A steady increase in the incidence and mortality burden correlated to thin melanomas (≤1 mm) has been reported in recent years in some international studies, but there is currently a paucity of data from the Mediterranean area. We aimed to describe the epidemiological characteristics of thin melanoma in Tuscany, Central Italy. A total of 6002 first cutaneous invasive melanomas occurring from 1985 to 2017 were selected for analysis; data were retrieved from the local population-based cancer registry. The standardized incidence rate was 15.0 per 100,000 in the population, higher among men than women (16.5 vs. 14.1). Incidence rates tended to increase over time across all age group-specific population strata, with annual percent changes moderately higher among men (+8.0%) than women (+6.9%), especially among the elderly. Among both sexes and in each age group, the trend toward increasing incidence rates was particularly strong for thin melanomas. Survival was better among women than men across all categories of thickness. Approximately 15% of deaths occurred among patients with thin lesions, with no major temporal changes in recent years. This study contributes to an improved understanding of melanoma epidemiology in Tuscany and underscores the need for primary prevention strategies tackling the growing burden of thin melanomas.

Adrenocortical carcinoma (ACC), a rare malignancy of the adrenocortex, is characterized by a crosstalk between the adipose microenvironment and tumor. Here, we assessed the involvement of carbonic anhydrase (CA) enzymes III and IX (CAIII and CAIX), in the metabolic alterations of the adipose tissue characterizing obesity and in the local crosstalk between the tumor adipose microenvironment and ACC. CAIII and CAIX expression is altered in visceral adipose tissue (VAT) in obesity and in ACC. A significant CAIX upregulation was present in ACC at advanced stages (n = 14) (fold increase FI = 7.4 ± 0.1, P < 0.05) associated with lower CAIII levels (FI = 0.25 ± 0.06, P < 0.001), compared with lower stages (n = 9). In vitro coculture between visceral adipose stem cells (ASCs) and ACC cell lines, H295R and MUC-1, mimicking the interaction occurring between VAT and advanced ACC, showed a significant CAIX upregulation in H295R but not in MUC-1 cells, and a decreased expression of CAIII. The effect on adipose cells was different when cocultured with H295R or MUC-1 cells. Coculture did not modulate CAIII expression in ASCs, which, however, was significantly downregulated with H295R (FI = 0.34 ± 0.11, P < 0.05) and upregulated by MUC-1 when cocultured ASCs were induced to differentiate toward adipocytes, with an expression profile similar to what found in VAT of obese subjects. CAIX expression was markedly increased in ASCs cocultured with H295R and to a less extent following adipogenesis induction (FI = 150.9 ± 46.5 and FI = 4.6 ± 1.1, P < 0.01, respectively). Our findings highlight a modulation of CAIII and CAIX in the metabolic crosstalk between ACC and its local adipose microenvironment, suggesting that CAs might represent a potential target for novel anticancer therapies.

RuvBL1 is a AAA+ ATPase involved in multiple cellular activities, such as cell proliferation, chromatin remodeling, DNA repair, transcription, translation and mTOR pathway activity. High RuvBL1 expression in HCC correlates with worse prognosis. We previously demonstrated that RuvBL1 is a key regulator of liver metabolism and glucose homeostasis, suggesting that this ATPase may also participate in the metabolic rewiring of HCC cells. We therefore aimed at dissecting RuvBL1 role in HCC cell metabolism. Metabolomics performed by GC/MS in RuvBL1-silenced Huh7 cells highlighted altered intermediates of glucose, TCA and aminoacid metabolism. Pathway enrichment analysis of modulated metabolites showed a significant association with processes related to cancer metabolic reprogramming and centered in mitochondria. RuvBL1 targeting by RNAi or by the selective inhibitor CB-6644 significantly impaired OXPHOS and ATP production in a dose- and time-dependent manner in AML-12, Hepa1-6, Huh7, Hep3B and HepG2 cell lines. Mitochondrial morphology assessed by Mitotracker and TEM was severely affected by RuvBL1 inhibition, that caused a reduction in matrix electrondensity, disruption of the cristae, swelling and fragmentation. Using superresolution STED microscopy and immunoglold/TEM, we detected RuvBL1 within mitochondria. Thus, we performed MS analysis of RuvBL1 co-immunoprecipitated complexes from purified mitochondria. Gene ontology analysis of mitochondrial RuvBL1-interactome revealed that this ATPase impact on TCA, aminoacid, purines, and lipid metabolism, mito-ribosome assembly, mitochondrial transmembrane transport, and membrane organization. Intriguingly, several members of the MIB complex (SAMM50, Mic19, Mic60), which plays a crucial role in shaping mitochondrial cristae, were identified in the RuvBL1-interactome. In the TCGA-LIHC dataset, RuvBL1 expression positively correlates with 9 out of 14 principal members of the MIB complex and genes differentially expressed between HCC with high- vs low-RuvBL1 were significantly enriched in mitochondria-related GO terms. Our data uncover a novel localization and function of RuvBL1 in mitochondria, and suggest that RuvBL1 overexpression support mitochondria-related processes in HCC. RuvBL1 is a AAA+ ATPase involved in multiple cellular activities, such as cell proliferation, chromatin remodeling, DNA repair, transcription, translation and mTOR pathway activity. High RuvBL1 expression in HCC correlates with worse prognosis. We previously demonstrated that RuvBL1 is a key regulator of liver metabolism and glucose homeostasis, suggesting that this ATPase may also participate in the metabolic rewiring of HCC cells. We therefore aimed at dissecting RuvBL1 role in HCC cell metabolism. Metabolomics performed by GC/MS in RuvBL1-silenced Huh7 cells highlighted altered intermediates of glucose, TCA and aminoacid metabolism. Pathway enrichment analysis of modulated metabolites showed a significant association with processes related to cancer metabolic reprogramming and centered in mitochondria. RuvBL1 targeting by RNAi or by the selective inhibitor CB-6644 significantly impaired OXPHOS and ATP production in a dose- and time-dependent manner in AML-12, Hepa1-6, Huh7, Hep3B and HepG2 cell lines. Mitochondrial morphology assessed by Mitotracker and TEM was severely affected by RuvBL1 inhibition, that caused a reduction in matrix electrondensity, disruption of the cristae, swelling and fragmentation. Using superresolution STED microscopy and immunoglold/TEM, we detected RuvBL1 within mitochondria. Thus, we performed MS analysis of RuvBL1 co-immunoprecipitated complexes from purified mitochondria. Gene ontology analysis of mitochondrial RuvBL1-interactome revealed that this ATPase impact on TCA, aminoacid, purines, and lipid metabolism, mito-ribosome assembly, mitochondrial transmembrane transport, and membrane organization. Intriguingly, several members of the MIB complex (SAMM50, Mic19, Mic60), which plays a crucial role in shaping mitochondrial cristae, were identified in the RuvBL1-interactome. In the TCGA-LIHC dataset, RuvBL1 expression positively correlates with 9 out of 14 principal members of the MIB complex and genes differentially expressed between HCC with high- vs low-RuvBL1 were significantly enriched in mitochondria-related GO terms. Our data uncover a novel localization and function of RuvBL1 in mitochondria, and suggest that RuvBL1 overexpression support mitochondria-related processes in HCC.

article: Awareness of melanoma in the wider population and role of general practitioners in melanoma screening: results from a survey in Florence (Tuscany, Italy) - Giornale Italiano di Dermatologia e Venereologia 2019 Nov 18 - Minerva Medica - Journals

PURPOSE:Thin melanomas (T1; ≤ 1 mm) constitute 70% of newly diagnosed cutaneous melanomas. Regional node metastasis determined by sentinel node biopsy (SNB) is an important prognostic factor for T1 melanoma. However, current melanoma guidelines do not provide clear indications on when to perform SNB in T1 disease and stress an individualized approach to SNB that considers all clinicopathologic risk factors. We aimed to identify determinants of sentinel node (SN) status for incorporation into an externally validated nomogram to better select patients with T1 disease for SNB.PATIENTS AND METHODS:The development cohort comprised 3,666 patients with T1 disease consecutively treated at the Istituto Nazionale Tumori (Milan, Italy) between 2001 and 2018; 4,227 patients with T1 disease treated at 13 other European centers over the same period formed the validation cohort. A random forest procedure was applied to the development data set to select characteristics associated with SN status for inclusion in a multiple binary logistic model from which a nomogram was elaborated. Decision curve analyses assessed the clinical utility of the nomogram.RESULTS:Of patients in the development cohort, 1,635 underwent SNB; 108 patients (6.6%) were SN positive. By univariable analysis, age, growth phase, Breslow thickness, ulceration, mitotic rate, regression, and lymphovascular invasion were significantly associated with SN status. The random forest procedure selected 6 variables (not growth phase) for inclusion in the logistic model and nomogram. The nomogram proved well calibrated and had good discriminative ability in both cohorts. Decision curve analyses revealed the superior net benefit of the nomogram compared with each individual variable included in it as well as with variables suggested by current guidelines.CONCLUSION:We propose the nomogram as a decision aid in all patients with T1 melanoma being considered for SNB.

We thank Hindi é1 for his interest in our study, 2 and we are happy to provide the clarifications requested.We agree that our nomogram has not been prospectively tested on unselected patients with thin melanoma.Although prospective testing is desirable, it would not be ethical to use unselected patients with stage T1 melanoma because sentinel node biopsy (SNB) would be overtreatment in most cases.

This corrects the article DOI: 10.23736/S0392-0488.17.05584-5.

BACKGROUND The epidemiologic trends of cutaneous melanoma are similar in several countries with a Western-type life style, where there is a progressive increasing incidence and a low but not decreasing mor- tality, or somewhere an increase too, especially in the older age groups. Also in Tuscany there is a steady rise in incidence with prevalence of in situ and invasive thin melanomas, with also an increase of thick melanomas. It is necessary to reduce the frequency of thick melanomas to reduce specific mortality. OBJECTIVE AND METHODS The objective of the current survey has been to compare, in the Tuscany population, by a case- case study, thin and thick melanoma cases, trying to find out those personal and tumour characteristics which may help to customize preventive interventions. RESULTS The results confirmed the age and the lower edu- cation level are associated with a later detection. The habit to perform skin self-examination is resulted protec- tive forward thick melanoma and also the diagnosis by a doctor. The elements emerging from the survey allow to hypothesize a group of subjects resulting at higher risk for a late diagnosis, aged over 50 and carrier of a fewer constitutional and environmental risk factors: few total and few atypical nevi, and lower sun exposure and burning. It is assumable that a part of people did not be reached from messages of prevention because does not recognize oneself in the categories of people at risk for skin cancers described in educational cam- paigns. CONCLUSIONS If we want to obtain better results on diagnosis of skin melanoma we have to think a new strategy. At least to think over the educational messages discriminating people more at risk of incidence of melanoma from people more at risk to die from melanoma, and to renewed active involvement of the Gen- eral Practitioners .

BACKGROUND:Lichenoid keratosis is a benign cutaneous lesion exhibiting many clinical faces and different dermoscopic features.OBJECTIVE:This study aims to determine the pattern of different clinical subtypes of lichenoid keratosis and to establish whether there is any correlation between the clinical variants of lichenoid keratosis and their dermoscopic appearance.METHODS:We retrospectively analyzed the medical records and clinical database of patients who had received a histological diagnosis of lichenoid keratosis. Based on the literature review and the clinical-dermoscopic features of lichenoid keratosis, we divided the lesions into 6 clinical subtypes to evaluate potential correlations between clinical and dermoscopic features in all subtypes.RESULTS:Fifty-one lesions were included in this clinical study. Preoperatively, only 1.9% of cases were clinically diagnosed as lichenoid keratosis, and the most common misdiagnosis was basal cell carcinoma (52.9%). We identified 6 subtypes of lichenoid keratosis and their corresponding dermoscopic features and clues.CONCLUSION:Since lichenoid keratosis has no pathognomonic dermoscopic clues and it is commonly misdiagnosed as malignant skin neoplasms, such as basal cell carcinoma and melanoma, improving the knowledge of both clinical and dermoscopic variability of lichenoid keratosis may help dermatologists to reduce unnecessary surgery and to reduce health care spending.

INTRODUCTION:In 2009, the American Joint Committee on Cancer (AJCC) incorporated the tumor mitotic rate in the melanoma pathological TNM staging system. To investigate the effect of this change on the pT1 substaging of primary cutaneous melanomas, we reclassified the cases collected by a cancer registry according to the 6th and the 7th editions of AJCC melanoma staging. METHODS:Patients with pathological T1 melanoma diagnosed in the period 2000-2008 were selected from Tuscan Cancer Registry. The histological reports were reviewed and pT1 melanomas classified according to both the 6th and the 7th editions of the AJCC staging system. The shift of melanomas between pT1 substages was analyzed. RESULTS:Among the 242 pT1 melanomas collected in the study period and with mitotic index available, there were 202 (83 % of all pT1) and 175 (72 %) pT1a, according to the 6th and the 7th editions of the AJCC melanoma staging, respectively. When the 7th edition was used, 20 % of all pT1a melanomas shifted to pT1b, and 32 % of all pT1b melanomas shifted to pT1a. A poor level agreement between the two TNM staging systems, measured by the Cohen's kappa coefficient, was found (K = 0.37). CONCLUSIONS:The addition of mitotic activity to the pathological staging resulted in an increase in pT1b proportion and in a change in the classification of some cases. This modification could influence the clinical approach, with a different use of the sentinel lymph node biopsy, and underlines the role of mitosis evaluation in the management of thin melanoma patients.

The objective of this study was to provide further insights into the prognostic role of female sex in skin melanoma. The prognostic effect of sex in a population-based case series of 3900 skin melanomas in central Italy has been evaluated considering the possible confounding role of many demographic and clinical variables (age, period of diagnosis, Breslow’s thickness, Clark level, ulceration, lymph node status, metastasis, histological type, skin site, and pathological T and N). Multiple imputations, according to chained equations, have been used for imputing incomplete values. A Cox proportional hazards model on the risk of death caused by melanoma was fitted. Univariate and multivariate effects of sex and of other variables were computed. The 5-year cause-specific survival was 87% (95% confidence interval: 86–89%) for women and 80% (78–82%) for men. Women had higher rates at any time since diagnosis. After adjustment for other confounders, women had a 34% reduced risk compared with men of dying from skin melanoma (hazard ratio=0.66, 95% confidence interval: 0.56–0.79). The present study confirmed a strong protective effect of female sex on skin melanoma mortality. The protective factor is still unknown.

BACKGROUNDNo studies are available in the literature on the distribution of different melanoma features and risk factors in the Italian geographical areas.OBJECTIVETo identify the differences in clinical-pathological features of melanoma, the distribution of risk factors and sun exposure in various Italian macro-areas.METHODSMulticentric-observational study involving 1,472 melanoma cases (713 north, 345 centre, 414 south) from 26 referral centres belonging to the Italian Multidisciplinary Group for Melanoma.RESULTSMelanoma patients in northern regions are younger, with thinner melanoma, multiple primaries, lower-intermediate phototype and higher counts of naevi with respect to southern patients; detection of a primary was mostly connected with a physician examination, while relatives were more involved in the south. Northern patients reported a more frequent use of sunbeds and occurrence of sunburns before melanoma despite sunscreen use and a lower sun exposure during the central hours of the day.CONCLUSIONSThe understanding of differences in risk factors distribution could represent the basis for tailored prevention programmes.

The most frequent site for melanoma is the back in men and the lower limbs in women, where intermittent sun exposure has been reported to be an environmental agent, although studies on age-specific incidence have suggested that melanoma in chronically sun-exposed areas, such as the face, increases with age. To identify the preferential development of melanoma in chronically or intermittently sun-exposed areas and the relationship between body site distribution and parameters such as sex, age, distribution of melanocytic naevi, atypical naevi and actinic keratoses, a prospective epidemiological multicentre study was carried out on all the consecutive melanoma cases diagnosed in a 2-year period from 27 Italian GIPMe centres (GIPMe: the Italian Multidisciplinary Group on Melanoma). Both the relative density of melanoma (RDM), defined as the ratio between observed and expected melanoma for a specific body site, and the average nevi density were identified. The most common melanoma site was the back, a factor that was not affected by either age or sex, even if men had higher density values. Statistically significant higher RDM values were observed in women aged more than 50 years for leg lesions and in the anterior thighs for young women (<50 years), whereas the lowest values were observed in the posterior thighs in women of any age. Facial RDM was statistically significantly higher than expected in both male and female patients more than 50 years of age. Melanoma was associated with a significantly higher atypical naevi density only for the back, chest and thighs. Indeed, facial melanoma was related to the presence of more than four actinic keratoses and not naevi density. To the best of our knowledge, the RDM method was applied for the first time together with naevus density calculation to obtain these data, which strongly substantiate the ‘divergent pathway’ hypothesis for the development of melanoma, but not find a direct correlation between melanoma and nevi for each anatomical site.

Objective. Evaluate the ecological relationship between skin melanoma epidemiology and latitude in Italy. Methods. We used data from the Italian network of cancer registries (Airtum). In a Poisson model, we evaluated the effect on incidence, mortality, and survival of latitude, adjusting for some demographic, social, phenotypic, and behavioural variables. Results. Incidence increased in Italy by 17% for each degree of increase in latitude. The effect of latitude was statistically significantly present also adjusting for other variables (incidence rate ratio = 1.08). The effect of latitude on increasing mortality (mortality rate ratio = 1.27) and improving survival (relative excess risk of death = 0.93) was no longer present in the multivariate model. Conclusion. Melanoma incidence, mortality, and survival vary in Italy according to latitude. After adjustment for several confounders, incidence still grows with growing latitude. Presumably, latitude expresses other variables that might be related to individual susceptibility and/or local care.

BACKGROUND:Having a familial member affected by cutaneous melanoma is a risk factor for this neoplasm. Only a few epidemiological case-control studies have been carried out to investigate whether familial and sporadic melanomas show different clinical and histopathological features.OBJECTIVE:The aim of this study was to evaluate eventual different features and risk factors in subjects affected by familial and sporadic cutaneous melanoma.METHODS:A case-control multicentre study interesting 1407 familial (n = 92) and sporadic (n = 1315) melanomas in the Italian population. The analysis was made using t-test for continuous variables and chi-squared test for categorized ones. The variables which have shown statistically significant differences in the two groups in the univariate analysis were included in a multivariate model.RESULTS:The results showed some main significantly clinical differences between the two groups investigated: earlier age at diagnosis, a greater proportion of sunburns and a higher number of naevi were observed for the familial cases compared with sporadic ones. Nevertheless, we did not find a diagnostic anticipation in familial melanomas, in fact the invasion level and the thickness of melanomas was similar in the two groups.CONCLUSION:Some relevant clinical differences are observed between the two groups examined. The familial melanoma members, although carriers of constitutional risk factors, are not careful enough to primary and secondary prevention.

While the incidence rates for skin melanoma have increased worldwide in the last decades, Breslow tumor thickness has decreased1. The incidence of in situ melanoma has also increased, and it doubled in the USA between 1988 and 20062. These recent trends are in part due to the diffusion of early diagnosis1,2, which is based on the assumption that the detection of less invasive lesions (i.e., those susceptible to more effective treatment) will prevent the occurrence of the more invasive and deadly ones. If the pattern for melanoma indicated a worsening progression from in situ to invasive lesions-thin, first, then thick-the mean age at diagnosis for such lesions should increase accordingly. We retrieved melanoma cases incident between 2000 and 2005 from theTuscany Cancer Registry archive. This is a population-based cancer registry active in central Italy since 1985 on a population of about 1.2 million inhabitants. Between 2000 and 2005, 1513 skin melanomas were newly diagnosed, 318 (21.0%) in situ and 1195 (79.0%) invasive. Among the latter, 607 (50.8%) were ≤1 mm, 410 (34.3%) >1 mm, while the Breslow thickness of 178 lesions (14.9%) could not be assessed. Themean ages of patients at diagnosis of melanomas in situ (57.69 years) and invasive melanomas (57.52) were similar (Student’s t-test, P = 0.87). However, among invasive melanomas, thin lesions (≤1 mm) were diagnosed at a younger age (54.03 years) than among in situ melanomas (P = 0.0014). By contrast, patients with >1 mm thick melanomas were older at the time of diagnosis (61.95 years) than patients with in situ melanomas (Table 1). These results are mainly due to lentigo malignant melanomas, which occur at a rather old age (mean age at diagnosis 71.3 years) and are more frequent among in situ (69/318, 21.6%) than among invasive melanomas (36/1195; 3.0%). According to the present data, in situmelanoma does not seem an obligate precursor of thin invasive melanoma, as it is diagnosed at an older age than invasive melanoma ≤1 mm. Although most of the results are driven by lentigo maligna melanomas, descriptive epidemiology suggests different pathways for in situ and invasive melanomas, at least for thin ones. There may be 2 different in situmelanomas, some with an indolent behavior and others which are more aggressive; micromelanomas invasive at diagnosis3may belong to the latter group.