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Supplementary Figure S1 shows IHC analysis of metastatic melanoma tissues of MM13, MM16, and MM27 patients and their paired PDX1/PDX2. Supplementary Figure S2 shows exome sequencing analysis of human metastatic melanoma MM13, MM16, and MM27 and their paired PDX1/PDX2. Supplementary Figure S3 shows silencing efficiency of BAZ1B, SMARCA4, CHD4 and KMT2D shRNAs. Supplementary Figure S4 shows results of the in vitro proliferation and migration assays with SMARCA4- and CHD4-overexpressed MM16 PDX cells. Supplementary Figure S5 shows the functional analysis of KMT2-knockout- SK-MEL30 or A375 melanoma cell lines generated using the CRISPR/Cas9 system. Supplementary Figure S6 shows NRAS- and BRAS-mutant overexpression in shKMT2 or shLUC melanoma cell lines. Supplementary Figure S7 shows comparison of in vitro shRNA screens on melanoma cell lines with in vivo screens on PDX melanoma cells. Supplementary Figure S8 shows Mutation rate and clinical relevance of epigenetic hits identified in our melanoma screens.

Supplementary Table S1. Patient Demographics, and Clinical Characteristics of the Metastatic Cutaneous Melanomas and the Patient-derived xenografts (PDXs). Supplementary Table S2. A, Analysis of the epigenetic screening performed in MM13, MM16 and MM27 PDXs. B, Summary of the epigenetic screening results. Supplementary Table S3. List of shRNAs composing the 80sh-library (shRNA ID), sequenced hairpins and associated barcodes, and Log2(ratio) values derived from the screening analysis of MM13, MM16 and MM27 PDXs. Supplementary Table S4. List of the 103 genes specifically de-regulated in the two NRAS-mutated patients. Supplementary Table S5. Values of RNA expression of 52 candidate genes in metastatic melanoma PDXs.

Supplementary Methods, Figure Legends

Merkel cell carcinoma (MCC) is a very rare and aggressive neuroendocrine carcinoma originating from Merkel cells, typically with a skin nodule; however, it exceptionally presents with only a basin lymph node localization, with neither a cutaneous primary site nor distant metastases. From 1996 to 2020, among patients with histologically confirmed MCC managed at a neuroendocrine neoplasm-referral center, we selected those with an exclusive nodal basin, no distant metastasis, and an unknown primary site defined by cross-sectional and physical examination. A total of 55 out of 310 patients fulfilled the selection criteria. The median age was 64 years and the majority were males. Inguinal lymph-nodes were the most common anatomic site. With a median follow-up of 4.3 years, the 5-year relapse-free survival (RFS) rate was 56.6 (95% CI 42.0–68.8%) and the 5-year cancer specific survival (CSS) rate was 68.5 (95% CI 52.8–79.9%) for the whole population. The 36 patients (65.5%) undergoing lymphadenectomy (LND) + radiotherapy (RT) ± chemotherapy had a 5-year RFS rate of 87.2% (95% CI 65.5–95.7%) and a 5-year CSS rate of 90.5% (95% CI 67.0–97.5), which were better than those receiving LND alone. In a multivariable analysis, the survival benefit for LND + RT remained significant. Results from one of the largest single-center series of nMCC-UP suggest that a curative approach including RT can be effective, similar to what is observed for stage IIIB MCC. Multicentric studies with homogenous populations should be carried out in this controversial clinical entity, to minimize the risk of biases and provide robust data.

This paper summarizes the position of the Italian Society of Vulvology on the clinical approach to vulval disease. A thorough history (general medical, gynaecological, and vulval history) is essential for a successful and fruitful vulvological examination. Characteristics of pruritus (itch) and pain, that are the two main vulval symptoms, should be collected and reported with precision, according to duration, temporal course, location, provocation, and intensity. Physical examination must consider both the general condition of the patient and the specific vulval region, that must be examined following a standardized methodology. The physical examination of the vulva is carried out with naked eye and adequate natural or halogen lighting. The subsequent use of instrumental magnification can be considered on particular parts of skin/mucosa, already highlighted with the first inspection. Also, palpation is essential, allowing to appreciate physical features of vulval lesions: consistency, surface, soreness, adherence to underlying plans. Finally, the five-step approach of the International Society for the Study of Vulvo-vaginal Disease about Terminology and Classification of Vulvar Dermatological Disorders (2012) is summarized. A vulval biopsy may be useful in the following situations: when clinical diagnosis is uncertain, lesion not responding to treatment; histologic confirmation for a clinical diagnosis and exclusion or confirmation of a suspected neoplastic intraepithelial or invasive pathology.

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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.

Not present

After coronavirus disease 2019 (COVID-19) caused a global pandemic, vaccines were rapidly developed to control the spread of the virus. Although they were effective in most of the cases at protecting people from becoming seriously ill and being hospitalized, they showed side effects, too. Among other adverse vaccine reactions, cutaneous eruptions following SARS-CoV-2 have been described in the literature, but they are not well-characterized yet. We described the morphology and timing of the spectrum of cutaneous reactions following most of the COVID-19 vaccines available in Italy, which were observed in outpatients referred to our non-invasive diagnostic clinic. Most of these reactions appeared after the second or third COVID-19 vaccine dose (most of them after mRNA COVID-19 vaccines). Our data support that cutaneous reactions to COVID-19 vaccination are generally self-limited; in addition, history of allergic reaction to a specific food, medicine or vaccine should not discourage vaccination in the general population, although patients with immune dysregulation should be accurately selected and monitored. Further research is necessary to better assess the true prevalence and preventive measures of skin reactions to COVID-19 vaccination.

Photodynamic therapy (PDT) using 5-aminolevulinic acid (5-ALA) is an emerging treatment option in the care of actinic keratosis (AK). A self-adhesive 5-ALA patch was recently developed that allows a precise PDT procedure. Here, we review the current literature and report the findings of our case series that observed the outcomes and safety of 5-ALA patch PDT. Ten patients with a total of 40 AKs were treated with a single session of conventional or daylight PDT using 5-ALA patch at the Department of Dermatology and Venereology, Sapienza University of Rome or at the European Institute of Oncology, Milan, Italy. Complete response was observed in three patients, while partial response was seen in seven patients. Overall tolerability was good or excellent, with local adverse events observed in four patients. This is the first case series reported where the 5-ALA patch was applied using daylight PDT, and its efficacy and tolerability in the treatment of AK were demonstrated. In conclusion, the self-adhesive 5-ALA patch is a convenient application of PDT that provides a well-tolerated and effective treatment option with satisfactory cosmetic outcomes.

Basal cell carcinoma (BCC) can sometimes affect the eyelids and in particular the eyelid margin, where it can often be misdiagnosed, mimicking other benign, more common diseases. Dermoscopy may provide additional diagnostic criteria for an earlier diagnosis of eyelid margin BCC, although the dermoscopic features of BCC affecting this anatomical site have seldom been reported. We highlight the peculiar presence of linear vessels perpendicular to the eyelid margin in BCCs of the eyelid margin. Our article represents the first report of these dermoscopic findings in a series of BCCs of the eyelid margin.

Background: Cutaneous malignant melanoma (CMM) is one of the most aggressive types of skin cancer. Currently, innovative approaches such as target therapies and immunotherapies have been introduced in clinical practice for the treatment of metastatic CMM. Data of clinical trials and real life studies that evaluate the outcomes of these therapeutic associations are necessary to establish their clinical utility. The aim of this study is to investigate the types of oncological treatments employed in the real-life clinical management of patients with advanced CMM in several Italian centers which are part of the Clinical National Melanoma Registry (CNMR), and the oncological outcomes obtained. Methods: CNMR collects data of patients with a histologically confirmed diagnosis of primary CMM treated in one of the 38 Italian institutions (hospitals, research institutes, etc.) participating in the network. Melanoma-specific survival and Overall survival were calculated. Kaplan-Meier curves and medians of OS and 95% CI are presented overall and by immunotherapy and target treatments. The Log-rank test compared curves by treatments. Multivariate Cox regression models were used to estimate the hazard ratios adjusting for confounders and other prognostic factors. Results: The median follow-up time was 36 months (range 1.2-185.1). 787 CMM were included in the analysis with completed information about therapies.Global immunotherapy showed a significant improved survival compared with all other therapies (p=0.001). 75% was the highest reduction of death reached by nivolumab/pembrolizumab immunotherapy (anti-PD1 HR=0.25 95% CI 0.14-0.42), globally immunotherapy was significantly associated with improved survival, either for anti-CTL A4 monotherapy or combined with anti-PD1 (HR=0.47;95% CI 0.33-0.66 and HR=0.26; 95% CI 0.15-0.46, respectively). Conclusions: The nivolumab/pembrolizumab and the combination of ipilimumab can be considered the best therapy to improve survival in a real-world-population. The CNMR can complement clinical registries with the intent of improving cancer management and standardizing cancer treatment.

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Hidradenoma papilliferum (HP) is a rare, slow-growing, benign adnexal tumour with apocrine differentiation. It usually affects the anogenital region in adult women and is clinically polymorphous, mimicking other benign or malignant neoformations. The dermoscopic features of vulval HP have not been reported yet. We report the clinical and dermoscopic features in a case series of histopathologically proven vulval HPs. Dermoscopy may be a useful tool for the diagnosis of vulval HP. To our knowledge, our paper represents the first report of dermoscopic findings in a series of vulval HPs in a multiracial population.

Background: Vulvar melanoma (VM) is rare and is often diagnosed late. Dermoscopy may aid in its recognition, differentiating VM from other more common vulvar lesions, such as melanosis and naevi. However, little is known about the dermoscopic features of thin VM. Aim: To retrospectively analyse a series of histopathologically diagnosed thin VMs and to highlight their most suggestive dermoscopic features. Methods: A multicentre, retrospective study was conducted, including histopathologically proven thin VMs, either intraepidermal or with Breslow thickness ≤0.5mm, diagnosed during the period 2016–2018. We particularly focused on their dermoscopic characteristics to highlight the most suggestive dermoscopic diagnostic clues. Results: In total, 14 cases of early-stage VM were included, in women with a mean age at diagnosis of 64.86years. The most frequently affected sites were the labia minora. Of these, 11 cases were unifocal. Dermoscopy most often revealed structureless areas, grey globules and areas, irregular black–brown dots, blue and white structures, and red areas. Conclusions: In our experience, early-stage VM often exhibits dermoscopic features that are more typical of thicker cutaneous melanomas. Dermoscopy may provide useful clues for the prompt diagnosis of thin VM.

Nonmelanoma skin cancer is the most common malignant tumor in the fair skin population, with each year several millions of diagnosed cases. Their most common risk factors are fair skin, a history of excessive ultraviolet light exposure, chronic inflammatory skin conditions, exposure to radiation, and contact with arsenic. Certain drugs can also be associated with a higher risk of nonmelanoma skin cancer. These include hydroxyurea, which acts as a metabolic inhibitor of ribonucleotide reductase and a potent nonalkylating myelosuppressive agent. It is used for the treatment of various myeloproliferative disorders, including chronic myeloid leukemia, polycythemia vera, and essential thrombocytopenia. Several publications describe an increased occurrence of skin manifestations following hydroxyurea treatment. A growing body of evidence indicates a possible role of hydroxyurea in skin cancer progression. In this review article, we summarize some relevant observations about the association of hydroxyurea and skin cancer, and we describe our own clinical experiences to provide up to date recommendations about the care of patients on hydroxyurea therapy.

Background and aim: Over the last decades, the incidence of melanoma has been steadily growing, with 4.2% of the population worldwide affected by cutaneous melanoma (CM) in 2020 and with a higher incidence and mortality in men than in women. We investigated both the risk factors for CM development and the prognostic and predictive factors for survival, stratifying for both sex and gender. Methods: We conducted a systematic review of studies indexed in PUB-MED, EMBASE, and Scopus until 4 February 2021. We included reviews, meta-analyses, and pooled analyses investigating differences between women and men in CM risk factors and in prognostic and predictive factors for CM survival. Data synthesis: Twenty-four studies were included, and relevant data extracted. Of these, 13 studies concerned potential risk factors, six concerned predictive factors, and five addressed prognostic factors of melanoma. Discussion: The systematic review revealed no significant differences in genetic predisposition to CM between males and females, while there appear to be several gender disparities regarding CM risk factors, partly attributable to different lifestyles and behavioral habits between men and women. There is currently no clear evidence of whether the mutational landscapes of CM differ by sex/gender. Prognosis is justified by a complex combination of phenotypes and immune functions, while reported differences between genders in predicting the effectiveness of new treatments are inconsistent. Overall, the results emerging from the literature reveal the importance of considering the sex/gender variable in all studies and pave the way for including it towards precision medicine. Conclusions: Men and women differ genetically, biologically, and by social construct. Our systematic review shows that, although fundamental, the variable sex/gender is not among the ones collected and analyzed.

Background: vulvar intraepithelial neoplasia is a non-invasive precursor lesion found in 50–70% of patients affected by vulvar squamous cell carcinoma. In the past, radical surgery was the standard treatment for vulvar intraepithelial neoplasia, however, considering the psychological and physical morbidities related to extensive surgery, several less aggressive treatment modalities have been proposed since the late 1970s. Photodynamic therapy is an effective and safe treatment for cutaneous non-melanoma skin cancer, with favorable cosmetic outcomes. Methods: in the present paper, the results of selected studies on photodynamic therapy in the treatment of vulvar intraepithelial neoplasia are reported and discussed. Results: Overall, complete histological response rates ranged between 20% and 67% and symptom response rates ranged between 52% and 89% according to different studies and case series. Conclusions: the real benefit of photodynamic therapy in the setting of vulvar intraepithelial neoplasia lies in its ability to treat multi-focal disease with minimal tissue destruction, preservation of vulvar anatomy and excellent cosmetic outcomes. These properties explain why photodynamic therapy is an attractive option for vulvar intraepithelial neoplasia treatment.

Vulvar intraepithelial neoplasia (VIN) is a subtype of in situ squamous cell carcinoma (SCC). The diagnosis is clinical and histopathological. Dermoscopy of VIN has been scarcely reported. Herein we describe the dermoscopic features in 4 female patients. This article is protected by copyright. All rights reserved.

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

The identification of genes maintaining cancer growth is critical to our understanding of tumorigenesis. We report the first in vivo genetic screen of patient-derived tumors, using metastatic melanomas and targeting 236 chromatin genes by expression of specific shRNA libraries. Our screens revealed unprecedented numerosity of genes indispensable for tumor growth (∼50% of tested genes) and unexpected functional heterogeneity among patients ( Significance: Drug targeting of biologically relevant cancer-associated mutations is considered a critical strategy to control cancer growth. Our functional in vivo genetic screens of patient-derived tumors showed unprecedented numerosity and interpatient heterogeneity of genes that are essential for tumor growth, but not mutated, suggesting that multiple, patient-specific signaling pathways are activated in tumors. Cancer Discov; 6(6); 650–63. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 561

Previous studies have reported an association between sun exposure and the increased survival of patients with cutaneous melanoma (CM). The present study analyzed the association between ultraviolet (UV) light exposure and various prognostic factors in the Italian Clinical National Melanoma Registry. Clinical and sociodemographic features were collected, as well as information concerning sunbed exposure and holidays with sun exposure. Analyses were performed to investigate the association between exposure to UV and melanoma prognostic factors. Between December 2010 and December 2013, information was obtained on 2,738 melanoma patients from 38 geographically representative Italian sites. A total of 49% of the patients were >55 years old, 51% were men, 50% lived in the north of Italy and 57% possessed a high level of education (at least high school). A total of 8 patients had a family history of melanoma and 56% had a fair phenotype (Fitzpatrick skin type I or II). Of the total patients, 29% had been diagnosed with melanoma by a dermatologist; 29% of patients presented with a very thick melanoma (Breslow thickness, >2 mm) and 25% with an ulcerated melanoma. In total, 1% of patients had distant metastases and 13% exhibited lymph node involvement. Holidays with sun exposure 5 years prior to CM diagnosis were significantly associated with positive prognostic factors, including lower Breslow thickness (P

Isotretinoin is used in the treatment of severe acne vulgaris (AV), but has controversially been associated with depression and suicide. Large prospective studies have failed to translate this clinically. We undertook a feasibility study to investigate the parameters of a triple-blind, randomized controlled trial (RCT) assessing the effect of oral isotretinoin on quality of life (QoL) and mood in patients with AV. Patients meeting the inclusion criteria were randomized for 2weeks to isotretinoin or doxycycline. Participants completed verified depression and QoL screening questionnaires at baseline and week 2. In total, 194 patients with AV were screened, with 48 meeting the inclusion criteria and 13 of these being willing to participate. The follow-up rate was 92% and questionnaire response rate was 96%. To our knowledge, this is the first study to demonstrate a successful design for a triple-blind RCT investigating the effects of isotretinoin on mood in patients with AV.

Industrial workers are exposed to occupational pollutants, which may cause diseases such as cancer, but links to melanoma are not established. The identification of industry-related risk factors for melanoma incidence and mortality might be of importance for workers, health providers, and insurance companies. To assess melanoma incidence and mortality among oil/petroleum, chemical, and electrical industry workers. All studies reporting standardized mortality ratios (SMR) and/or standardized incidence ratios (SIR) of melanoma in workers employed in oil/petroleum, chemical, and electrical industries were included. Random-effect meta-analyses were carried out to summarize SIR and SMR for melanoma among oil/petroleum, chemical, and electrical industry workers. Heterogeneity was assessed using χ and I statistics. Possible source bias and quality were assessed using the Strengthening the Reporting of Observational Studies in Epidemiology checklist and a modified version of the Newcastle-Ottawa scale. Of 1878 citations retrieved, we meta-analyzed 21, 6, and 9 studies for the oil/petroleum, electrical, and chemical industry, respectively. Oil/petroleum industry: summary standardized incidence ratio (SSIR) = 1.23 [95% confidence interval (CI): 1.11-1.36, I = 45%]; summary standardized mortality ratio (SSMR) = 1.02 (95% CI: 0.81-1.28, I = 48%); subgroups: SSIR = 1.16 (95% CI: 1.01-1.32, I = 15%), SSMR = 1.19 (95% CI: 1.00-1.42, I = 20%). Electrical industry: SSIR = 1.00 (95% CI: 0.93-1.11, I = 72%); SSMR = 1.16 (95% CI: 0.74-1.81, I = 11%). Chemical industry: SSIR = 2.08 (95% CI: 0.47-9.24, I = 73%); SSMR = 2.01 (95% CI: 1.09-3.72, I = 33%). Our meta-analysis suggests a slightly increased risk of developing melanoma among oil/petroleum industry workers and an increased melanoma mortality among oil/petroleum and chemical industry workers. No increased risks were found among electrical industry workers.

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Caini, Saverio Boniol, Mathieu Tosti, Giulio Magi, Serena Medri, Matelda Stanganelli, Ignazio Palli, Domenico Assedi, Melania Marmol, Veronique Del Gandini, Sara eng Meta-Analysis Research Support, Non-U.S. Gov't Review England 2014/08/05 06:00 Eur J Cancer. 2014 Oct;50(15):2649-58. doi: 10.1016/j.ejca.2014.06.024. Epub 2014 Jul 30.; International audience; Vitamin D is formed mainly in the skin upon exposure to sunlight and can as well be taken orally with food or through supplements. While sun exposure is a known risk factor for skin cancer development, vitamin D exerts anti-proliferative and pro-apoptotic effects on melanocytes and keratinocytes in vitro. To clarify the role of vitamin D in skin carcinogenesis, we performed a review of the literature and meta-analysis to evaluate the association of vitamin D serum levels and dietary intake with cutaneous melanoma (CM) and non-melanoma skin cancer (NMSC) risk and melanoma prognostic factors. Twenty papers were included for an overall 1420 CM and 2317 NMSC. The summary relative risks (SRRs) from random effects models for the association of highest versus lowest vitamin D serum levels was 1.46 (95% confidence interval (CI) 0.60-3.53) and 1.64 (95% CI 1.02-2.65) for CM and NMSC, respectively. The SRR for the highest versus lowest quintile of vitamin D intake was 0.86 (95% CI 0.63-1.13) for CM and 1.03 (95% CI 0.95-1.13) for NMSC. Data were suggestive of an inverse association between vitamin D blood levels and CM thickness at diagnosis. Further research is needed to investigate the effect of vitamin D on skin cancer risk in populations with different exposure to sunlight and dietary habits, and to evaluate whether vitamin D supplementation is effective in improving CM survival.

The melanoma of the genital mucosa is a rare melanocytic neoplasm that affects both sexes. The diagnosis is often delayed; videodermatoscopy may represent a useful diagnostic tool. The treatment is complex and multidisciplinary. We report the main diagnostic features and therapeutic approaches for mucosal melanoma of the genital tract.

Laboratory studies suggested that caffeine and other nutrients contained in coffee and tea may protect against non-melanoma skin cancer (NMSC). However, epidemiological studies conducted so far have produced conflicting results. We performed a literature review and meta-analysis of observational studies published until February 2016 that investigated the association between coffee and tea intake and NMSC risk. We calculated summary relative risk (SRR) and corresponding 95 % confidence intervals (95 % CI) by using random effects with maximum likelihood estimation. Overall, 37,627 NMSC cases from 13 papers were available for analysis. Intake of caffeinated coffee was inversely associated with NMSC risk (SRR for those in the highest vs. lowest category of intake: 0.82, 95 % CI 0.75–0.89, I 2 = 48 %), as well as intake of caffeine (SRR 0.86, 95 % CI 0.80–0.91, I 2 = 48 %). In subgroup analysis, these associations were limited to the basal cell cancer (BCC) histotype. There was no association between intake of decaffeinated coffee (SRR 1.01, 95 % CI 0.85–1.21, I 2 = 0) and tea (0.88, 95 % CI 0.72–1.07, I 2 = 0 %) and NMSC risk. There was no evidence of publication bias affecting the results. The available evidence was not sufficient to draw conclusions on the association between green tea intake and NMSC risk. Coffee intake appears to exert a moderate protective effect against BCC development, probably through the biological effect of caffeine. However, the observational nature of studies included, subject to bias and confounding, suggests taking with caution these results that should be verified in randomized clinical trials.

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.

Nowadays, melanoma is one of the most common fatal malignancy of young adults. Incidence is increasing, but mortality rates from melanoma have remained stable. In-transit metastases from extremity or trunk melanoma are subcutaneous or cutaneous deposits of melanoma distant from the primary site, but not reaching the draining nodal basin. According to American Joint Committee on Cancer classification of stages based on Tumor, Node, Metastases classification stages IIIb and IIIc are considered local advanced disease and survival outcomes is quite poor, with 5-year survival rates of 24-54%. Loco-regional recurrence is an important risk factor for distant metastatic disease, either synchrone or metachrone. Therapy for this pattern of recurrence is limited and options vary based on the volume and site of disease. Definitive surgical resection remains the preferred therapeutic approach. However, when surgery cannot be performed with a reasonable cosmetic and functional outcome, other options must be utilized. Treatment options are classified as local, regional, or systemic. The choice of therapy depends on the number of lesions, their anatomic location, whether or not they are dermal or subcutaneous, the size, and the presence or absence of extra-regional disease.

Heat-shock proteins are highly conserved, stress-induced proteins with chaperone function for trafficking and delivering peptides within the different compartments of the cell. Tumor-derived heat-shock protein–peptide complexes (HSPPCs) can be used for vaccination against malignancies. In particular, the HSPPC-96-based vaccine vitespen (formerly Oncophage®) is the first autologous cancer vaccine made from individual patients’ tumors that has shown encouraging results in clinical trials. In Phase I and II clinical trials, this vaccine has shown activity on different malignancies, such as gastric cancer, colorectal cancer, pancreatic cancer, non-Hodgkin’s lymphoma and chronic myelogenous leukemia. In Phase III clinical trials in melanoma and kidney cancer, it demonstrated an excellent safety profile with almost no toxicity. Heat-shock protein-based vaccines can be considered as a novel therapeutic approach with a promising role in cancer management.

Heat shock proteins (HSPs) are highly conserved, stress-induced proteins that function as chaperones stabilizing and delivering peptides. In several preclinical studies, tumor derived HSP-peptide complexes (HSPPCs) have been shown to induce immunity against several malignancies. HSP-based vaccines, indeed, work across tumor types, bypassing the need for the identification of the single immunogenic peptide and thus emerging as a class of tumor- and patient-specific vaccines. HSPPC-96-based vaccine vitespen® (formerly Oncophage®) is the first autologous cancer vaccine made from individual patients’ tumors which not only confirmed its activity in different malignancies (e.g., gastric cancer, colorectal cancer, pancreatic cancer, non-Hodgkin’s lymphoma and chronic myelogenous leukemia), but was also successfully tested in phase III clinical trials in melanoma and kidney cancer. HSPPC-96-based vaccine also demonstrated an excellent safety profile with almost no toxicity. HSP-based vaccines are emerging as a no...

Purpose To assess the antitumor activity of vitespen (autologous, tumor- derived heat shock protein gp96 peptide complexes) by determining whether patients with stage IV melanoma treated with vitespen experienced longer overall survival than patients treated with physician's choice. Patients and Methods Patients (N = 322) were randomly assigned 2:1 to receive vitespen or physician's choice (PC) of a treatment containing one or more of the following: dacarbazine, temozolomide, interleukin-2, or complete tumor resection. This open-label trial was conducted at 71 centers worldwide. Patients were monitored for safety and overall survival. Results Therapy with vitespen is devoid of significant toxicity. Patients randomly assigned to the vitespen arm received variable number of injections (range, 0 to 87; median, 6) in part because of the autologous nature of vitespen therapy. Intention-to-treat analysis showed that overall survival in the vitespen arm is statistically indistinguishable from that in the PC arm. Exploratory landmark analyses show that patients in the M1a and M1b substages receiving a larger number of vitespen immunizations survived longer than those receiving fewer such treatments. Such difference was not detected for substage M1c patients. Conclusion These results are consistent with the immunologic mechanism of action of vitespen, indicating delayed onset of clinical activity after exposure to the vaccine. The results suggest patients with M1a and M1b disease who are able to receive 10 or more doses of vitespen as the candidate population for a confirmatory study.