Tuscan Consensus on the diagnosis, treatment and follow up of adult atopic dermatitis.

Atopic dermatitis (AD) is an inflammatory disease with a chronic-relapsing course that is intensely itchy. A correct diagnosis of AD in adults and consequently appropriate clinical therapeutic management is a critical issue for extreme clinical expression heterogeneity and various grades of disease severity. In order to ensure high levels of care and standardization of clinical therapeutic management of Adult AD, the decision was taken to create an AD Tuscan Consensus Group (the Group), to work on and validate a consensus based regional clinical-therapeutic management model. The aims of the Group were to find agreement on the criteria for diagnosis, scoring of severity, multidisciplinary approach and treatment of adult atopic dermatitis and to create an easier way for patients to access specialized dermatology outpatient services and importantly to reduce waiting lists and costs related to the management of AD. The Tuscan Consensus Group adopted a simplified Delphi method, in three principal steps: 1) literature metanalysis and critical review of patient's clinical experience to identify the main areas considered questionable or uncertain; 2) discussion of those areas requiring consensus and statement definition through four different sub-committees (diagnosis, severity evaluation, scoring and comorbidities); 3) a consensus based simplified process with final approval of each statement by plenary vote with approval >80% of the participants. The Group here presents and discusses the consensus based recommendation statements on adult atopic dermatitis.

Tuscan consensus on the use of UVBnb phototherapy in the treatment of psoriasis.

Psoriasis (PSO) is traditionally defined as an immune-mediated, inflammatory dermatological disease characterized by a chronic-relapsing course and associated with multifactorial inheritance (genetic predisposition and influence of various environmental factors). Considered until recently a dermatological disease only, today PSO is correctly known as a systemic one because of the involvement of multiple organs with important impact on social life and relationships. PSO is found in the 0.3-4.6% of the world's population, while its prevalence in the Italian population is estimated at 2.8%. Therefore, if we consider that in Tuscany more than 100,000 people out of 3,672,202 suffer of psoriasis, it is of paramount importance to focus on a shared clinical and therapeutic protocol to manage the disease. With the aim of ensuring diagnostic-therapeutic suitability, high levels of care and standardization of treatment, a unique clinical-therapeutic management model has been developed and validated in Tuscany, involving all accredited regional dermatological centers. Among the possible alternatives to be implemented in the treatment of patients with mild, moderate-severe psoriasis, UVBnb phototherapy is widely used alone or in association with other systemic and non-systemic devices. Despite this, there is still no universally shared therapeutic protocol. In this context the CO.FO.TO working group (Consensus Fototerapia Toscana) is born with the aim of defining and validating the main guidelines in the use of phototherapy with UVBnb in psoriasis; the guidelines are based both on the real-life experience of the different centers of reference in the region and on the revision of the recent literature.

Sun-Protection Behavior, Pubertal Development and Menarche: Factors Influencing the Melanocytic Nevi Development-The Results of an Observational Study of 1,512 Children.

Observational studies consistently show that melanocytic nevus prevalence increases with age and that phenotypic traits are significantly associated with nevus count in children. An observational study of 1,512 children and adolescents from 2010 to 2013 was conducted. Study dermatologists counted the full body, arm, and facial nevi of each participant. Children and their parents were asked to complete a survey to gather data on personal characteristics, pubertal development, and early-life sun exposure. The main aim of the study was to establish pediatric nevus prevalence and its relationship with age, phenotype, sex, menarche, early-life sun exposure, and sun-protection behaviors. Females had a significantly lower nevus count compared with males, but this sex-related difference was significantly modified by menarche. Sun exposure and sun-protection habits were all significantly associated with nevus count; in particular, children who used sunscreen with a sun-protection factor > 30 had a lower nevus count compared with sun-protection factor ≤ 30 sunscreen users. This study shows that sex, menarche status, and sun-protection practices significantly influence nevus count in this pediatric population.

Propranolol for Off-label Treatment of Patients With Melanoma: Results From a Cohort Study.

IMPORTANCE: Preclinical and retrospective studies showed that ß-blockers inhibit angiogenesis and disrupt migration of melanoma cells via inhibition of noradrenaline-dependent responses. OBJECTIVE: To study the clinical effectiveness of ß-blocker therapy in patients with melanoma and to determine whether propranolol improves progression-free survival in patients with melanoma. DESIGN, SETTING, AND PARTICIPANTS: We conducted a prospective study in patients treated for melanoma in our center with propranolol for off-label use. Patients with histologically confirmed stage IB to IIIA cutaneous melanoma and no evidence of metastasis were eligible for the study. At the time of diagnosis, they were asked to take propranolol (80 mg daily) as an off-label adjuvant treatment. If they accepted the treatment, they were considered part of the propranolol cohort (PROP). If they refused treatment but agreed to participate in the study control group, they were considered part of the nonpropranolol cohort (No-PROP). MAIN OUTCOMES AND MEASURES: The primary outcome was progression-free survival. Disease progression was assessed by evaluating the presence of lymphatic, in-transit, or visceral metastases, and the cause of death was recorded. RESULTS: Among the 53 patients (median [interquartile range] age 63 [48-75] years; 33 men) included in the study, 19 were eligible for the PROP cohort. Thirty-four patients otherwise eligible but unwilling to take propranolol were enrolled in the No-PROP cohort. The 2 cohorts were comparable in terms of demographic characteristics and primary prognostic factors at baseline. After adjusting for known prognostic factors, Cox models confirmed that use of propranolol at the time of diagnosis was significantly inversely associated with recurrence of melanoma with approximately an 80% risk reduction for propranolol users (hazard ratio, 0.18; 95% CI, 0.04-0.89; P = .03). CONCLUSIONS AND RELEVANCE: In the absence of randomized, double-blind, placebo-controlled clinical trials, this study is the first off-label study of which we are aware of propranolol for melanoma treatment. These results confirm recent observation that ß-blockers protect patients with thick cutaneous melanoma from disease recurrence. This study is in accordance with the present policy of "drug repurposing" in oncology. Repurposing the vast arsenal of approved drugs with a nononcology primary purpose may prove an attractive and inexpensive strategy for offering more effective treatment options to patients with cancer.

ß-Blocker use and reduced disease progression in patients with thick melanoma: 8 years of follow-up.

Previous observational studies have reported the protective effect of ß-blockers on the progression of different types of cancers. In 2011, we published a prospective study, including patients with histologically confirmed malignant melanoma in stage II-IIIA. In total, 25% of them reported previous use of ß-blockers that were administered at any time for any other diseases. After a median follow-up of 2.5 years, 34% of the patients in the untreated group showed disease progression. In contrast, only 3% of the patients in the treated group showed progression. We report the findings obtained in the same cohort after a longer period of ß-blocker therapy and follow-up (8 years). We prospectively reviewed data of the patients enrolled in the original prospective study. Disease progression was assessed by evaluating the presence of lymphatic, in-transit or visceral metastases. Deaths by any cause and deaths because of melanoma were recorded. A multivariate Cox proportional hazards model was used to evaluate the effect of ß-blocker use on disease-free survival and overall survival, adjusting for significant confounders. After a median follow-up of 8 years and a median duration of ß-blocker use of 7.6 years, 45% of the patients in the untreated group and 30% of the patients in the treated group showed disease progression. Notably, in the untreated group 35% patients died from melanoma and only 17% patients died from melanoma in the treated group. Results of this hospital-based prospective cohort study with a median follow-up of 8 years confirmed our previous results that the use of ß-blockers significantly reduced the risk of recurrence and mortality in melanoma patients.

Clinical and dermoscopic features of truly amelanotic plantar melanoma.

Currently, there are no specific clinical and dermoscopic features for diagnosing truly amelanotic plantar melanoma (TAPM). The present study aimed to investigate the dermoscopic features of all clinical variants of TAMPS and to evaluate their histopathological correlations. A retrospective analysis of prospectively collected data was carried out during a 10-year period (2003-2013). We analyzed the clinical data of 1321 patients, who had received a histological diagnosis of melanoma at the Melanoma Unit of the University of Florence. We selected the clinical and dermoscopic images of TAPMs and analyzed the presence of dermoscopic parameters. Incorrect preoperative diagnoses were analyzed to highlight peculiar dermoscopic features of pinkish plantar melanomas, the clinical diagnosis of which is extremely challenging for the dermatologist. Of all 1321 patients, 29 (24%) had TAPMs. Importantly, only 20.7% of patients with TAPMs had a correct preoperative diagnosis of suspicious melanocytic lesion. On the basis of the initial misdiagnosis, TAPMs were categorized as eczema-like, verruca-like, angioma-like lesions. Dermoscopically, all TAPMs showed the presence of a well-defined 'erythematous homogeneous area' with an atypical polymorphous vascular pattern with dotted, globular, and glomerular vessels. Our study highlights a crucial dermoscopic feature of TAPMs, the 'erythematous homogeneous area' that is characteristic of the plantar region, and, to our knowledge and experience, has not been described in nonacral amelanotic melanomas.

Teledermoscopy in doubtful melanocytic lesions: is it really useful?

INTRODUCTION: The diagnosis of cutaneous pigmented lesions remains a challenge for both dermatologists and pathologists. Our aim was to determine the diagnostic concordance between the conventional face-to-face diagnosis and the telediagnosis of 10 dermatologists with expertise in dermato-oncology of 10 challenging pigmented lesions. METHODS: Using a store-and-forward teledermatology method, clinical and dermoscopic digital images of all selected lesions were transmitted via e-mail to 10 dermatologists. Dermatologists were called to provide their telediagnoses with a step-by-step approach. When the dermatologists responded with their first clinical telediagnosis, they received a second email that contained dermoscopic images of the 10 cases. Final histopathological diagnosis was considered the gold standard for comparison with face-to-face and teledermatology diagnoses in statistical analysis. RESULTS: Face-to-face results indicated moderate agreement between clinical and histopathological diagnoses (K = 0.6). After the first clinical step, interobserver concordance of telediagnosis was lower than face-to-face diagnosis (K = 0.52). After the second dermoscopy step, the concordance declined further (K = 0.38). CONCLUSIONS: Teledermatology was inferior to face-to-face dermatology. Moreover, the diagnostic concordance of telediagnosis decreased after the teledermoscopic step. This finding may be justified by the dermoscopic difficulty of the selected lesions, including Spitzoid proliferations and atypical melanocytic nevi of the elderly. These lesions may represent a potential diagnostic pitfall given their confounding dermoscopic aspects.

Tumor-Related Methylated Cell-Free DNA and Circulating Tumor Cells in Melanoma.

Solid tumor release into the circulation cell-free DNA (cfDNA) and circulating tumor cells (CTCs) which represent promising biomarkers for cancer diagnosis. Circulating tumor DNA may be studied in plasma from cancer patients by detecting tumor specific alterations, such as genetic or epigenetic modifications. Ras association domain family 1 isoform A (RASSF1A) is a tumor suppressor gene silenced by promoter hypermethylation in a variety of human cancers including melanoma. The aim of the present study was to assess the diagnostic performance of a tumor-related methylated cfDNA marker in melanoma patients and to compare this parameter with the presence of CTCs. RASSF1A promoter methylation was quantified in cfDNA by qPCR in a consecutive series of 84 melanoma patients and 68 healthy controls. In a subset of 68 cases, the presence of CTCs was assessed by a filtration method (Isolation by Size of Epithelial Tumor Cells, ISET) as well as by an indirect method based on the detection of tyrosinase mRNA by RT-qPCR. The distribution of RASSF1A methylated cfDNA was investigated in cases and controls and the predictive capability of this parameter was assessed by means of the area under the ROC curve (AUC). The percentage of cases with methylated RASSF1A promoter in cfDNA was significantly higher in each class of melanoma patients (in situ, invasive and metastatic) than in healthy subjects (Pearson chi-squared test, p < 0.001). The concentration of RASSF1A methylated cfDNA in the subjects with a detectable quantity of methylated alleles was significantly higher in melanoma patients than in controls. The biomarker showed a good predictive capability (in terms of AUC) in discriminating between melanoma patients and healthy controls. This epigenetic marker associated to cfDNA did not show a significant correlation with the presence of CTCs, but, when the two parameters are jointly considered, we obtain a higher sensitivity of the detection of positive cases in invasive and metastatic melanomas. Our data suggest that cell-free tumor DNA and CTCs represent two complementary aspects of the liquid biopsy which may improve the diagnosis and the clinical management of melanoma patients.

The impact of body area in melanoma self-detection: a retrospective study.

To assess the patient's capability of performing a correct skin-check examination we investigated the association of melanoma detection pattern with Breslow thickness, by melanoma body area. In this prospective observational study, patients with primary cutaneous melanoma who presented at the Department of Dermatology at the University of Florence between January 2000 and November 2011 were interviewed as part of their clinical data recording procedure at the time of their final histopathological diagnoses of melanoma. With the aim of evaluating a self skin-check, we included patients with melanoma in the anterior part of the trunk (abdomen and chest area), which is generally considered visible in the mirror, and the posterior part of the trunk, which is a more complex area to be self-checked. The treating physician specifically questioned all patients about who had first detected or suspected the lesion that resulted in the histological diagnosis of melanoma in order to compare those who had self-detected (SD) their melanoma with those who had discovered their melanoma during a regular skin-check (RSC) with a dermatologist. A total of 186 melanoma patients were analyzed, with 67% (n=125) of melanomas located on the back and 33% (n=61) in the chest and abdominal area; the majority (55%, n=103) were in the SD group. The median Breslow thickness of the SD group was significantly greater than that of the RSC group: 0.60 versus 0.50 mm (P<0.0001). In the posterior trunk, the frequency of thick melanomas (Breslow≥1.00 mm) was significantly greater in the SD group than in the RSC group (34 vs. 11%; P=0.003), whereas there was no difference in the frequency of thick melanoma by detection patterns in the anterior trunk. Given the influence of the body area in detecting threatening melanoma, we should encourage people to obtain dermatological skin-checks more often. Skin self-examinations cannot be sufficiently accurate.

Effect of ß-blockers and other antihypertensive drugs on the risk of melanoma recurrence and death.

OBJECTIVE: To verify preliminary studies on patients with melanoma exposed to ß-blockers that suggested a reduced risk of disease recurrence and death. PATIENTS AND METHODS: Data were obtained from all consecutive patients diagnosed as having melanoma between January 1, 1993, and December 31, 2009, at the Department of Dermatology of the University of Florence, Azienda Sanitaria di Firenze. Participants were excluded if at baseline they reported a previous diagnosis of cutaneous malignant melanoma or another malignant disease. We also excluded participants with evidence of visceral, lymph nodal, and in-transit metastasis at the time of the diagnosis. RESULTS: Of 741 consecutive patients with melanoma, 79 (11%) were prescribed ß-blockers (for hypertension in most cases) for 1 or more years (treated) and 662 (89%) were not (untreated). The multivariate Cox model indicated that the treated group had improved overall survival after a median follow-up of 4 years (P=.005). For each year of ß-blocker use, the risk of death was reduced by 38%. The presence of hypertension, the use of antihypertensive agents for 1 or more years, or the use of other commonly used medicines were not associated with a better outcome for patients with melanoma. CONCLUSION: The results confirm and strengthen previous findings that ß-blocker use is associated with a reduced risk of melanoma recurrence and death. The results also indicate the strong need for a randomized clinical trial to conclusively assess whether ß-blockers afford protection against melanoma recurrence and death.

Redefining the number needed to excise.

The number needed to excise (NNE) is a metric used to convey the efficiency of dermatological practice by serving as a gauge for the diagnostic accuracy of melanoma. Rather than an NNE for melanoma alone, we assert that the NNE should measure all skin cancer types and we present data on NNE from two clinical sites demonstrating the utility and trends in NNE over time.

Excess body weight and increased Breslow thickness in melanoma patients: a retrospective study.

Excess body weight has been shown to increase the risk for development of several common cancers, such as postmenopausal breast, colon, endometrium, kidney, and esophagus cancers. The main aim of the present study was to investigate the potential relationship between excess body weight, assessed in terms of BMI, and Breslow thickness in 605 patients affected by primary cutaneous melanoma. Particularly, we evaluated the occurrence of thick melanoma (>1 mm) in overweight compared with nonoverweight patients. The effect of BMI (≥25 vs. <25 kg/m2) on the risk of having a diagnosis of thick melanoma was estimated in terms of odds ratio (OR) by logistic regression analysis, adjusted for age, sex, and histological type. Significant differences in overweight versus nonoverweight patients were found with respect to sex distribution. In fact, the occurrence of thick melanoma was greater in overweight women than in nonoverweight women (OR=1.64). When the analysis was restricted to postmenopausal women, the corresponding OR increased further to 2.50. In conclusion, a positive association between excess body weight and the risk of thick melanoma was found only in female patients. On stratifying patients into subgroups, the relationship between the risk of being diagnosed with a thick melanoma (>1.0 mm) and overweight status (BMI≥25 kg/m2) was significantly affected by both sex and menopausal status. Despite limitations because of both the study design and the relatively small numbers of patients in certain subgroups, overweight status may be associated with an increased Breslow thickness in postmenopausal women.