aggressive behavior and a better survival rate for ATM compared with conventional melanoma, but the underlying pathways related to this favorable outcome are still unknown., Observations: Five women and 2 men aged 20 to 92 years presented with pigmented skin nodules (n = 5) or plaques (n = 2), varying in size from 1.0 to 4.5 cm. Findings from microscopic examination showed monotypic-appearing melanocytes with abundant intracytoplasmic melanin in a nodular or fascicular arrangement (mean Breslow thickness, 4.97 mm). Immunohistochemical analysis of ATM cells demonstrated the typical positive staining for S-100, vimentin, HMB-45, and melan-A. The investigation of the pi isoform of glutathione S-transferase, a family of enzymes involved in tumor progression, revealed that nuclear expression is reduced in ATMs compared with control melanomas, whereas results from cytoplasmic staining did not vary. One patient died of cardiac failure without evidence of disease progression; the remaining patients are disease-free at 3 (n = 4) and 5 years (n = 3)., Conclusions: Our findings confirm that ATM is a variant of melanoma with distinctive clinical and histological features. Low nuclear expression of glutathione S-transferase pi expression is a characteristic of ATM and could add new insight to better understand the unusual biological behavior of this rare neoplasm.

Patients who respond only partially to etanercept may require additional treatments that act synergistically to improve their therapeutic response while at the same time reducing the dose required and the risk of side-effects. The aim of this study was to evaluate the effecti veness of topical calcipotriol in etanercept partial responder patients. We enrolled 120 patients affected by psoriasis vulgaris and psoriatic arthritis. A 50 mg dose of etanercept was administered twice weekly for the first 12 weeks, followed by a 25 mg dose twice weekly for an additional 12 weeks. At week 12, for 45 patients who had not achieved PASI 50, calcipotriol cream was also prescribed twice daily for 4 weeks and then once daily for a further 8 weeks. At week 24, of the 45 patients in the group treated with etanercept plus calcipotriol, 14 (31.1%) had achieved PASI 75, and 23 PASI 50, while 8 (17.7%) had dropped out of therapy; of the 75 patients who continued etanercept in monotherapy with a 25 mg dose twice weekly for another 12 weeks, 71 (94.6%) had achieved PASI 50 and 57 (76.0%) PASI 75. The application of calcipotriol in etanercept partial responder patients had therefore helped 37 out of 120 patients (31%) achieve at least PASI 50. This is the first report about the controlled combination of topical calcipotriol and etanercept in a large group of psoriatic patients. The efficacy and cost-effectiveness of the combined treatment is evidenced by the good response shown at week 24 by a group of etanercept low-responder patients using drugs sparingly and limiting likely toxicity.

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.

Background: Imiquimod is an immune response modifier shown to be effective in basal cell carcinoma (BCC)., Objective: To evaluate the efficacy, tolerability, and response durability of imiquimod 5% cream in selected patients with superficial and/or nodular BCCs., Methods: Seventy-five superficial and 19 nodular BCCs in 49 patients were treated with imiquimod once daily three times a week for up to 12 weeks., Results: Of the 49 enrolled patients, 1 discontinued the study and 1 was lost to follow-up. After 12 weeks of treatment, a complete response occurred in 70 of 75 (93.3%) superficial BCCs and a partial response in 4 of 75 (5.3%) superficial BCCs. Ten of 19 (52.6%) nodular BCCs cleared after 12 weeks, whereas 7 (36.8%) showed partial remission. Adverse side effects were limited to local skin reactions. Recurrence was observed in 2 of 70 (2.9%) successfully treated superficial BCCs 6 and 8 months after treatment discontinuation. No recurrence was detected in 68 of 70 (97.1%) superficial BCCs and in 10 successfully treated nodular BCCs after 12 to 34 months of follow-up (mean 23 months)., Conclusions: In our patient population, treatment of superficial BCCs with topical imiquimod for 12 weeks produced an excellent clinical response overall, with complete remission maintained after a mean of 23 months.

Background: Basal cell carcinoma (BCC) is the most common cancer in humans. Medical treatment modalities offer cost reductions and clinical advantages in selected cases such as low-risk areas, surgically inaccessible sites, patients with multiple neoplasms, and older, infirm or anticoagulated subjects. Tazarotene has been proposed for the treatment of BCC; however, data on its efficacy are lacking., Objectives: To investigate the efficacy of tazarotene in a large series of BCCs, better to define the clinical advantages and the mechanisms of action in vivo., Methods: Tazarotene 0.1% gel was applied daily for 24 weeks to 154 small superficial and nodular BBCs. Clinicopathological changes were followed during the therapy by dermoscopic and histological examination. Proliferation, retinoic acid receptors and apoptosis were investigated by immunohistochemistry and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labelling on biopsies., Results: At 24 weeks of therapy, 70.8% of the BCCs showed > 50% clinical and dermoscopic regression, and 30.5% healed without recurrences after 3 years of follow-up. At 12 weeks, biopsies showed that regression was associated with reduced proliferation and increased apoptosis of basaliomatous cells. Most unresponsive tumours displayed a keratotic differentiation., Conclusions: Tazarotene was effective in the majority of superficial and nodular undifferentiated BCCs treated, possibly by antiproliferative and proapoptotic actions in vivo. Keratotic BCCs were the major type among the unresponsive tumours, and were characterized by overexpression of p53 and cellular retinol binding protein-1 in comparison with undifferentiated tumours. Topical tazarotene represents an alternative medical choice for selected cases of BCC.

A preliminary clinical experience suggested tazarotene, a new acetylenic retinoid, as an effective alternative topical treatment of basal cell carcinomas (BCC). The mechanisms of action of this synthetic retinoid, however, have not been yet clarified. In this work we assessed the in vivo effects of daily application of tazarotene for 24 wk, on 30 small superficial and nodular BCC, and the in vitro effects of tazarotene on immortalized basal and squamous tumor epidermal cells. Cellular proliferation, apoptosis and changes in expression of retinol and retinoic acid receptors (RAR), p53, bcl-2, and bax were studied by immunohistochemistry, western blotting and PCR. Overall, 76.7% of treated tumors showed >50% regression. Complete healing was observed in 46.7% of all treated BCC, without recurrences at 2-y observation. Regression was associated with reduced proliferation and increased apoptosis, demonstrated by Ki-67- and TdT-mediated dUTP-biotin nick-end labelling-positive nuclear staining, and with enhanced RAR-beta and bax expression, with RAR-alpha and -gamma expression unchanged. In vitro, tazarotene induced a concentration-dependent increase of RAR-beta and bax associated with a greater rate of apoptosis and growth inhibition in basaloid tumor cells compared with squamous tumor cells. Our studies provide convincing evidence that tazarotene induces BCC regression possibly by synergistic RAR-beta-dependent anti-proliferative and pro-apoptotic pathways.

Skin cancer is the most common malignancy in humans and accounts for one-third of newly diagnosed cancers. Basal cell carcinoma (BCC) is one of the most prevalent and persistent types, and appears in two main histological forms, superficial and nodular. Typical treatments include surgery; however, this may leave scarring, which is undesirable, especially in facial lesions. We report the results of seven individual patients with one or more BCCs (both nodular and superficial) treated with imiquimod 5% cream. Eleven of 13 lesions cleared following daily topical treatment for 10-18 weeks. Any local skin reactions resolved at the end of treatment.

Actinic keratoses (AKs) are intraepidermal tumours, which result from the proliferation of transformed neoplastic keratinocytes. They are typically induced by chronic exposure to ultraviolet radiation, and can often develop into squamous cell carcinoma (SCC). Six patients, who presented with AKs located on the head, face and chest, were treated with the immune response modifier, imiquimod, as a 5% cream five times per week for up to 8 weeks. The majority of patients experienced mild to moderate side-effects, consisting of erythema, itching and burning. Topical application of imiquimod for 4-8 weeks resulted in complete clearance in all patients. No new or recurrent lesions were observed during a 6-8 month follow-up period.

The efficacy of tazarotene 0.1% gel in a 30-year-old woman with type I lamellar ichthyosis is reported. The drug was applied to 15% of the total body surface area as follows: once daily for 2 weeks, three times a week for further 2 weeks, followed by a once weekly maintenance application. During the first week of treatment there was partial improvement obtained and in the next 14 days further reduction of scaling within the tazarotene-treated areas was observed. After 4 months of maintenance application, there was a marked overall improvement in the treated areas. Side-effects consisted only of mild pruritus, slight burning and irritation. In essence, the therapeutic benefit obtained was comparable with that of systemic retinoids but without the adverse systemic side-effects. As noted in other reports, tazarotene 0.1% gel seems to be a valuable and safe therapeutic option for this severe genodermatosis.

Background: Dermoscopy has been shown to enhance the diagnosis of melanoma. However, use of dermoscopy requires training and expertise to be effective., Objectives: To determine whether an Internet-based course is a suitable tool in teaching dermoscopy, and to evaluate the diagnostic value of pattern analysis and diagnostic algorithms in colleagues not yet familiar with this technique., Methods: Sixteen colleagues who were not experts in dermoscopy were asked to evaluate the dermoscopic images of 20 pigmented skin lesions using different diagnostic methods (i.e. pattern analysis, ABCD rule, seven-point checklist and Menzies' method), before and after an Internet-based training course on dermoscopy. Mean +/- SEM sensitivity, specificity and diagnostic accuracy, and kappa (kappa) intraobserver agreement were evaluated for each diagnostic method before and after training for the 16 participants. Differences between mean values were assessed by means of two-tailed Wilcoxon rank-sum tests., Results: There was a considerable improvement in the dermoscopic melanoma diagnosis after the Web-based training vs. before. Improvements in sensitivity and diagnostic accuracy were significant for the ABCD rule and Menzies' method. Improvements in sensitivity were also significant for pattern analysis, whereas the sensitivity values were high for the seven-point checklist in evaluations both before and after training. No significant difference was found for specificity before and after training for any method. There was a significant improvement in the kappa intraobserver agreement after training for pattern analysis and the ABCD rule. For the seven-point checklist and Menzies' method there was already good agreement before training, with no significant improvement after training., Conclusions: We demonstrated that Web-based training is an effective tool for teaching dermoscopy.

High-dose intravenous immunoglobulin has been proposed as an alternative treatment for several immuno-mediated inflammatory skin diseases, usually at a dosage of 1 - 2 g/kg. We describe the treatment of 10 patients affected by toxic epidermal necrolysis using 400 mg/kg per day on 5 consecutive days--a schedule that is lower than previously reported schedules. According to the SCORTEN, the earlier predicted mortality rate was 35%. After high-dose intravenous immunoglobulin therapy, a mortality rate of 10% and a survival rate of 90% were reached. In particular, nine patients showed a dramatic improvement already after one course of infusion started at an early stage of the disease. It is our experience, and that of others, that high-dose intravenous immunoglobulin can be considered the drug of first choice for toxic epidermal necrolysis, one of the most severe life-threatening dermatological conditions, and a valid alternative therapy for different long-standing chronic dermatological diseases. This therapy can also be effective in avoiding high steroid dosages and consequently steroid-related or immunosuppressive-related side effects. It is therefore reasonable to propose high-dose intravenous immunoglobulin treatment as a valuable therapeutic tool for dermatologists.

Pyoderma vegetans (PV) is a chronic, vegetating pustular disorder characterized clinically by erythematous vesiculopustular vegetating cutaneous plaques. Marked epidermal hyperplasia, intraepidermal and subepidermal neutrophilic microabscesses and a dermal inflammatory infiltrate are the prominent histopathological findings. We describe a patient with PV associated with ulcerative colitis and mammary Paget's disease. Pustular eruptions associated with ulcerative colitis are reviewed.

Background: Immunosuppressive medications such as corticosteroids and cyclosporin are the most commonly employed therapies in pyoderma gangrenosum. We describe a patient with multiple ulcers of pyoderma gangrenosum on the lower extremities in whom immunosuppressive therapy caused serious side effects and had to be discontinued but who was subsequently treated successfully with high dose intravenous immunoglobulin (IVIG)., Methods: IVIG was given intravenously at a dose of 400 mg/kg per day for 5 consecutive days. After 1 week there was an arrest in the progression of the ulcers and a marked reduction in pain. Two weeks later clinical improvement of the ulcers was observed. Subsequently, IVIG was given at a dose of 1 g/kg per day for 2 consecutive days., Results: The treatment induced a dramatic clinical improvement of one ulcer and healing of the others. Side effects were minimal and well tolerated, and consisted of chills and a slight fever, which resolved with the administration of acetaminophen., Conclusion: We feel that IVIG can be used in patients with pyoderma gangrenosum in whom conventional therapies are ineffective or produce serious side effects.