The potential impact of dietary choices on melanoma risk: an anti-inflammatory diet.

The role of inflammation in the aetiology of cancer is recognized. However, no study yet examined the association between an anti-inflammatory diet and cutaneous melanoma and explored whether it could be modified by genetic variations in cyclooxygenase-2 (COX-2), a key enzyme in inflammation. A case-control study was conducted in the IDI-IRCCS hospital in Rome, Italy with 273 cases of primary cutaneous melanoma and 269 controls frequency matched to cases. Information on socio-demographic and pigmentary characteristics, medical history, sun exposure and dietary habits were collected for all subjects. The - 765G > C polymorphism was identified in DNA extracted from blood samples. An anti-inflammatory diet score was created. Logistic regression models were fitted to obtain odds ratios (ORs) and 95% confidence intervals (CIs). A high anti-inflammatory diet score (≥ 8 anti-inflammatory dietary items) was associated with a decreased risk of cutaneous melanoma (OR: 0.29; 95%CI: 0.17-0.49, Ptrend < 0.0001) after adjusting for sex, age, education, number of common nevi, skin photo-type, solar lentigines and sunburns in childhood. COX-2 -765 G > C polymorphism was not an independent risk factor for cutaneous melanoma. Although interaction between - 765G > C genotypes and anti-inflammatory diet score was not statistically significant (p = 0.25), when stratified by -765 G > C genotypes the effect of the anti-inflammatory diet was slightly more pronounced for participants carrying - 765GG (OR: 0.17; 95%CI: 0.06-0.47, Ptrend < 0.001). Our study findings suggest that adherence to an anti-inflammatory diet is associated with a decreased risk of developing cutaneous melanoma. These results suggest the potential impact of dietary choices on melanoma risk.

Histone deacetylase inhibition mitigates fibrosis-driven disease progression in recessive dystrophic epidermolysis bullosa.

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a blistering disease caused by mutations in the gene encoding type VII collagen (C7). RDEB is associated with fibrosis, which is responsible for severe complications. The phenotypic variability observed in RDEB siblings suggests that epigenetic modifications contribute to disease severity. Identifying epigenetic changes may help to uncover molecular mechanisms underlying RDEB pathogenesis and new therapeutic targets. OBJECTIVES: To investigate histone acetylation in RDEB skin and to explore histone deacetylase inhibitors (HDACis) as therapeutic molecules capable of counteracting fibrosis and disease progression in RDEB mice. METHODS: Acetylated histone levels were detected in human skin by immunofluorescence and in RDEB fibroblasts by ELISA. The effects of Givinostat and valproic acid (VPA) on RDEB fibroblast fibrotic behaviour were assessed by collagen-gel contraction assay, Western blot and immunocytofluorescence for α-smooth muscle actin, ELISA for released transforming growth factor-ß1 (TGF-ß1). RNA-seq was performed in HDACi- and vehicle-treated RDEB fibroblasts. VPA was systemically administered to RDEB mice, and effects on overt phenotype were monitored. Fibrosis was investigated in the skin using histological and immunofluorescence analyses. Eye and tongue defects were examined microscopically. Mass spectrometry proteomics was performed on skin protein extracts from VPA-treated RDEB and control mice. RESULTS: Histone acetylation decreases in RDEB skin and primary fibroblasts. RDEB fibroblasts treated with HDACis lowered fibrotic traits including contractility, TGF-ß1 release, and proliferation. VPA administration to RDEB mice mitigated severe manifestations affecting eyes and paws. These effects were associated with fibrosis inhibition. Proteomic analysis of mouse skin revealed that VPA almost normalised protein sets involved in protein synthesis and immune response, processes linked to the increased susceptibility to cancer and bacterial infections observed in RDEB patients. CONCLUSIONS: Dysregulated histone acetylation contributes to RDEB pathogenesis by facilitating the progression of fibrosis. Repurposing of HDACi could be considered for disease-modifying treatments of RDEB.

Incidence of keratinocyte carcinomas in Italy: an exercise in indirect estimation based on melanoma data.

BACKGROUND: The occurrence of keratinocyte carcinomas (KC) worldwide appears to be increasing, however, information on the actual incidence of these tumours is often incomplete. OBJECTIVES: The aim of this study was to provide information on the KC/melanoma ratio in order to indirectly estimate the occurrence of KC. MATERIALS & METHODS: Data were collected according to a snowball sampling procedure between Italian dermatologists. Colleagues working on melanoma and non-melanoma units were excluded. These ratios were applied to estimates derived from histopathological records, namely melanoma incidence estimates available from the Italian National Cancer Registry Network. The final estimates for KC incidence were thus obtained using the formula: KC incidence (per 100,000) = melanoma incidence (per 100,000) * (KC/melanoma ratio). RESULTS: Our results revealed a BCC/melanoma ratio of 4.4 and SCC/melanoma ratio of 1.7; values that are approximately 4 to 5 times smaller than those self-reported by dermatologists. Interestingly, this large discrepancy was not observed for the BCC/SCC ratio, which was 2.5 in the north, 2.7 in the centre, and 3.2 in the south of Italy, with an overall value of 2.8. Based on the histopathological data, this ratio was 2.6. CONCLUSION: In Italy, the actual occurrence of BCC and SCC seems to be vastly underestimated based on histopathological data, compared to data reported by dermatologists.

Early inflammatory biomarkers and melanoma survival.

BACKGROUND: Few studies have investigated the role of inflammatory markers in predicting cutaneous melanoma survival. The aim of the study was to identify, if any, early inflammatory markers in the prognosis of all stages of primary cutaneous melanoma. METHODS: We conducted a 10-year cohort study among 2,141 melanoma patients from the same geographic area (Lazio) with primary cutaneous melanoma diagnosed between January 2005 and December 2013. In situ cutaneous melanoma was excluded from the analysis (N = 288), leaving 1,853 cases of invasive cutaneous melanoma. The following hematological markers were obtained from clinical records: white blood cells count (WBC), count and percentages of neutrophils, basophils, monocytes, lymphocytes, and large unstained cells (LUC). Survival probability was estimated by Kaplan-Meier methods, and prognostic factors were evaluated by multivariate analysis (Cox proportional hazards model). RESULTS: In the multivariate analysis, high levels of NLR (>2.1 vs. ≤2.1, HR: 1.61; 95% CI: 1.14-2.29, P = 0.007) and high levels of d-NLR (>1.5 vs. ≤1.5, HR: 1.65; 95% CI: 1.16-2.35, P = 0.005) were independently associated with an increased risk of 10-year melanoma mortality. However, when we stratified by Breslow thickness and clinical stage, we observed that NLR and d-NLR were good markers of prognosis only for patients with Breslow thickness of 2.0 mm and more (NLR, HR: 1.62; 95% CI: 1.04-2.50; d-NLR, HR: 1.69; 95% CI: 1.09-2.62) or clinical stage II-IV (NLR, HR: 1.55; 95% CI: 1.01-2.37; d-NLR, HR: 1.72; 95% CI: 1.11-2.66), independent of other prognostic factors. CONCLUSION: We suggest that a combination of NLR and Breslow thickness may be a useful, cheap, and readily available prognostic marker for cutaneous melanoma survival.

Occupational exposure to arsenic, mercury and UV radiation and risk of melanoma: a case-control study from Italy.

BACKGROUND: Melanoma is mainly caused by sunlight radiation, but other environmental risk factors are not well known. We investigated the association between cutaneous melanoma and occupational exposure to arsenic, mercury and UV radiation. METHODS: A hospital-based case-control study was conducted in the inpatient wards of IDI-San Carlo Rome, Italy, including 304 incident cases of cutaneous melanoma and 305 frequency-matched controls. Detailed sociodemographic, clinical and host-related factors were collected, and all participants were physically examined using dermoscopy and following standard protocol for recording pigmented lesions. Four experts assessed exposure to arsenic, mercury and UV radiation based on occupational history. A multidimensional variable was created for each risk factor, by combining intensity and probability of exposure. Multivariable logistic regression models were run to calculate odds ratios (OR) and 95% confidence intervals (CI) of the association between exposure to these agents and melanoma. RESULTS: A total of 5.4% of the cases vs 2.4% of the controls were exposed to arsenic (OR = 3.12; 95% CI = 1.10-8.86 for high probability and high exposure to arsenic) after controlling for sex, age, smoking status, number of nevi, phototype and history of sunburns in childhood/adolescence. Occupational exposure to mercury and UV radiation was not associated with the risk of melanoma. CONCLUSIONS: Subjects exposed to arsenic at the workplace may be at increased risk of developing cutaneous melanoma in comparison to subjects not exposed to this agent. Further studies should be designed to investigate occupational exposure to arsenic and mercury and melanoma and confirm the findings are warranted.

A Comparative Demographic Study of Atypical Spitz Nevi and Malignant Melanoma.

Spitz tumors are a subset of melanocytic neoplasms characterized by epithelioid or spindled melanocytes(1). The benign nature of the "Spitz nevus" has since been clarified, but the debate regarding Spitzoidtumors (STs) is still ongoing. Spitzoid tumors encompass a wide spectrum of cutaneous lesions ranging from benign Spitz nevus (SN) to Spitzoid melanoma (SM), the latter displaying capacity for widespread metastasis and a potentially lethal outcome (2). The term atypical Spitz tumors (ASTs) refers to melanocytic tumors exhibiting the morphological features of SN, as well as some features associated with malignancy, but not sufficient to classify them as SMs. Currently, histopathology is the gold standard for the diagnosis of STs and cutaneous MM. However, the differential diagnosis between benign and malignant melanocytic lesions with spitzoid features remains challenging (3-6). In order to facilitate the work of clinicians and pathologists, we attempted a comparative clinical and demographic study comparing ASTs and MMs of patients referred to two Italian institutes. Patient data were obtained from two different Italian dermatological centers (Melanoma Registry of the Instituto Dermopaticodell'Immacolata IDI-IRCCS Rome, Lazio and the Skin Cancer Unit of Dermatology, Hospital Sant'Orsola-Malpighi, University of Bologna), from January 2007 to December 2017. Histological reports presenting pre-operative queries of both "atypical Spitz nevi" or "malignant melanoma" and a final diagnosis confirming one of the queries were included in the study. The chi-square test or Mann-Whitney U-test were applied to analyze differences between the groups for categorical variables such as sex, diagnosis, and continuous variables (age). The "anatomic site" variable was classified into three categories as follows: the limbs, trunk, and head/neck. A multivariate binary logistic model was used to investigate if the anatomic site was an independent predictor of MM. Age and sex were considered confounding factors. A total of 504 patients (51.8% men; 48.2% women) met the inclusion study criteria (mean age 52 years, SD = 22.8) (Table 1). 373 were cases of MM and 131 were cases of AST. Mean age of MM cases and AST were 61.2 years old (SD = 17.6) and 25.8 years old (SD = 13.8), respectively. Subjects with MM were predominantly men (58.2% versus 33.6%) (P<0.0001) and older (median age 62 years versus 25 years) (P=0.0001) than subjects with AST. The most frequent anatomic site for MM was the trunk (39.7 %), while the lower limb was the most frequent anatomic site for AST (48.1 %) (P<0.0001). Table 2 shows the multivariable analysis used to assess if anatomic site was an independent predictor of cutaneous melanoma. Multivariate analysis confirmed an increased risk for MM in comparison with AST for both localization on the trunk (OR:2.78; 95 %CI: 1.74-4.45) (P<0.0001) and head/neck (OR:3.20; 95% CI: 1.60-6.38) (P=0.0001). After introducing age (model 1, OR: 2.11; 95% CI: 1.08-4.12) (P=0.003) and sex into the model, the only anatomic site that remained statistically significant was the trunk (model 2, OR: 2.03; 95% CI: 1.0.3-3.99) (P=0.04). The results show that if the lesion was located on the trunk, the probability of being a MM was two times higher than that of AST, independent of sex, age, or center. After stratifying for sex, the effect was stronger for women (OR: 2.72; 95% CI: 1.14-6.50). After stratifying for age, the effect was stronger for younger subjects (<40 years) (OR: 2. 59; 95% CI: 1.20-5.60) (P=0.02). In this study, we focused on the clinical-epidemiological data in an attempt to improve the identification of nodular melanocytic lesions by providing clinicians with further information in order to reduce the rate of misdiagnosis and assist in providing critical clinical information to surgeons and pathologists. Consistently with the literature, ASTs were mainly found in young-adult patients (mean age was 25.8 years), in the female sex (66.4%), and were typically located on the lower limbs (48.1%) (3,7-10). MM were found to be slightly more common in male patients (58.2%) in the overall patient group; the mean age at the time of the diagnosis was 61.2 years old, and the majority of lesions were located on the trunk (39.7%). These data were similar to those reported by other authors (11-13). ASTs cases were mainly women and younger than MM cases, and were typically located on the lower limbs (Figure 3 and Figure 4). Nodules located on the trunk resulted in a two times greater risk of MM in comparison with AST. In summary, distinguishing ASTs from MMs is often challenging, and histopathology remains the diagnostic gold standard for melanocytic neoplasms, but a specific clinical framework may help surgeons, pathologists, and clinicians to correctly diagnose and manage these lesions in children and adults.

Testing some psychometric properties of the Italian version of the Skin Cancer Index: A questionnaire for measuring quality of life in patients with non-melanoma skin cancer.

Objectives: Non-melanoma skin cancers (NMSC) include two main types: basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC). Generic Health-Related Quality of Life (HRQoL) instruments revealed little to no HRQoL impairment in NMSC patients. Instead, the use of specific skin disease HRQoL tools contradicted those observations. For example, the Skin Cancer Index (SCI) was suggested as a validated instrument for the evaluation of the impact of skin cancers on HRQoL, and has already been validated in several languages, but not in Italian. The aim of this study is to testing some psychometric properties of the Italian version of the SCI questionnaire in a large sample of NMSC patients. Methods: This is a cross-sectional, single-center, observational study. Firstly, different factor models proposed in the literature were compared and the model with the best fit was identified. Secondly, the psychometric properties of the SCI, convergent validity and reliability, were evaluated. Results: The sample was composed of 371 NMSC patients. The factor analysis revealed that a revised version of the original model had the best fit [χ2(df = 85) = 354.53, p < 0.001, RMSEA = 0.09, CFI = 0.98, TLI = 0.97, SRMR = 0.03]. The SCI had satisfactory internal consistency for all subscales (Emotional subscale: ordinal alpha = 0.95; Social subscale: ordinal alpha = 0.94; Appearance subscale: ordinal alpha = 0.94). The convergent validity with Skindex-17 psychosocial subscale was adequate for all the SCI subscales (Emotional Subscale: rho = -0.50; Social Subscale: rho = -0.54; Appearance subscale: rho = -0.44; Total Skin Cancer Index: rho = -0.56; and p < 0.001). Conclusion: The tested psychometric properties of the Italian version of the SCI may suggest that it is an appropriate tool to measure the HRQoL in NMSC patients, however, further studies are needed in order to confirm and tested other psychometric features of this tool.

Circulating miR-1246 and miR-485-3p as Promising Biomarkers of Clinical Response and Outcome in Melanoma Patients Treated with Targeted Therapy.

Despite the significant improvements in advanced melanoma therapy, there is still a pressing need for biomarkers that can predict patient response and prognosis, and therefore support rational treatment decisions. Here, we investigated whether circulating miRNAs could be biomarkers of clinical outcomes in patients treated with targeted therapy. Using next-generation sequencing, we profiled plasma miRNAs at baseline and at progression in patients treated with BRAF inhibitors (BRAFi) or BRAFi + MEKi. Selected miRNAs associated with response to therapy were subjected to validation by real-time quantitative RT-PCR. Receiver Operating Characteristics (ROC), Kaplan-Meier and univariate and multivariate Cox regression analyses were performed on the validated miR-1246 and miR-485-3p baseline levels. The median baseline levels of miR-1246 and miR-485-3p were significantly higher and lower, respectively, in the group of patients not responding to therapy (NRs) as compared with the group of responding patients (Rs). In Rs, a trend toward an increase in miR-1246 and a decrease in miR-485-3p was observed at progression. Baseline miR-1246 level and the miR-1246/miR-485-3p ratio showed a good ability to discriminate between Rs and NRs. Poorer PFS and OS were observed in patients with unfavorable levels of at least one miRNA. In multivariate analysis, a low level of miR-485-3p and a high miR-1246/miR-485-3p ratio remained independent negative prognostic factors for PFS, while a high miR-1246/miR-485-3p ratio was associated with an increased risk of mortality, although statistical significance was not reached. Evaluation of miR-1246 and miR-485-3p baseline plasma levels might help clinicians to identify melanoma patients most likely to be unresponsive to targeted therapy or at higher risk for short-term PFS and mortality, thus improving their management.

Vitiligo-specific soluble biomarkers as early indicators of response to immune checkpoint inhibitors in metastatic melanoma patients.

Immunotherapy with checkpoint inhibitors (CPIs) strongly improved the outcome of metastatic melanoma patients. However, not all the patients respond to treatment and identification of prognostic biomarkers able to select responding patients is currently of outmost importance. Considering that development of vitiligo-like depigmentation in melanoma patients represents both an adverse event of CPIs and a favorable prognostic factor, we analyzed soluble biomarkers of vitiligo to validate them as early indicators of response to CPIs. Fifty-seven metastatic melanoma patients receiving CPIs were enrolled and divided according to the best overall response to treatment. Patient sera were evaluated at pre-treatment and after 1 and 3 months of therapy. We found that basal CD25 serum levels were higher in stable and responding patients and remained higher during the first 3 months of CPI therapy compared to non-responders. CXCL9 was absent in non-responding patients before therapy beginning. Moreover, an increase of CXCL9 levels was observed at 1 and 3 months of therapy for all patients, although higher CXCL9 amounts were present in stable and responding compared to non-responding patients. Variations in circulating immune cell subsets was also analyzed, revealing a reduced number of regulatory T lymphocytes in responding patients. Altogether, our data indicate that a pre-existing and maintained activation of the immune system could be an indication of response to CPI treatment in melanoma patients.

Vitiligo-like leukoderma as an indicator of clinical response to immune checkpoint inhibitors in late-stage melanoma patients.

PURPOSE: Although development of immune checkpoint inhibitors has revolutionized the treatment of metastatic melanoma, more than a half of treated patients experience disease progression during therapy. Cases of spontaneous vitiligo-like leukoderma have been described in melanoma patients and have been associated with a favorable outcome. This vitiligo-like leukoderma can also appear in melanoma patients undergoing immune therapies such as immune checkpoint inhibitors. However, no consensus exists about the relationship between vitiligo-like leukoderma onset and improved overall survival. Our study investigates the possible association between the onset of vitiligo-like leukoderma during immune checkpoint inhibitor treatment and a better prognosis. METHODS: A non-concurrent cohort study was conducted by identifying retrospectively 280 patients who had inoperable or metastatic melanoma and had undergone immune therapy with checkpoint inhibitors in any line of treatment. Toxicities developed during therapy were evaluated. RESULTS: Among the 280 study participants, 50% developed at least one type of toxicity, and vitiligo-like leukoderma was observed in 43 patients (15.4%). In the multivariate Cox model, a protective effect for mortality was observed for patients with vitiligo-like leukoderma development (HR : 0.23; 95% CI 0.11-0.44, p < 0.0001). In a sub-group analysis comprising only cutaneous melanoma in first line of treatment (N = 153), occurrence of vitiligo-like leukoderma was also an independent predictor factor for duration of clinical benefits measured by time to the next treatment (HR: 0.17; 95% CI 0.06-0.44). CONCLUSION: Our findings indicate that onset of vitiligo-like leukoderma during melanoma treatment could be a marker of favorable outcome in patients treated with immune checkpoint inhibitors.

Differences in individual and environmental factors between cutaneous melanoma and atypical Spitz tumour in children and adolescents.

It is not known if children and adolescents with atypical Spitz tumour and cutaneous melanoma differ in terms of etiological factors. The aim of this study was to explain differences in individual and environmental factors between cutaneous melanoma and atypical Spitz tumour. In the context of a study on melanocytic lesions, all subjects aged under 20 years with either cutaneous melanoma or atypical Spitz tumour were included (N = 105). Information on socio-demographic characteristics, individual and environmental factors were collected for both mother and child. The Fisher's exact test and the Mann-Whitney U test were used for categorical variables and continuous variables respectively. A multivariate logistic model was used to explain differences in outcome by differences in explanatory variables. In comparison to patients with cutaneous melanoma, patients with atypical Spitz tumour had less freckles (p = 0.020), lower number of common nevi (p = 0.002), and lower body mass index (p = 0.001) and experienced less sunburns episodes (p = 0.008). However, in the multivariate analysis, only a low number of common nevi remained statistically significant. Children and adolescents with cutaneous melanoma have a high number of nevi in comparison to the same-age group with atypical Spitz tumour.Conclusion: The results of this study suggest that the only difference in individual and environmental risk factors between cutaneous melanoma and atypical Spitz tumour in children and adolescents is the number of nevi. What is Known: •Atypical Spitz tumours and cutaneous melanoma in children and adolescents are clinically similar, but compared with melanoma, they have a good overall prognosis. •Risk factors for cutaneous melanoma in children and adolescents are similar to the ones found in adults in the literature What is New: •Differences in individual and environmental risk factors for atypical Spitz tumour in children and adolescents are described for the first time in this study. •Individual and environmental factors for atypical Spitz tumour in children and adolescents are comparable to cutaneous melanoma, except for the presence of low number of nevi.

Factors associated with sunbed use among 3692 outpatients in 18 centers of the Italian Cancer League (LILT).

Indoor tanning is associated with an increased risk of skin cancer. Nonetheless, its use is still widespread. We aimed to investigate the socio-demographic and clinical characteristics of sunbed users in a group of participants in the skin cancer prevention campaign organized by the Italian Cancer League (LILT). During almost 2 years, 4409 individuals were screened in 18 centers. Participants reported having used sunbeds before the age of 15 years in 2.2% of cases, while after age 15 the prevalence of use was 22.2%. Participants with complete information were 3692. Sunbed users aged > 15 years were significantly more frequently females, young, living in Northern Italy, highly educated, and current or former smokers. They had darker phototype, more common nevi, had used sunbeds more frequently before the age of 15, reported a history of sunburns, and use of sunscreens. Indoor tanning is an important public health issue and a relevant target for primary prevention. However, not all countries have adopted the recommendations issued by the World Health Organization (WHO) on health risks associated with artificial tanning. A deeper insight into the topic may contribute to identify the best prevention strategies.

Reduced Interleukin-17-Expressing Cells in Cutaneous Melanoma.

Characterization of tumor associated lymphocytes (TILs) in tumor lesions is important to obtain a clear definition of their prognostic value and address novel therapeutic opportunities. In this work, we examined the presence of T helper (Th)17 lymphocytes in cutaneous melanoma. We performed an immunohistochemical analysis of a small cohort of primary melanomas, retrospectively selected. Thereafter, we isolated TILs from seven freshly surgically removed melanomas and from three basal cell carcinomas (BCC), as a comparison with a non-melanoma skin cancer known to retain a high amount of Th17 cells. In both studies, we found that, differently from BCC, melanoma samples showed a lower percentage of Th17 lymphocytes. Additionally, TIL clones could not be induced to differentiate towards the Th17 phenotype in vitro. The presence or absence of Th17 cells did not correlate with any patient characteristics. We only observed a lower amount of Th17 cells in samples from woman donors. We found a tendency towards an association between expression by melanoma cells of placenta growth factor, angiogenic factors able to induce Th17 differentiation, and presence of Th17 lymphocytes. Taken together, our data indicate the necessity of a deeper analysis of Th17 lymphocytes in cutaneous melanoma before correlating them with prognosis or proposing Th17-cell based therapeutic approaches.

Sexuality in Persons With Hidradenitis Suppurativa: Factors Associated With Sexual Desire and Functioning Impairment.

Hidradenitis Suppurativa (HS) is a chronic skin disease involving intimate and sensitive areas and affecting physical and mental health. We investigated the prevalence of sexual desire and functioning impairment, and their associations with quality of life, anxiety, depression, minor psychiatric disorders (MPD), and clinical features (e.g., disease severity) in 77 patients with HS who completed self-report measures and answered to questions assessing socio-demographic characteristics, lifestyle habits, and hindered sexuality due to HS. The majority of patients reported hindered sexuality, and poor sexual functioning, while showing good levels of dyadic and solitary sexual desire. No associations were found between clinical severity and sexuality measures. Multivariate analyses showed significant associations of sexual outcome measures with alcohol consumption, low Body Mass Index, family history of HS, and severe skin symptoms. Moreover, we found that the presence of negative psychological factors (i.e., MPD, anxiety, poor mental status) increased the risk of sexual impairment. These findings underline the important role of psychological and sexual aspects in HS patients and suggest that physicians should consider the effect of disease burden on patients' sexual health.

Mediterranean diet, walking outdoors and polypharmacy in older patients with type II diabetes.

BACKGROUND: Polypharmacy and its adverse health effects is an emerging public health issue, with increasing prevalence among patients with multiple chronic conditions, such as older adults with diabetes. A healthy lifestyle has been shown to improve both diabetes and polypharmacy incidence. We conducted a cross-sectional study to investigate the association of a healthy lifestyle with polypharmacy and comorbidities in older people with diabetes. METHODS: All out-patients from January 2013 to June 2015 with type II diabetes aged 65 years or more from a Lazio Region reference centre for diabetes were included in the study. Socio-demographic, clinical and lifestyle data were collected from medical records and through face-to-face standardized questionnaires. The comorbidity-polypharmacy score (CPS) was used to characterize the overall patients' frailty, by assessing concurrently the presence of comorbidities and polypharmacy. The cumulative logit model was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Adjusted ORs for age, sex, body mass index, physical activity and cognitive status, showed that CPS score was inversely related to weekly consumption of cruciferous vegetables (OR: 0.56, 95% CI: 0.35-0.90; P-trend = 0.015), leafy green vegetables (OR: 0.54, 95% CI: 0.33-0.87; P-trend = 0.013) and daily intake of fruits (OR: 0.63, 95% CI: 0.41-0.97; P-trend = 0.036). Walking outdoors was found inversely related to CPS score (age- and sex-adjusted OR: 0.60, 95% CI: 0.42-0.86). CONCLUSION: Our findings suggest that eating some dietary factors present in the Mediterranean diet and walking outdoors regularly is associated with a lower intensity of medicines need to treat comorbidities among older people with diabetes.

miR-126-3p down-regulation contributes to dabrafenib acquired resistance in melanoma by up-regulating ADAM9 and VEGF-A.

BACKGROUND: Development of resistance to inhibitors of BRAF (BRAFi) and MEK (MEKi) remains a great challenge for targeted therapy in patients with BRAF-mutant melanoma. Here, we explored the role of miRNAs in melanoma acquired resistance to BRAFi. METHODS: miRNA expression in two BRAF-mutant melanoma cell lines and their dabrafenib-resistant sublines was determined using Affymetrix GeneChip® miRNA 3.1 microarrays and/or qRT-PCR. The effects of miR-126-3p re-expression on proliferation, apoptosis, cell cycle, ERK1/2 and AKT phosphorylation, dabrafenib sensitivity, invasiveness and VEGF-A secretion were evaluated in the dabrafenib-resistant sublines using MTT assays, flow cytometry, immunoblotting, invasion assays in Boyden chambers and ELISA. ADAM9, PIK3R2, MMP7 and CXCR4 expression in the sensitive and dabrafenib-resistant cells was determined by immunoblotting. Small RNA interference was performed to investigate the consequence of VEGFA or ADAM9 silencing on proliferation, invasiveness or dabrafenib sensitivity of the resistant sublines. Long-term proliferation assays were carried out in dabrafenib-sensitive cells to assess the effects of enforced miR-126-3p expression or ADAM9 silencing on resistance development. VEGF-A serum levels in melanoma patients treated with BRAFi or BRAFi+MEKi were evaluated at baseline (T0), after two months of treatment (T2) and at progression (TP) by ELISA. RESULTS: miR-126-3p was significantly down-regulated in the dabrafenib-resistant sublines as compared with their parental counterparts. miR-126-3p replacement in the drug-resistant cells inhibited proliferation, cell cycle progression, phosphorylation of ERK1/2 and/or AKT, invasiveness, VEGF-A and ADAM9 expression, and increased dabrafenib sensitivity. VEGFA or ADAM9 silencing impaired proliferation and invasiveness of the drug-resistant sublines. ADAM9 knock-down in the resistant cells increased dabrafenib sensitivity, whereas miR-126-3p enforced expression or ADAM9 silencing in the drug-sensitive cells delayed the development of resistance. At T0 and T2, statistically significant differences were observed in VEGF-A serum levels between patients who responded to therapy and patients who did not. In responder patients, a significant increase of VEGF-A levels was observed at TP versus T2. CONCLUSIONS: Strategies restoring miR-126-3p expression or targeting VEGF-A or ADAM9 could restrain growth and metastasis of dabrafenib-resistant melanomas and increase their drug sensitivity. Circulating VEGF-A is a promising biomarker for predicting patients' response to BRAFi or BRAFi+MEKi and for monitoring the onset of resistance.

Pre-natal folic acid and iron supplementation and atopic dermatitis in the first 6 years of life.

Exposure in utero has been suggested to influence health later in life. The aim of this study was to investigate, if the use of prenatal food supplements was associated with atopic dermatitis in the offspring. Mothers who gave birth in the hospital G. B. Grassi were invited to participate in the study (n = 395). Information on socio-demographic characteristics, clinical data of the mothers and babies, vegetables and fruit intake, food avoidance, and food supplements use during pregnancy, depression status, and environmental exposure was obtained for all subjects in the hospital at the time of delivery. Data on breastfeeding practice, introduction of weaning foods, day care attendance, and atopic dermatitis were collected in the postnatal follow-ups. Logistic regression was applied to estimate odds ratio (OR) and 95% confidence intervals (CI). Children in which mothers used both iron and folic acid supplementation had a fourfold decreased risk of developing atopic dermatitis [OR = 0.22; 95% confidence interval (CI) 0.06-0.79, p = 0.02], after adjusting for possible confounding factors. Findings suggest an independent and protective effect of prenatal folic acid and iron supplementation for atopic dermatitis in children.