Physician-patient communication and patient-reported outcomes in the actinic keratosis treatment adherence initiative (AK-TRAIN): a multicenter, prospective, real-life study of treatment satisfaction, quality of life and adherence to topical field-directed therapy for the treatment of actinic keratosis in Italy.

BACKGROUND: Patients with multiple actinic keratoses (AKs) should be treated with field-directed therapy. Such treatments challenge patients' adherence due to out-of-pocket costs, length of treatment and severity of local skin reactions (LSRs). Effective physician-patient communication (PPC) may buffer therapy-related distress, thus improving quality of life, treatment satisfaction and adherence. OBJECTIVES: We evaluated the interplay between PPC, LSR intensity (safety) and lesion clearance rates (effectiveness) on treatment satisfaction, quality of life and treatment adherence among patients with multiple AKs receiving topical field-directed therapies. METHODS: In this observational, multicentre, longitudinal, cohort study, we included 1136 adult patients with discrete, clinically detectable, visible, multiple (three or more lesions in a 25 cm2 area), Grade I/II AKs, for whom the attending dermatologist has prescribed treatment with a topical field-directed therapy. We matched self-reported data and medical information recorded by dermatologists in standard clinical forms. Patients were followed up at two time points (T1: 8 days; T2: 25-30 days) RESULTS: Most patients were elderly, married, men with poor socio-economic status and multiple lesions of the scalp or face. The majority (n = 961) had a prescription of ingenol mebutate (IMB) and 175 received either diclofenac 3% in hyaluronic acid (DHA) or imiquimod 5% (IMQ). Clearance rate at 1 month was 84%. Most patients felt very supported (n = 819, 73%) and rated dermatologist's explanations very clear (n = 608, 54%). Treatment satisfaction (effectiveness and convenience scales) increased along the follow-up, especially for those on IMB (Δpre-post  = -4.00; other: Δpre-post  = -0.25; interaction P < 0.001). Communication clarity was associated with higher treatment satisfaction scores (ß = 0.4-0.6, P < 0.01) and lower risk of non-adherence among IMB patients (risk difference: 16%, P < 0.01). CONCLUSION: Communication clarity was associated with patient-reported outcomes and adherence beyond AK-related clinical parameters. Our study questions the current episodic approach to AK management and provides the rationale to develop chronic care models fostering patients' engagement and treatment alliance.

Superhydrophobic lab-on-chip measures secretome protonation state and provides a personalized risk assessment of sporadic tumour.

Secretome of primary cultures is an accessible source of biological markers compared to more complex and less decipherable mixtures such as serum or plasma. The protonation state (PS) of secretome reflects the metabolism of cells and can be used for cancer early detection. Here, we demonstrate a superhydrophobic organic electrochemical device that measures PS in a drop of secretome derived from liquid biopsies. Using data from the sensor and principal component analysis (PCA), we developed algorithms able to efficiently discriminate tumour patients from non-tumour patients. We then validated the results using mass spectrometry and biochemical analysis of samples. For the 36 patients across three independent cohorts, the method identified tumour patients with high sensitivity and identification as high as 100% (no false positives) with declared subjects at-risk, for sporadic cancer onset, by intermediate values of PS. This assay could impact on cancer risk management, individual's diagnosis and/or help clarify risk in healthy populations.

Innate immunity in cutaneous melanoma.

The skin immune system is composed of a vast network of immune cells, including lymphocytes, macrophages, neutrophils, dendritic cells and Langerhans cells, which not only are involved in inflammatory responses but also contribute to homeostatic function and may participate in the various steps of carcinogenesis. Many studies support the notion that innate immunity has a key role in the development, growth and prognosis of cutaneous malignant melanoma (MM), through the release of pro- and/or anti-inflammatory cytokines and tumour growth factors. The tumour environment in a major subset of cutaneous MM shows evidence of a T cell-infiltrated phenotype, but there is less known about the presence and the phenotype of other immune system cells. Response to immunotherapy is largely correlated with the presence of T cells in the tumour microenvironment, while the regulation exerted by stromal components such as macrophages and mast cells has been less investigated. In the current report, we review the recent literature, focusing our attention on the role of macrophages, dendritic cells, mast cells and natural killer cells in orchestrating MM progression, to better understand tumour immunobiology. The identification of new therapeutic targets and the application of approaches aimed at modulating crosstalk between immune and tumour cells, could have a crucial impact on immunotherapy and result in better clinical outcome. We hope this review will be helpful in cutaneous MM research.

An unusual case of mammary Paget’s disease in a woman with psoriasis.

Mammary Paget’s disease (MPD) is a malignant breast tumor, which is characterized by intraepidermal infiltration from malignant glandular epithelial cells. Often it may include an underlying ductal carcinoma in situ or an invasive ductal carcinoma. Clinically it appears as an erythematous patch, moist or crusted, with or without desquamation that in some cases becomes ulcerated, causing infiltration and inversion of the nipple. We report the clinical case of a 60-year-old woman, treated in our department for psoriasis, presenting with erythema of nipple and areola with nipple erosion, ulceration and poor secretion. Suspecting Paget’s disease of the nipple, radiological exams (mammography and breast MRI) were performed. A biopsy for histological examination was carried out and confirmed the diagnosis of mammary Paget’s disease. MPD is sometimes difficult to diagnose both clinically and radiologically, therefore it is important to distinguish from other conditions: in literature MPD is reported in differential diagnosis with psoriasis given its similar clinical features, and in some cases MPD has been treated with topical and systemic steroids due to a wrong diagnosis. However, the concomitance, in the same individual, of mammary Paget’s disease and psoriasis has never been described.

Pharmacoeconomy of drugs used in the treatment of actinic keratoses.

Actinic keratosis (AK) represents an emerging issue in the area of skin diseases which undergo high risk for developing squamous cell carcinoma (SCC). Recently, evidence has been accumulated that 3% diclofenac sodium and ingenol mubetate may efficiently counteract the development of progressive AK even if the pharmacoeconomic impact of such a treatment remains poorly defined. With the objective of assessing the efficacy of 3% diclofenac sodium versus ingenol mebutate, a comparative cost-efficacy analysis was performed between both pharmacological treatments. In the present analysis, data of efficacy of clinical studies were combined with information on the quality of life associated with AK lesions based on available literature data. Furthermore, the cost associated with the management of these lesions in Italy has been taken into account. To this purpose, we carried out a literature survey on the clinical and economic data among clinical reports available in Italy based on the assessment of related expenditure of public resources and their relationship with the subsequent health benefits.

Is the prognosis and course of acral melanoma related to site-specific clinicopathological features?

OBJECTIVE: Acral melanoma is an uncommon type of melanoma in Caucasian patients. However, acral melanoma is the most common type of melanoma in African and Asian patients. Comparison analyses between hand-acral melanoma and foot-acral melanoma have been rarely reported in the literature. Acral melanoma is an uncommon melanocytic tumor characterized by an intrinsic aggressiveness, with specific histological and clinicopathological features. Acral melanoma involves the palms, soles and sub-ungueal sites. PATIENTS AND METHODS: A total of 244 patients with acral melanoma were included in our analysis. The current study was performed in three different medical centers: Sapienza University of Rome, San Gallicano Institute of Rome and University of Magna Graecia (Italy). The Kaplan-Meier product was used to estimate survival curves for disease-free survival and overall survival. The log-rank test was used to evaluate differences between the survival curves. Assuming that the effects of the predictor variables are constant over time, the independent predictive factors were assessed by Spearman's test and subsequently data were analyzed performing Cox proportional-hazard regression. RESULTS: In both univariate and multivariate analyses Breslow thickness (p < 0.0001) and ulceration (p = 0.003) remained the main predictors. General BRAF mutation was detected in 13.8% of cases. We found that median Breslow value and the percentage of recurrences were similar in hand-acral melanoma and foot-acral melanoma, as well as there were no differences in both short and long-term. CONCLUSIONS: The absence of differences in survival between hand-acral melanoma and foot-acral melanoma shows that the aggressiveness of the disease is related to distinct mutational rate, as well as to anatomical site-specific features, rather than to the visibility of the primary lesion.

Daylight-Photodynamic Therapy for the Treatment of Actinic Keratosis in Different Seasons.

BACKGROUND: non-melanoma skin cancer (NMSC) is the most common malignancy, whose public health significance is often unrecognized. Its incidence continues to grow at an alarming rate, becoming an occupational disease. Available treatments alternative to surgery include: photodynamic therapy, electrochemiotherapy, cryotherapy, ablative lasers, 5-fluorouracil, imiquimod, ingenol mebutate, and diclofenac. Each of these options has its advantages and disadvantages. Photodynamic therapy (PDT), using topically applied photosensitizer precursors such as methylaminolaevulinate (MAL), is a useful nonsurgical treatment, well accepted by patients, but the main limitation is pain. Recently, in order to overcome this limit, visible light irradiation photherapy was considered. AIM: we report our experience comparing conventional PDT (406 patients) with daylight-mediated PDT (D-PDT) 240 patients with multiple actinic keratoses (AK), afferent to our photodynamic outpatients clinic from September 2013 to June 2014. MATERIALS AND METHODS: to establish predictors for the clinical response to conventional PDT and daylight PDT (DPDT), a retrospective study on 646 patients was performed. The following parameters have been evaluated: sex, age, anatomic site of the primary tumor and local skin reactions. We used the Spearmen's coefficient between the clinical response and the predictors analyzed; while Odds Ratio (OR) was performed to evaluate general clinical response and local skin reaction between PDT and D-PDT patients. Subsequently, we performed a sub-analysis, focusing to the anatomical sites, and we subdivided anatomical sites in face and scalp, nose, trunk, and extremities. RESULTS: a total of 406 patients treated with PDT and 240 patients treated with D-PDT, were enrolled in the current report. The median age was 71 years in PDT and 73 years in D-PDT. The mean clinical response in PDT was of 74.4% and 95% in D-PDT. Performing OR between PDT and D-PDT, according to the clinical response, we found a better behavior in patients treated with D-PDT (P < 0.03); the same significance was maintained according to the presence or absence of local skin reaction (P < 0.0002). Using no parametric Spearman's Coefficient test among predictive factors and the therapeutical response we found that D-PDT showed a better clinical response in patients with AK size ≥ 0.6 mm (P < 0.03), while this evidence was not present in PDT. The nose remained in both PDT and DPDT the main anatomical site with a better clinical response to the treatment. CONCLUSION: Since efficacy of D-PDT is comparable or superior to conventional type, but is simpler and better appreciated by patients, in our opinion it may be used routinely to treat sun exposed multiple AKs especially in sun damaged skin also for aesthetic purposes.

Dialysis-associated pseudoporphyria successfully treated with vitamin D. Report of two cases.

Pseudoporphyria refers to a rare bullous dermatosis characterized by the clinical and histological features of porfiria cutanea tarda without abnormalities in porphyrin metabolism. The pathogenesis is heterogeneous and several exogenous factors may promote the bullous lesion formation, including medications, end stage renal disease, dialysis and tanning beds. Regarding treatment of this condition, in literature different therapy have been reported, such as glutathione and his precursor N-acetylcysteine, which presents anti-oxidant properties; however even more toxic drugs, such as chloroquine, are used. Moreover, in patients with drug-induced PP discontinuation of the offending agent, if possible, is a crucial aspect of the clinical management. We report two cases of dialysis patients presenting blisters on extremities, which healed with the avoidance of UV exposure and oral Vitamin D supplementation. Interestingly Vitamin D despite the lack of antioxidant properties led to a completely resolution of PP in both our patients within 30 days. A possible explanation of this finding is that Vitamin D, playing a key role in the regulation of serum Ca2+, can modulated cadherin-cadherin interactions and led to healing of pseudoporphyria bullous lesions. Finally we highlight the prominent role of UV-exposure in PP elicitation thus a good photoprotection is essential for all patients with pseudoporphyria.

Improvement of survival in patients with melanoma and non-melanoma skin cancers compared to patients without double cutaneous malignancies.

OBJECTIVE: The worldwide incidence of cutaneous malignant melanoma (MM) has been rising steadily over the past 30 years. At the same time non-melanoma skin cancers (NMSC) are the most prevalent type of cancer in United States and Europe. Up to date, no paper has explored the influence on the general survival in patients with MM and NMSC. We decided to perform a study with the aim to evaluate the different survival in patients with MM-NMSC compared to control patients (MM-CTRL). PATIENTS AND METHODS: To evaluate prognosis in both groups, we analyzed disease-free survival (DFS) and overall survival (OS).Kaplan-Meier product was performed for the survival analysis. Median DFS was 73 months in group and 72 months in MM-CTRL patients (p = 0.4); while, median OS was 74.2 months in MM-NMSC patients and 63.1 in MM-CTRL (p < 0.001). Also at Odds-Ratio (OR), the statistical significance was maintained (p < 0.007) with a better prognostic value for MM-NMSC. RESULTS: Among group patients, the ones with a basal cell carcinoma showed a batter behavior, than the ones with squamous cell carcinoma (p = 0.01). CONCLUSIONS: Patients with MM-NMSC showed a better survival than MM-CTRL patients (p < 0.001). The causes of this improved survival are still unknown; probably the endogenous immune response can play a pivotal role in this class of patients. However, further studies are necessary to better understand this phenomenon, not yet explored in literature.

Cutaneous manifestations in antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is a hypercoagulable state that leads to thrombosis and recurrent pregnancy loss related to the presence of antiphospholipid antibodies (LAC, anticardiolipin, antiA2-glycoprotein). Among cutaneous manifestations, livedo reticularis is the most frequent form of APS. In the literature, there are rare cases associated with diffuse skin necrosis (widespread skin necrosis) and intravascular thrombosis in the small vessels of the dermis. We describe the case of a 44-year-old man with positive anticardiolipin antibodies and protein S deficiency that developed scattered, bullous skin lesions, haemorrhagic in appearance with signs of necrosis as first clinical manifestation of antiphospholipid syndrome.

Differences in clinicopathological features and distribution of risk factors in Italian melanoma patients.

BACKGROUND: No studies are available in the literature on the distribution of different melanoma features and risk factors in the Italian geographical areas. OBJECTIVE: To identify the differences in clinical-pathological features of melanoma, the distribution of risk factors and sun exposure in various Italian macro-areas. METHODS: Multicentric-observational study involving 1,472 melanoma cases (713 north, 345 centre, 414 south) from 26 referral centres belonging to the Italian Multidisciplinary Group for Melanoma. RESULTS: Melanoma patients in northern regions are younger, with thinner melanoma, multiple primaries, lower-intermediate phototype and higher counts of naevi with respect to southern patients; detection of a primary was mostly connected with a physician examination, while relatives were more involved in the south. Northern patients reported a more frequent use of sunbeds and occurrence of sunburns before melanoma despite sunscreen use and a lower sun exposure during the central hours of the day. CONCLUSIONS: The understanding of differences in risk factors distribution could represent the basis for tailored prevention programmes.

Evaluation of Ingenol mebutate efficacy for the treatment of actinic keratosis with Antera 3D camera.

OBJECTIVE: Cumulative exposure of the skin to ultraviolet radiation promotes mutation in keratinocytes and their abnormal growth led to the formation of scaly lesions, called actinic keratoses (AKs). Its incidence is growing at an emerging rate, becoming a worldwide problem especially for occupational ultraviolet (UV) rays exposure. Detectable lesions are often associated with field changes, where the surrounding skin is altered and subclinical lesions may be present. Thus, a field-directed therapy, such as topical treatment, should be preferred for the prevention of invasive cancer development. A retrospective analysis was made, evaluating the efficacy of ingenol-mebutate gel, using a novel device the 3D in vivo optical skin Imaging (Antera 3D, Miravex, Ireland). PATIENTS AND METHODS: We included all patients with multiple non-hypertrophic Aks, to whom it was prescribed ingenol-mebutate gel, applied at the dosages of 0.015 for lesions in the scalp/face (for 3 consecutive days) and at the dosage of 0.05% for lesions in the trunk and/or extremities (for 2 consecutive days). RESULTS: A reduction of the lesions and of median hemoglobin levels, after a follow-up of 60 days, was observed in 100% of patients. CONCLUSIONS: Ingenol mebutate gel, the last topical molecule appeared in the Italian market showed its efficacy using Antera 3D also in terms of hemoglobin reduction. Therefore, this camera could be considered an useful tool for the identification of the area to be treated and for therapeutic follow-up.

Association between autoimmune disease and cutaneous melanoma with regard to melanoma prognosis.

BACKGROUND: An association between autoimmune disease and malignant melanoma (MM) has often been reported in the literature as a positive prognostic factor for MM. Consequently, we evaluated the influence of different autoimmune diseases on the prognosis of MM. AIM: To evaluate the prognosis of patients with MM who also had an autoimmune disorder, whether tumour-associated, paraneoplastic or drug-induced. METHODS: Autoimmune diseases were classified and analysed as tumour-associated, paraneoplastic or drug-induced. Patients were enrolled according to their clinicopathological features and matched with control groups. Kaplan-Meier analysis was used to estimate disease-free survival (DFS) and overall survival (OS), and log-rank test was used to evaluate differences between the survival curves. RESULTS: In total, 49 patients with MM and tumour-associated autoimmune disease were included in our analysis. No case of paraneoplastic autoimmune disease was detected. The survival analyses showed a range of results, from a worsening of DFS and OS to a lack of any difference. In a second analysis, we separately analysed patients who developed autoimmune disorders after starting adjuvant therapy with interferon-α; we did not find significant differences between these patients and the untreated patients. CONCLUSIONS: Autoimmune disease, whether tumour-associated or drug-induced, was not associated with better prognosis in patients with MM. The results suggest that the reported relationship between autoimmunity and MM may be a result of individual variation in sensitivity to the autoimmune disease, the tumour or the treatments.

Granuloma annularis revealing Wegener's granulomatosis.

Skin manifestations are often associated with systemic autoimmune diseases (SAD). Some SAD, such as systemic lupus erythematosus, psoriatic arthritis and scleroderma display pathognomonic dermatological features, whereas other systemic diseases such as sarcoidosis, vasculitis and rheumatoid arthritis can present with non-specific skin manifestations that range from erythema nodosum to necrotic lesions. Here we report the case of a 25-year-old man with uveitis, polyarthrirtis, pulmonary involvement, nephrotic syndrome, cutaneous granuloma and pneumonia by E. coli.

Basal cell carcinoma: differences according to anatomic location and clinical-pathological subtypes.

AIM: Basal cell carcinoma (BCC) is the most common skin malignant neoplasm in humans. Its localization and its clinical-pathological aspects are fundamental for the treatment and the outcome of these tumors. We wanted to verify if different clinical-pathological subtypes of BCC may be present with different frequencies on single skin areas. METHODS: Three hundred six patients affected by BCC seen in Sant'Andrea Hospital, U.O.C. Dermatology, NESMOS Department, Faculty of Medicine, University of Rome "Sapienza", from January 2008 to December 2010, were retrospectively included in this study. Findings from all patients were tabulated and analyzed to characterize the clinical-pathological aspects of BCC according to their anatomic localization. We considered the following clinical subtypes of BCC, nodular, superficial, sclerodermiform, pearly and ulcerative. RESULTS: One hundred ninety-seven out of 306 patients (64.4%) were localized on the head, 6 (1.9%) on the neck, 73 patients (23.9%) on the trunk, 2 (0.6%) on the perineum, 4 (1.3%) on upper limbs and 24 (7.9%) on legs. On the head BCC were mostly nodular (44.7%). On the trunk they were mostly superficial (34.3%). BCC on legs were ulcerative in all the 24 patients. CONCLUSION: Our data confirm that BCC may have different clinical-pathological aspects on single skin areas. Interestingly in our casistic BCC on the legs were present in an uncommon high percentage. They presented as ulcerative lesions and this fact leads to conclude that in every patient presenting a chronic ulcer on the leg with difficulty to be cured a biopsy is mandatory to put in evidence the possible presence of BCC and consequently to perform the correct surgical treatment to obtain a complete response for the patient.

Melanoma and IFN alpha: potential adjuvant therapy.

Interferon alpha (IFNalpha) is the most used adjuvant treatment in clinical practice for melanoma (MEL) high-medium risk patients; however, the use of IFNalpha has yielded conflicting data on Overall Survival (OS) and disease free survival (DFS) rates. Starting from these considerations, we carried out an analysis on our MEL patients who received adjuvant IFNalpha therapy, in order to identify possible predictors for their outcome. A total of 140 patients were included in our analysis. Patients with Breslow thickness ≤2.00 mm presented a significantly longer mean DFS than patients with Breslow ≥2.01 mm (p = 0.01). Using non- parametric Spearman’s Coefficient test we found association between DFS and Breslow thickness (p < 0.001) and between DFS and ulceration (p = 0.03). Performing Multiple Regression test, Breslow thickness (p < 0.001) remained the only statistically significant predictor. From the OS analysis we found that patients with lower Breslow values ≤ 2.00 mm (p < 0.0001), and absence of ulceration (p <0.004) showed a significantly better long-term survival. From the current analysis we found that the use of low dose IFNalpha is justified only for cutaneous melanoma ≤ 4.01 mm that was not ulcerated; patients with Breslow ≥ 4.01 mm, in our opinion, should not carry out adjuvant treatment with low dose IFNalpha, because its side effects could be higher than the its benefits.

Multiple skin ulcers due to Serratia marcescens in a immunocompetent patient.

Serratia marcescens is a species of gram negative bacillus, classified as a member of the Enterobacteriaceae, mainly involved in opportunistic infections, particulary in the hospital environment. Cutaneous infections have rarely reported in literature and are predominantly observed in elderly or in immunocompromised patients. The clinical manifestations of skin infections include granulomatous lesions, necrotizing fasciitis, nodules, cellulitis, ulcers, dermal abscesses. Infections caused by S. marcescens may be difficult to treat because of resistance to a variety of antibiotics, including ampicillin and first and second generation cephalosporins. Aminoglycosides have good activity against S. marcescens, but resistant strains have also been described. We report a very intriguing case of S. marcescens infection, in an immunocompetent 18-year-old man, causing multiple rounded ulcers of varying sizes, along with few pustular lesions that both clinically and histopathologically mimic a pyoderma gangrenosum (PG). This is a non infectious neutrophilic skin disorder, characterized by painful and rapidly progressing skin ulceration. According to our experience, we would strongly recommend to perform cultures of multiple skin ulcers resembling PG, even in young healthy patients, to ensure correct diagnosis and treatment, since resistant to conventional antibiotics bacteria such as S. marcescens may be the cause of these lesions, like in the case here reported.

Pemphigus vulgaris in a patient with arthritis and uveitis: successful treatment with immunosuppressive therapy and acyclovir.

A case of pemphigus vulgaris in a 41-year-old man with undifferentiated arthritis and uveitis is described. Histology of labial mucosa showed acantholytic, necrotic, and multinucleated giant keratinocytes having some nuclear inclusions suggestive of a virus infection. Specific serological tests revealed IgG positivity for HSV-1, CMV, and EBV, while real-time polymerase chain reaction assay from a biopsy of the mucosal lesion showed the presence of HSV-1/2 DNA. Treatment with prednisone, methotrexate, and acyclovir induced the complete remission of mucosal and joint symptoms, which then relapsed after interruption of antiviral therapy or immunosuppressive therapy. Therefore, a combined treatment with low doses of prednisone, methotrexate, and acyclovir was restarted and during 18 months of follow-up no recurrence was registered. Correlations between pemphigus and the herpes virus infection and also between autoimmune arthritis and herpetic agents have been well documented, but the exact role of the herpes virus in these disorders still needs further discussion. Our case strongly suggests that when autoimmune disorders do not respond to immunosuppressive agents, a viral infection should be suspected, researched, and treated.