Giuseppe Spadola

Sunny Holidays before and after Melanoma Diagnosis Are Respectively Associated with Lower Breslow Thickness and Lower Relapse Rates in Italy

Background Previous studies have reported an association between sun exposure and improved cutaneous melanoma (CM) survival. We analysed the association of UV exposure with prognostic factors and outcome in a large melanoma cohort. Methods A questionnaire was given to 289 (42%) CM patients at diagnosis (Group 1) and to 402 CM patients (58%) during follow-up (Group 2). Analyses were carried out to investigate the associations between sun exposure and melanoma prognostic factors and survival. Results Holidays in the sun two years before CM diagnosis were significantly associated with lower Breslow thickness (p=0.003), after multiple adjustment. Number of weeks of sunny holidays was also significantly and inversely associated with thickness in a dose-dependent manner (p=0.007). However when stratifying by gender this association was found only among women (p=0.0004) the risk of CM recurrence in both sexes was significantly lower in patients (n=271) who had holidays in the sun after diagnosis, after multiple adjustment including education: HR=0.30 (95%CI:0.10-0.87; p=0.03) conclusions: Holidays in the sun were associated with thinner melanomas in women and reduced rates of relapse in both sexes. However, these results do not prove a direct causal effect of sun exposure on survival since other confounding factors, such as vitamin D serum levels and socio-economic status, may play a role. Other factors in sun seeking individuals may also possibly affect these results.

Prognostic significance of hematological profiles in melanoma patients

Cancer‐related inflammation may play an important role in disease progression and patient outcome, and could be easily monitored through indirect parameters routinely evaluated at diagnosis. Here, we investigated if peripheral blood cells and the ratios of neutrophils to lymphocytes (NLR) and of lymphocytes to monocytes (LMR) as surrogate markers of cancer related inflammation are associated with disease progression and survival of melanoma patients at any stage of the disease. Records of 1,182 melanoma patients included in an Institutional tumor registry in the period 2000–2010, were reviewed. Among them, 584 patients with a cutaneous or unknown primary melanoma and available pre‐operative blood tests were analyzed. Survival was estimated with the Kaplan–Meier method, and analyzed using Log‐rank test, Cox regression and multivariate Cox proportional hazard models. We found that patients presenting with distant metastases had higher leukocytes, neutrophils and monocytes, and lower lymphocytes compared to Stage I–III patients. Furthermore, at a single‐patient level, hematological profiles changed on disease progression from regional to distant metastatic, with significantly increased circulating leukocytes, neutrophils and monocytes, and decreased lymphocytes. Peripheral blood cell counts were not associated with survival of patients with a localized or regionally metastasized melanoma. Instead, in Stage IV patients, leukocytes (p = 0.001), neutrophils (p = 0.0002), monocytes (p = 0.002), NLR (p < 0.0001) and LMR (p = 0.005) were all significantly associated with survival, independently of other known prognostic factors. These results suggest that cellular components of peripheral blood do count for survival of patients with advanced melanoma.

Multiple primary melanomas (MPMs) and criteria for genetic assessment: MultiMEL, a multicenter study of the Italian Melanoma Intergroup

BACKGROUND Multiple primary melanoma (MPM), in concert with a positive family history, is a predictor of cyclin-dependent kinase (CDK) inhibitor 2A (CDKN2A) germline mutations. A rule regarding the presence of either 2 or 3 or more cancer events (melanoma and pancreatic cancer) in low or high melanoma incidence populations, respectively, has been established to select patients for genetic referral. OBJECTIVE We sought to determine the CDKN2A/CDK4/microphthalmia-associated transcription factor mutation rate among Italian patients with MPM to appropriately direct genetic counseling regardless of family history. METHODS In all, 587 patients with MPM and an equal number with single primary melanomas and control subjects were consecutively enrolled at the participating centers and tested for CDKN2A, CDK4, and microphthalmia-associated transcription factor. RESULTS CDKN2A germline mutations were found in 19% of patients with MPM versus 4.4% of patients with single primary melanoma. In familial MPM cases the mutation rate varied from 36.6% to 58.8%, whereas in sporadic MPM cases it varied from 8.2% to 17.6% in patients with 2 and 3 or more melanomas, respectively. The microphthalmia-associated transcription factor E318K mutation accounted for 3% of MPM cases altogether. LIMITATIONS The study was hospital based, not population based. Rare novel susceptibility genes were not tested. CONCLUSION Italian patients who developed 2 melanomas, even in situ, should be referred for genetic counseling even in the absence of family history.

Risk of second primary malignancies among 1537 melanoma patients and risk of second primary melanoma among 52 354 cancer patients in Northern Italy.

The number of melanoma survivors has been increasing for decades due to early diagnosis and improved survival. These patients have an increased risk of developing a second primary cancer (SPC); also, melanoma is frequently diagnosed among patients firstly diagnosed with an extracutaneous malignancy.

Anti-hypertensive drugs and skin cancer risk: a review of the literature and meta-analysis

INTRODUCTION Several anti-hypertensive drugs have photosensitizing properties, however it remains unclear whether long-term users of these drugs are also at increased risk of skin malignancies. We conducted a literature review and meta-analysis on the association between use of anti-hypertensive drugs and the risk of cutaneous melanoma and non-melanoma skin cancer (NMSC). METHODS We searched PubMed, EMBASE, Google Scholar and the Cochrane Library, and included observational and experimental epidemiological studies published until February 28th, 2017. We calculated summary relative risk (SRR) and 95% confidence intervals (95% CI) through random effect models to estimate the risk of skin malignancies among users of the following classes of anti-hypertensive drugs: thiazide diuretics, angiotensin converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), calcium channel blockers (CCB) and β-blockers. We conducted sub-group and sensitivity analysis to explore causes of between-studies heterogeneity, and assessed publication bias using a funnel-plot based approach. RESULTS Nineteen independent studies were included in the meta-analysis. CCB users were at increased skin cancer risk (SRR 1.14, 95% CI 1.07-1.21), and β-blockers users were at increased risk of developing cutaneous melanoma (SRR 1.21, 95% CI 1.05-1.40), with acceptable between-studies heterogeneity (I2 < 50%). There was no association between thiazide diuretics, ACEi or ARB use and skin cancer risk. We found no evidence of publication bias affecting the results. CONCLUSION Family doctors and clinicians should inform their patients about the increased risk of skin cancer associated with the use of CCB and β-blockers and instruct them to perform periodic skin self-examination. Further studies are warranted to elucidate the observed associations.

Tuning of a deformable image registration procedure for skin component mechanical properties assessment.

Several studies report the mechanical properties of skin tissues but their values largely depend on the measurement method. Therefore, we investigated the feasibility of recognizing the cellular constituents mechanical properties of pigmented skin by Confocal Laser Scanner Microscopy (CLSM). With this purpose, an healthy volunteer was examined in three areas nearby a pigmented skin lesion in two configurations: deforming and non deforming the nevus. The tissue displacement of the nevus was then assessed by means of deformable registration of the images in these two configurations. There are several registration strategy able to overcome this task, among them, we proposed two methods with different deformation models: a Free Form Deformation (FFD) model based on b-spline and a second one based on Demons Registration Algorithm (DRA). These two strategies need the definition of several parameters in order to obtain optimal registration performances. Thus, we tuned these parameters by means of simulated data and evaluated their registration abilities on the real in vivo CLSM acquisitions in the two configurations. The results showed that the registration using DRA had a better performance in comparison to the FFD one, in particular in two out of the three areas the DRA performance was significantly better than the FFD one. The registration procedure highlighted deformation differences among the chosen areas.

Combined approach for the biomechanical characterization of skin lesions.

Melanocytic nevi are common benign skin lesions, known as moles, due to proliferation of melanocytes, the pigmented skin cells. The uncontrolled growth of these cells leads instead to cutaneous malignant melanoma, an aggressive tumour whose rate of survival dramatically increases if early diagnosis is provided. Alteration on the mechanical properties of the skin in presence of lesions has been assessed. In this context, we aim at developing a combined approach consisting of an experimental and a computational study to biomechanically characterize the skin and both malign and benign skin lesions (i.e., nevi and malignant melanoma). In particular, the former study is performed to evaluate the biomechanical response of the different skin layers after the application of a displacement field and relies on a multi-scale strategy, ranging from the tissue level to the cellular level. Computational models will be tuned against experimental data (e.g., confocal laser scanning microscopy data) to estimate the mechanical properties of the different layers of the skin and the skin lesions. In particular, the confocal laser scanning microscopy is able to provide non-invasive histomorphological analysis of skin in vivo. The integration of the experimental and the computational results will allow the evaluation of possible alterations of the local mechanical properties occurring in case of pathological condition.

P20 Electrochemotherapy with bleomycin: a local treatment with possible systemic implication

A new, promising application of bleomycin was discovered and developed by Mir in 1991, combining this drug with electroporation. This new technique was called electrochemotherapy (ECT). The new treatment is based on the increased bleomycin delivery into tumor cells after cell membrane permeabilization by electric pulses administered locally at the site of superficial tumor localizations. Since 1991 more than 300 articles were published on the argument and experiences from many institutes in Europe seems to be very promising. Actually ECT is used for the treatment of cutaneous and subcutaneous tumoral lesions from different tumoral types. Favorable results in treating superficial metastatic lesions have been published with a complete response rate for treated nodules raging from 70 to 90%. In our Institute we treated 94 patients (78 evaluable patients with follow-up > 5 weeks) from 2006 to 2009 for superficial cancer lesions, especially metastatic melanomas (60 patients) and squamous or large basal cell carcinomas (16 patients), obtaining overall response rates (OR) of 88% with complete response rates (CR) of 75% in melanoma lesions and OR of 89% and CR of 67% in non melanoma lesions. Only 8/75 patients experienced relapse in the treatment field. Sixty-six patients underwent one treatment session; 17 patients had 2 sessions; 11 patients underwent 3 sessions. The treatment was well tolerated either under general or local anesthesia with minimal side effects or discomfort for patients. We conclude that ECT is a safe and well tolerated procedure; by clinical indication can be distinguished from being directed to obtain a definitive cure, a pure palliation of symptoms like bleeding, pain and tumor growth, a chronicization of the disease or possibly, and this appears as the most intriguing development, ECT can be a stimulus to activate the immune system which can be the basis to obtain a local and mainly a distant control of the disease. Furthermore we are currently evaluating development of immune responses elicited by ECT, by comparing serum levels of pro-inflammatory cytokines, and frequency and activation of T cell populations in peripheral blood of selected patients, before and after therapy. Some clinical results will be presented.