MC1R gene variants and non-melanoma skin cancer: a pooled-analysis from the M-SKIP project.

BACKGROUND: The melanocortin-1-receptor (MC1R) gene regulates human pigmentation and is highly polymorphic in populations of European origins. The aims of this study were to evaluate the association between MC1R variants and the risk of non-melanoma skin cancer (NMSC), and to investigate whether risk estimates differed by phenotypic characteristics. METHODS: Data on 3527 NMSC cases and 9391 controls were gathered through the M-SKIP Project, an international pooled-analysis on MC1R, skin cancer and phenotypic characteristics. We calculated summary odds ratios (SOR) with random-effect models, and performed stratified analyses. RESULTS: Subjects carrying at least one MC1R variant had an increased risk of NMSC overall, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC): SOR (95%CI) were 1.48 (1.24-1.76), 1.39 (1.15-1.69) and 1.61 (1.35-1.91), respectively. All of the investigated variants showed positive associations with NMSC, with consistent significant results obtained for V60L, D84E, V92M, R151C, R160W, R163Q and D294H: SOR (95%CI) ranged from 1.42 (1.19-1.70) for V60L to 2.66 (1.06-6.65) for D84E variant. In stratified analysis, there was no consistent pattern of association between MC1R and NMSC by skin type, but we consistently observed higher SORs for subjects without red hair. CONCLUSIONS: Our pooled-analysis highlighted a role of MC1R variants in NMSC development and suggested an effect modification by red hair colour phenotype.

Dermoscopic features of cutaneous melanoma are associated with clinical characteristics of patients and tumours and with MC1R genotype.

BACKGROUND: Several algorithms are available for the dermoscopic diagnosis of pigmented skin lesions. The MC1R gene is a key determinant of pigmentation characteristics that are established host-related melanoma risk factors. OBJECTIVES: To investigate the association of dermoscopic features of sporadic cutaneous melanomas with clinical characteristics of patients and corresponding tumours and with genetic changes in the MC1R and BRAF genes. METHODS: A total of 64 dermoscopic images of 62 patients were scored by ABCD rule and modified pattern analysis. Detailed patients' and melanomas' characteristics were collected. Patients were screened for germline MC1R variants and related melanomas for somatic V600 BRAF mutations. RESULTS: A lower total dermoscopic score (TDS) was observed in melanomas of patients with red hair (P = 0.019), due to reduced dermoscopic structures (P < 0.0001). Thicker melanomas showed higher TDS values (P = 0.021) due to sharper borders (P < 0.0001) and higher number of colors (P = 0.004). An atypical pigment network was prevalent in superficial spreading melanomas (P = 0.010), in individuals with dark skin (P = 0.043) and hair color (P = 0.001). An atypical vascular pattern was more frequent in nodular (P < 0.0001) and thick (P < 0.0001) melanomas, in individuals with skin type I-II (P = 0.037), blond or red hair color (P = 0.032) and blue or green eyes (P = 0.014). Melanomas of MC1R R carriers showed lower TDS value (P = 0.037), reduced dermoscopic structures (P = 0.001) and lower prevalence of atypical pigment network (P = 0.001). No differences were identified between BRAF-mutated or wild-type melanomas. CONCLUSIONS: We suggest a phenotypic/MC1R profile for melanoma patients and their tumours. Melanomas of MC1R R carriers show a significant lower TDS value, with reduced dermoscopic structures, and a lower prevalence of an atypical pigment network. Non-carriers of MC1R R variants develop melanomas dermoscopically characterized by an atypical pigment network which is prevalent in superficial spreading melanomas, in patients with dark complexion and less frequent in red-haired individuals.

Association between dietary meat consumption and incident type 2 diabetes: the EPIC-InterAct study.

AIMS/HYPOTHESIS: A diet rich in meat has been reported to contribute to the risk of type 2 diabetes. The present study aims to investigate the association between meat consumption and incident type 2 diabetes in the EPIC-InterAct study, a large prospective case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. METHODS: During 11.7 years of follow-up, 12,403 incident cases of type 2 diabetes were identified among 340,234 adults from eight European countries. A centre-stratified random subsample of 16,835 individuals was selected in order to perform a case-cohort design. Prentice-weighted Cox regression analyses were used to estimate HR and 95% CI for incident diabetes according to meat consumption. RESULTS: Overall, multivariate analyses showed significant positive associations with incident type 2 diabetes for increasing consumption of total meat (50 g increments: HR 1.08; 95% CI 1.05, 1.12), red meat (HR 1.08; 95% CI 1.03, 1.13) and processed meat (HR 1.12; 95% CI 1.05, 1.19), and a borderline positive association with meat iron intake. Effect modifications by sex and class of BMI were observed. In men, the results of the overall analyses were confirmed. In women, the association with total and red meat persisted, although attenuated, while an association with poultry consumption also emerged (HR 1.20; 95% CI 1.07, 1.34). These associations were not evident among obese participants. CONCLUSIONS/INTERPRETATION: This prospective study confirms a positive association between high consumption of total and red meat and incident type 2 diabetes in a large cohort of European adults.

Dermoscopy of scalp tumours: a multi-centre study conducted by the international dermoscopy society.

BACKGROUND: Little is known about the dermoscopic features of scalp tumours. Objective To determine the dermoscopic features of scalp tumours. METHODS: Retrospective analysis of dermoscopic images of histopathologically diagnosed scalp tumours from International Dermoscopy Society members. RESULTS: A total of 323 tumours of the scalp from 315 patients (mean age: 52 years; range 3-88 years) were analysed. Scalp nevi were significantly associated with young age (<30 years) and exhibited a globular or network pattern with central or perifollicular hypopigmentation. Melanoma and non-melanoma skin cancer were associated with male gender, androgenetic alopecia, age >65 years and sun damage. Atypical network and regression were predictive for thin (≤1 mm) melanomas, whereas advanced melanomas (tumour thickness > 1 mm) revealed blue white veil, unspecific patterns and irregular black blotches or dots. CONCLUSIONS: The data collected provide a new knowledge regarding the clinical and dermoscopy features of pigmented scalp tumours.

Three-point checklist of dermoscopy: an open internet study.

BACKGROUND: In a pilot study, the three-point checklist of dermoscopy has been shown to represent a valid and reproducible tool with high sensitivity for the diagnosis of skin cancer in the hands of a small group of nonexperts. OBJECTIVES: To re-evaluate these preliminary results in a large number of observers independently from their profession and expertise in dermoscopy. METHODS: The study was conducted via the internet to provide worldwide access for participants. After a short web-based tutorial, the participants evaluated dermoscopic images of 165 (116 benign and 49 malignant) skin lesions (15 training and 150 test lesions). For each lesion participants scored the presence of the three-point checklist criteria (asymmetry, atypical network and blue-white structures). Kappa values, odds ratios, sensitivity, specificity and likelihood ratios were estimated. RESULTS: Overall, 150 participants joined the study. The three-point checklist showed good interobserver reproducibility (kappa value: 0.53). Sensitivity for skin cancer (melanoma and basal cell carcinoma) was 91.0% and this value remained basically uninfluenced by the observers' professional profile. Only 20 participants lacking any experience in dermoscopy performed significantly more poorly, but the sensitivity was still remarkably high (86.7%) when considering that they were untrained novices in dermoscopy. The specificity was 71.9% and was significantly influenced by the profession, with dermatologists performing best. CONCLUSIONS: Our study confirms that the three-point checklist is a feasible, simple, accurate and reproducible skin cancer screening tool.

Interleukin-1 gene polymorphisms and gastric cancer risk in a high-risk Italian population.

OBJECTIVES: Host genetic factors, including the IL1 gene cluster, play a key role in determining the long-term outcome of Helicobacter pylori infection. The aim of the study was to investigate the relationship between selected IL1 loci polymorphisms and gastric cancer risk in an Italian population. METHODS: In a case-control study we compared the IL1B-31 and IL1B+3954 biallelic and IL1RN pentaallelic variable number of tandem repeats (VNTR) polymorphisms in 185 gastric cancer patients and 546 controls randomly sampled from the general population of an area at high gastric cancer risk (Tuscany, Central Italy). RESULTS: Genotype frequencies of the IL1B-31 T/C, IL1B+3954 C/T, and IL1RN polymorphisms among our population controls were in Hardy-Weinberg equilibrium. In multivariate analyses, no increase in gastric cancer risk was observed for the IL1B-31*C- and IL1B+3954*T- carriers; a significant 50% increase emerged for IL1RN*2 allele carriers (OR = 1.49; 95% CI: 1.01-2.21). Analyses based on combined genotypes showed also that the association with IL1RN*2 allele was limited to two-variant allele carriers who were also homozygous for the IL1B-31*T allele (OR = 2.23; 95% CI: 1.18-4.23) with a statistically significant interaction between these two genotypes (p= 0.043). Haplotype analysis showed an increased risk for the haplotype IL1RN*2/IL1B-31*T. CONCLUSIONS: Our results suggest that host genetic factors (such as the IL1RN and the IL1B-31 polymorphisms) interact in the complex process of gastric carcinogenesis in this high-risk Italian population. Overall, this effect appears more modest than previously reported in other populations, supporting the hypothesis that other still-to-be-defined factors are important in gastric carcinogenesis. These findings might be due to a haplotype effect.

Circulating CD8+ lymphocytes, white blood cells, and survival in patients with mycosis fungoides.

BACKGROUND: There is a need for reliable, easily measurable laboratory markers that may help dermatologists to predict the course of mycosis fungoides (MF) when they first evaluate their patients. OBJECTIVES: Our objective was to identify clinical, haematological or immunological parameters as predictors of mortality in patients with MF. METHODS: We conducted a retrospective study on a prevalent cohort of 124 patients with MF hospitalized at IDI-IRCCS, Rome, Italy, from 1983 to 2001. We calculated the proportion of patients surviving (Kaplan-Meier product-limit estimates) 5 and 10 years after first hospital admission, and hazard ratios (HR) from the Cox proportional hazards model. RESULTS: Patients' survival was linked to age and staging (lower survival in older patients and in patients with staging IIB-IV). Higher numbers of white blood cells (WBC) and neutrophils, lower numbers of CD8+ lymphocytes, low haematocrit and lower levels of albumin were significantly associated with a lower survival probability. When simultaneously accounting for age and staging, CD8+ [HR = 3.02, 95% confidence interval (CI) 1.01-9.07 for CD8+ < 250 vs. > or = 600 cells microL(-1)] and WBC (HR = 2.59, 95% CI 0.96-6.96 for WBC > or = 9000 vs. < 6000 cells microL(-1)) were associated with survival. In addition, we observed an exceedingly high risk of death (HR = 12.40, 95% CI 3.11-49.43) for patients with a combination of WBC > or = 9000 and CD8+ < 600 cells microL(-1) vs. WBC < 9000 and CD8+ > or = 600 cells microL(-1)). CONCLUSIONS: The measurement of CD8+ cells and WBC in MF seems to be a promising criterion to predict survival, and possibly to support treatment decisions and inclusion of patients in randomized controlled trials.

Clinically equivocal melanocytic skin lesions with features of regression: a dermoscopic-pathological study.

BACKGROUND: Benign melanocytic skin lesions may be difficult to differentiate from melanoma both clinically and dermoscopically. One of the most confounding dermoscopic features, commonly seen in melanoma but in our experience also in melanocytic naevi, is represented by the so-called blue-white structures (BWS). OBJECTIVES: To evaluate diagnostic significance and histopathological correlates of BWS seen by dermoscopy in a series of clinically equivocal melanocytic skin lesions that were excised. METHODS: Patients were recruited from six specialized pigmented lesion clinics in Austria, Italy and Spain over a period of 9 months. All consecutive patients showing one or more melanocytic lesions with BWS, but not classified as melanoma dermoscopically, were included. Each lesion was photographed clinically and dermoscopically. All images were reviewed by one of us and the degree, type and location of BWS evaluated for each lesion. A panel of four experienced dermatopathologists independently reviewed all specimens for diagnosis and one of them evaluated presence and degree of melanosis and/or fibrosis. The main outcome measures were the percentage and histopathological correlates of lesions with different degree, type and location of BWS. RESULTS: All included lesions with BWS (n = 158) showed partial or focal regression histopathologically. One hundred and thirty-five (85.4%) lesions were diagnosed as melanocytic naevi (complete histopathological interobserver agreement), whereas 23 (14.6%) were defined as equivocal because at least one of four pathologists diagnosed the given lesion as melanoma. Only one lesion was diagnosed as melanoma by all four pathologists. The majority of naevi exhibited blue areas (84.4%) with a central distribution (57%) and involving < 50% of the lesion surface (89.6%). By contrast, 78.3% of equivocal lesions revealed a combination of white and blue areas with an irregular distribution (60.9%) and involving > 50% of the lesion surface (47.8%). CONCLUSIONS: Using degree and type of BWS, an algorithm was constructed that can be applied for the management of lesions exhibiting dermoscopic features of regression.

Adjuvant therapy of melanoma patients (stage II, III): a pilot immuno-toxicological study.

A pilot study was conducted to assess the tolerability and the effect on host immunity of a post-surgery adjuvant treatment of melanoma patients with an anti-angiogenic agent, Tamoxifen (TAM, 20 mg/die p.o., daily), combined with immunomodulating cytokines, i.e. recombinant interleukin-2 (IL-2, 4 MUI/m2 s.c., day 8,10,12) and alpha-2b-interferon (IFN, 3 MUI/m2 i.m., day 15,17,19), starting a new cycle on day 21, for a total of 12 cycles. Fifty patients (pts) entered into the study, 27 males and 23 females with a median age of 55 years (range 25-75), performance status (ECOG) 0 with melanoma stage IIA (12 patients), stage IIB (28 patients), stage III (10 patients). Preliminary in vitro studies showed that TAM does not interfere with up-regulation of natural immunity induced by IFN, IL-2, or IFN + IL-2 in normal peripheral blood mononuclear cells (MNC). The clinical study indicates that the protocol was well tolerated. Increase of NK and LAK activity of patient MNC was observed on day 15. The mean disease-free interval was 10 months and 40 pts were alive at 5 years of follow-up. Further investigations should be performed to test effectiveness of this protocol in a randomized study.

The epidemiology of atopic dermatitis in Italian schoolchildren.

BACKGROUND: Atopic dermatitis (AD) is common in children in industrialized countries. Only one large population study on its prevalence has been conducted in Italy, based on self-report questionnaire. The present study was designed to estimate the prevalence of AD in schoolchildren in Italy by dermatologists' assessment and by UK Working Party criteria, and to investigate associated symptoms and factors. METHODS: Cross-sectional survey on a random sample of 9-year-old schoolchildren from seven Italian cities. Children were examined by experienced dermatologists. Parents and teachers answered standardized questionnaires. RESULTS: Of the 1369 children examined, 88 had a diagnosis of AD, with an estimated point prevalence of 5.8% (95% CI 4.5-7.1) in the reference population. The reported lifetime prevalence was 15.2 (95% CI 12.2-18.2) for AD, 11.9% (95% CI 9.0-14.8) for asthma, and 17.6% (95% CI 14.6-20.7) for rhino-conjunctivitis. The strongest associated factor was the presence of AD in at least one parent. No association of AD with maternal smoking during pregnancy, birth weight, maternal age at the time of the child birth and breast-feeding was observed. The environmental characteristics of the house and the school did not correlate with the prevalence of AD. Episodes of lower respiratory tract infections were associated with asthma, and to a lower extent also with AD and rhinitis. CONCLUSIONS: The prevalence of doctor-diagnosed AD in Italian schoolchildren is comparable to those reported for other developed countries. Family history of atopy was the single most important associated factor, while the complex interplay of environmental factors remains to be elucidated.

Magnetic resonance imaging in the diagnosis of melanoma: in vivo preliminary studies with dynamic contrast-enhanced subtraction.

The aim of this study was to analyse the potential of fast dynamic subtraction magnetic resonance (MR) imaging in differentiating in vivo melanomas from benign melanocytic lesions. Dynamic MR imaging was performed after intravenous administration of gadopentetate dimeglumine (Gd-DTPA) in 18 patients with melanocytic skin lesions. Using a post-processing algorithm, time-signal intensity curves were obtained for the lesions and classified according to their shapes as type I (steady enhancement increase), type II (plateau of signal intensity) or type III (wash-out of signal intensity). Other parameters evaluated for their potential to differentiate melanomas from benign lesions were the enhancement rate (percentage of signal intensity increase) in the first minute after Gd-DTPA administration, the peak value of the enhancement rate, and the wash-out slope. The pigmented lesions were then surgically excised and the MR results compared with the histological assessment. In melanomas, the mean value of the enhancement rate in the first minute was 611%, whereas in benign lesions it was 131% (P = 0.001). The distribution of curve types was also different: seven of the nine naevi showed type I curves, while eight of the nine melanomas displayed a type III curve. In addition, distinctive wash-out dynamics were observed: the enhancement rate began to decrease between the first and third minutes for melanomas, but continued to increase until the sixth minute for naevi (P = 0.000). These findings, which are most likely related to the neoangiogenesis present in melanomas, indicate that dynamic MR imaging can be helpful in the differential diagnosis of pigmented skin lesions.

Risk factors for basal cell carcinoma in a Mediterranean population: role of recreational sun exposure early in life.

OBJECTIVE: To investigate the role of pigmentary traits, different patterns of sun exposure, artificial sources of UV radiation, and lifestyle-related factors on the risk of basal cell carcinoma (BCC) in a Mediterranean population from central-southern Italy. DESIGN: Hospital-based case-control study. SETTING: A referral dermatological hospital in Rome, Italy. PATIENTS: A convenience sample of 166 case patients with histologically confirmed BCC and 158 cancer-free control subjects with minor dermatological conditions observed between March 1995 and June 1997. RESULTS: In the multivariate analysis, the mean number of weeks per year spent at the beach before the age of 20 years was significantly associated with BCC. A dose-response trend was found for subjects who had spent 3 to 4 (odds ratio, 1.8; 95% confidence interval, 0.8-4.4), 5 to 8 (odds ratio, 3.7; 95% confidence interval, 1.5-9.0), or more than 8 (odds ratio, 4.5; 95% confidence interval, 1.9-10.5) weeks per year at the beach (P =.01 for trend). There was a significant association with the presence of actinic keratoses or solar lentigines, whereas no effect was found for skin type, history of sunburns, exposure to nonsolar UV radiation, and lifestyle-related habits such as cigarette smoking, alcohol consumption, and coffee drinking. Subjects reporting a family history of skin cancer had an extremely increased risk of BCC. CONCLUSION: The definite association with recreational sun exposure during childhood and adolescence and the strong relation with family history of skin cancer suggest that genetic predisposition and peculiar exposure patterns to UV radiation are key independent risk factors for the development of BCC in a southern European population.

Chest wall invasion in non-small cell lung carcinoma: a rationale for en bloc resection.

OBJECTIVE: The choice of surgical approach to non-small cell lung cancer invading the chest wall, extrapleural resection versus en bloc chest wall resection, is much more related to the experience of the surgeon than to objective criteria. The aim of the present study is to help to establish a rationale for en bloc chest wall resection in lung cancer invading the chest wall. METHODS: From January 1990 to June 1999, of 1855 patients having major pulmonary resections for non-small cell lung carcinoma, 104 (5.6%) patients with neoplasms involving the chest wall underwent en bloc chest wall and lung resection plus radical mediastinal lymphadenectomy. RESULTS: All patients underwent complete resection with microscopically disease-free tissue margins. Depth of invasion was into the parietal pleura only in 28 (26.92%), into the pleura and soft tissue in 36 (34.62%), and into the pleura, soft tissue, and bone in 40 (38.46%). No operative mortality was reported. Follow-up was completed in 96 patients. One patient had a local recurrence. The overall 5-year estimated survival was 61.4%. Survival in the subsets T3 N0 and T3 N2 were, respectively, 67.3% and 17.9% (P =.007). The 5-year survival was 79.1% in involvement of parietal pleura only and 54.0% in involvement of soft tissue with or without bone invasion (P =.014). Five-year survival was 53.0% in adenocarcinoma versus 71.8% in squamous cell carcinoma (P =.329) and 74.1% in patients who did undergo radiation therapy versus 46.7% in patients who did not undergo radiation therapy (P =.023). CONCLUSIONS: En bloc resection of the chest wall and lung is the procedure of choice to obtain complete resection in lung carcinoma invading the chest wall. Survival is highly dependent on the completeness of resection, nodal involvement, and depth of chest wall invasion.

Suture materials and other factors associated with tissue reactivity, infection, and wound dehiscence among plastic surgery outpatients.

The most common complications in plastic surgery are tissue reactivity, infections, and wound dehiscence. In the literature, there are only a few studies with sample sizes large enough and methods of statistical analysis appropriate for evaluating the role of suture materials in inducing such complications. In the 1000 plastic surgery outpatients in this study, the association of different suture materials, individual patient characteristics, surgeon skill, and wound site and length with postoperative wound complications (i.e., tissue reactivity, infection rate, and wound dehiscence) were investigated. No substantial differences were found between the different suture materials and suturing techniques. A moderate increase in the risk of tissue reactivity for silk and polyglactin 910 and a protective effect of thinner internal sutures were observed. In multivariate analysis, such differences were not statistically significant. Male sex [odds ratio (OR), 1.7; 95 percent confidence interval (CI), 1.06 to 2.72] and older age (OR, 2.34; 95 percent CI, 1.36 to 4.05) were found to be the most important risk factors for tissue reactivity and infection rate (male sex: OR, 5.1; 95 percent CI, 1.7 to 15.9; older age: OR, 5.6; 95 percent CI, 1.9 to 16), whereas younger age was associated with an increased risk of dehiscence (OR, 3.06; 95 percent CI, 1.41 to 6.65). Wounds on the lower limbs showed a lower risk of tissue reactivity and wounds on the back a higher risk of dehiscence. Wound length was associated with the risk of tissue reactivity in one-layer sutures (OR, 2.92; 95 percent CI, 1.51 to 5.65). An increased risk of both tissue reactivity (OR, 1.53; 95 percent CI, 1.03 to 2.27) and dehiscence (OR, 2.44; 95 percent CI, 1.1 to 5.43) was observed for operations performed by less-experienced surgeons. Rather than factors related to suture materials and different surgical techniques, and with the exception of surgeon experience, general characteristics of the patients (i.e., sex and age) and of the wounds (i.e., length and site) seemed to be primarily responsible for local wound complications.

Factors that influence the DNA repair capacity of normal and skin cancer-affected individuals.

DNA repair capacity (DRC) was studied in 49 patients affected by basal cell carcinoma (BCC) and 68 cancer-free controls belonging to a larger case-control population enrolled for studying BCC risk factors. DRC was measured in the subjects' peripheral blood lymphocytes by using a host-cell reactivation assay that measures cellular activation of a reporter gene irradiated with UV light. A statistically significant age-related decline in DRC was observed in the controls from 20 to 70 years of age but not in the BCC cases. When the DRC values of the BCC patients and controls were compared by age, young BCC cases (age, < or =40 year) repaired less than the controls, although the difference was not statistically significant. Conversely, older BCC patients (age, >40 years) presented an enhanced repair capacity (P < 0.001) as compared with their controls. The search for possible factors associated with the high repair rate of elderly BCC cases revealed that both target cell physiology and life-style habits may affect host DNA repair. Smoking was the variable that explained most of the increase in DRC among older patients. The understanding of how these factors affect host DRC will be relevant for a correct use of this biomarker.