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Patients with newly resected stage II melanoma (n = 104) were randomized to receive adjuvant vitamin D3 (100,000 IU every 50 days) or placebo for 3 years to investigate vitamin D3 protective effects on developing a recurrent disease. Median age at diagnosis was 50 years, and 43% of the patients were female. Median serum 25-hydroxy vitamin D (25OHD) level at baseline was 18 ng/mL, interquartile range (IQ) was 13–24 ng/mL, and 80% of the patients had insufficient vitamin D levels. We observed pronounced increases in 25OHD levels after 4 months in the active arm (median 32.9 ng/mL, IQ range 25.9–38.4) against placebo (median 19.05 ng/mL, IQ range 13.0–25.9), constantly rising during treatment. Remarkably, patients with low Breslow score (&lt, 3 mm) had a double increase in 25OHD levels from baseline, whereas patients with Breslow score ≥3 mm had a significantly lower increase over time. After 12 months, subjects with low 25OHD levels and Breslow score ≥3 mm had shorter disease-free survival (p = 0.02) compared to those with Breslow score &lt, 3 mm and/or high levels of 25OHD. Adjusting for age and treatment arm, the hazard ratio for relapse was 4.81 (95% CI: 1.44–16.09, p = 0.011). Despite the evidence of a role of 25OHD in melanoma prognosis, larger trials with vitamin D supplementation involving subjects with melanoma are needed.

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 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.

The contribution of recently established or candidate susceptibility genes to melanoma missing heritability has yet to be determined. Multigene panel testing could increase diagnostic yield and better define the role of candidate genes. We characterized 273 CDKN2A/ARF and CDK4-negative probands through a custom-designed targeted gene panel that included CDKN2A/ARF, CDK4, ACD, BAP1, MITF, POT1, TERF2IP, ATM, and PALB2. Co-segregation, loss of heterozygosity (LOH)/protein expression analysis, and splicing characterization were performed to improve variant classification. We identified 16 (5.9%) pathogenic and likely pathogenic variants in established high/medium penetrance cutaneous melanoma susceptibility genes (BAP1, POT1, ACD, MITF, and TERF2IP), including two novel variants in BAP1 and 4 in POT1. We also found four deleterious and five likely deleterious variants in ATM (3.3%). Thus, including potentially deleterious variants in ATM increased the diagnostic yield to about 9%. Inclusion of rare variants of uncertain significance would increase the overall detection yield to 14%. At least 10% of melanoma missing heritability may be explained through panel testing in our population. To our knowledge, this is the highest frequency of putative ATM deleterious variants reported in melanoma families, suggesting a possible role in melanoma susceptibility, which needs further investigation.

Purpose To evaluate toxicity and clinical outcomes in patients with eyelid tumour treated with contact high-dose-rate brachytherapy (HDR-BT). Material and methods Between April 2010 and August 2017, 10 consecutive patients with tumour of the eyelid underwent contact HDR-BT and custom-made surface mould. Every applicator was manually built using conventional thermoplastic material and standard plastic catheters. The median dose prescribed was 42 Gy (range, 30-48) with a median dose per fraction of 3.5 Gy (range, 2-4.5). The dose was delivered in a median of 12 fractions (range, 10-17) over a median of 16 days. In all cases, an ocular shield was placed to reduce the dose to the eye. Acute and late toxicity was evaluated according to RTOG toxicity criteria. Results We analyzed data of 9 of 10 patients (one patient was excluded because he did not give consent for investigation). The median age was 68 years (range, 31-88). According to the TNM-UICC staging system, 4, 1 and 4 patients were stage IA, IB and IC, respectively. Basal cell and sebaceous gland carcinomas were reported in 5 and 2 patients, respectively; other histological types were non-Hodgkin lymphoma and plasmacytoma. After a median follow-up of 51 months (range, 16-90), there was no evidence of local or distant recurrence. The treatment was very well tolerated. Most commonly acute reactions consisted of low grade (G1-G2) conjunctivitis and skin erythema. Only one patient required a temporary interruption of the treatment due to acute G2 conjunctivitis and G3 lid erythema. Only one G2 late toxicity was reported (corneal ulceration), without resulting in functional impairment or blindness. Conclusions Our results suggest that contact HDR-BT with a customized applicator is safe, effective and offers very good local control and can be considered for the treatment of eyelid tumours.

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

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.

Dabrafenib is a potent BRAF-kinase inhibitor. Its activity was evaluated on 40 consecutive metastatic melanoma patients (pts) harboring the V600BRAF mutations. Dabrafenib was administered orally at the dosage of 150 mg b.i.d. daily. ORR was 82%, with 7% CR, 62% PR, 13% SD and 18% PD. The median PFS and OS were seven and 17 months, respectively (median follow-up: 8.5 months). Increased risk of progression was found in pts with elevated LDH, ECOG PS >1 and more than two metastatic sites. Grade 3–4 adverse events were recorded in 4 pts. In this retrospective analysis, Dabrafenib confirmed its role as the standard clinical option in metastatic melanoma pts.

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.

Background 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. Objective We evaluated the risk of developing a SPC among 1537 melanoma patients, and the risk of second primary melanoma (SPM) in 52 354 extracutaneous cancer patients, who were treated at the European Institute of Oncology in Milan, Italy, during 2000–2010. Material and methods We calculated standardized incidence ratios (SIR) by applying gender-, age-, year- and region-specific reference rates to the follow-up time accrued between the diagnosis of the first and the second primary malignancies. Results Seventy-six SPC were diagnosed during a median follow-up of 4 years, of which 49 (64%) during the first 2 years upon melanoma diagnosis. The SIR was increased for cancer of breast (4.10, 95% CI 2.79–6.03), thyroid (4.67, 95% CI 1.94–11.22), brain (6.13, 95% CI 2.30–16.33) and for non-Hodgkin lymphoma (3.12, 95% CI 1.30–7.50). During a median follow-up of 4 years, 127 SPM were diagnosed: thick lesions were less frequent than for melanoma diagnosed as first cancer. The SIR was increased for cancer of breast (5.13, 95%CI 3.91–6.73), thyroid (16.2, 95%CI: 5.22–50.2), head and neck (5.62, 95%CI 1.41–22.50), soft tissue (8.68, 95%CI 2.17–34.70), cervix (12.5, 95% CI 3.14–50.20), kidney (3.19, 95%CI 1.52–6.68), prostate (4.36, 95%CI 2.63–7.24) and acute myeloid leukaemia (6.44, 95%CI 2.42–17.20). Conclusions The most likely causes of these associations are the clustering of lifestyle risk factors in the same subgroups of population, mainly on a sociocultural basis and surveillance bias. This raises important questions about how to best follow cancer survivors by avoiding an inefficient use of resources and an excessive medicalization of these patients' lives.

Long-term analysis of the NIBIT-M1 trial continues to demonstrate efficacy of the combination of ipilimumab and fotemustine in metastatic melanoma patients with or without brain metastases. The addition of fotemustine to ipilimumab does not impair its immunomodulatory activity. Background In the NIBIT-M1 study, we reported a promising activity of ipilimumab combined with fotemustine in metastatic melanoma (MM) patients with or without brain metastases. To corroborate these initial findings, we now investigated the long-term efficacy of this combination. Patients and methods This analysis captured the 3-year outcome of MM patients who received ipilimumab combined with fotemustine as first- or second-line treatment. Median overall survival (OS), 3-year survival rates, immune-related (ir) progression-free survival (irPFS), brain PFS, and ir duration of response (irDOR) for the entire population and for patients with brain metastases were assessed. Clinical results were correlated with circulating CD3+CD4+ICOS+CD45RO+ or CD45RA+ T cells, neutrophil/lymphocyte (N/L) ratios, and tumorBRAF-V600 mutational status. Results Eighty-six MM patients, including 20 with asymptomatic brain metastases that had been pre-treated with radiotherapy in 7 subjects, were enrolled in the study. With a median follow-up of 39.9 months, median OS and 3-year survival rates were 12.9 months [95% confidence interval (CI) 7.1–18.7 months] and 28.5% for the whole study population, and 12.7 months (95% CI 2.7–22.7 months) and 27.8% for patients with brain metastases, respectively. Long-term ir adverse events consisting of G1 rush and pruritus occurred in 21% of patients. The absolute increase from baseline to week 12 in ‘memory’ but not in ‘naive’ T cells identified patients with a better survival (P = 0.002). The N/L ratio correlated with a significantly better survival at early time points.BRAF status did not correlate with clinical outcome. Conclusions Long-term analysis of the NIBIT-M1 trial continues to demonstrate efficacy of ipilimumab combined with fotemustine in MM patients. Fotemustine does not seem to impair the immunologic activity of ipilimumab. EudraCT number 2010-019356-50. CinicalTrials.gov NCT01654692.

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.

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Electroporation uses pulsed, high-intensity electric fields to temporarily increase cell membrane permeability by creation of pores, through which small molecules, such as chemotherapeutic agents, can diffuse inside cells before they reseal. The combination of electroporation with the administration of otherwise low-permeant cytotoxic drugs is known as electrochemotherapy (ECT). The two most commonly used drugs are bleomycin and cisplatin. ECT has already been proven to be effective in diverse tumor histotypes, including melanoma and basal and squamous cell carcinoma, Kaposi sarcoma, and breast cancer, also in those cases nonresponding to classical chemotherapies or other loco-regional treatment modalities, with a good safety profile. ECT can be proposed as loco-regional therapy for disseminated cutaneous and subcutaneous tumor lesions as alternative treatment modality to conventional therapies or as palliative care, in order to improve patients' quality of life.

Nevus depigmentosus is an uncommon hypopigmented macule or patch that is congenital and stable in its relative size and distribution throughout life; it occurs sporadically and may be localized, segmental or, less often, systematized. We report the case of a 17-year-old girl with a segmental achromic nevus of the left leg and a patch on the lower back with late age of onset who developed lentigines after prolonged intense ultraviolet B exposure as a consequence of an incorrect diagnosis of segmental vitiligo.

e20037 Title: Brain metastasis in melanoma patients: associations with BRAFstatus and age. Background: Somatic BRAF mutations are found in 40-50% melanoma patients. While associations with patient ...

e19035 Background: There is no consensus regarding the appropriate management of melanoma patients at stage IV and resectable metastases. Methods: We conducted a systematic review and meta-analysis to examine the effect of surgery on overall survival (OS) in patients with resectable metastases. The systematic review was performed by searching MEDLINE, EMBASE, Cochrane and ISI Web of Science. The meta-analysis was performed using time-to-event data from which hazard ratios (HRs) and 95% confidence intervals (CIs) of OS were estimated and summary estimates were obtain through random effects model. Heterogeneity and publication bias were investigated by sensitivity analyses and funnel plot regression Results: Thirty-three retrospective studies evaluating survival from resected and unresected metastases were found from 1978 until 2010. In resected patients median follow-up is 1.5 years and 2-year OS is 27% whereas in unresected the median follow-up is 6 months and 2-year OS is 12%. Meta-analysis was carried out on the seven studies reporting information on visceral metastases and including 1,165 patients. We included also 93 patients at stage IV treated at the European Institute of Oncology, Milan, Italy. Surgery has shown an improvement in survival of patients managed with palliative resection of their visceral metastases: the summary estimate suggests a significant decrease in the risk of mortality of 40% for patients who undergo surgery, with no indication of heterogeneity (HR=0.6 (0.45-0.78); I2=0). However we found indication for publication bias (P=0.03) suggesting that small studies published only mainly if they found significant results. Conclusions: Our results suggest the benefit of surgical resection for advanced-stage melanoma. Patients with limited sites and numbers of metastases should be considered for curative resection regardless of the location of the disease.

e19036 Background: Vulvar melanoma (VM) represents 3-7% of melanoma in women. The 5-year survival rate ranges from 8 to 55%. Surgical excision represents the best definitive therapy but surgical radicality does not impact on recurrence or survival. Methods: Thirty women with histologically confirmed VM diagnosed between 1993 and 2009 were selected for this monocentric retrospective study. One patient with metastases at time of diagnosis was excluded from the statistical analysis. Clinical, pathological and follow-up data were collected. Cumulative incidences of events were calculated and compared across subgroups by means of the Gray test. Results: Average age at diagnosis was 62 years. Average Breslow thickness was 4.91 mm. Ulceration was present in 11 cases and was unknown in 5. One case of VM was multifocal at presentation. Eleven patients underwent a wide local excision, 11 a hemivulvectomy and 7 a radical vulvectomy Sentinel node biopsy was performed in 23 patients and at least one positive sentinel node was found in 8 cases. Eight patients received adjuvant therapy. Ten patients had a second tumor (other than melanoma); of these, a breast cancer was recorded in 5 cases. Four patients had a second primary melanoma: of the vulva (n=2), vagina (n=1), and urethra (n=1). Median follow-up among ongoing survivors was 79 months and median overall survival was 69 months. The 5-year overall survival was 55.4%. Median event free survival 34 months. Positive lymph nodal status was associated with an increased risk of loco-regional recurrences (P=0.04). Positive lymph nodal status (P=0.06), Breslow thickness > 2mm (P=0.05) and number of mitoses > 10/mm2 (P=0.04) increased the risk of distant metastases. Age, ulceration and type of surgery were not significantly associated with any type of event. Conclusions: Lymph node involvement, elevated depth of invasion and a high number of mitoses were the most important prognostic factors for locoregional recurrence and distant metastases. The same trends were observed for the overall survival, but results were not statistically significant. Conservative surgery in the form of wide local excision with adequate margins may replace vulvectomy. Sentinel node biopsy is feasible and its role in VM should be further investigated.

8589 Background: A new, promising application of bleomycin was discovered and developed by Mir in 1991, combining the 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%. Methods: In our Institute we treated 75 consecutive patients from 2006 to 2009 for superficial cancer lesions, especially metastatic melanomas (58 patients) and squamous or large basal cell carcinomas (1...