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AIM OF THE STUDY: We performed a meta-analysis to assess whether MC1R variants increase the risk of melanoma in CDKN2A mutation carriers of melanoma-prone families. METHODS: Data from 96 CDKN2A-positive melanoma-prone families from seven independent populations of Europe, United States and Australia were included in the analysis. Summary risk estimates were calculated by random-effect models. We explored between-study heterogeneity and publication bias. Association between MC1R variants and age at diagnosis was assessed by the non-parametric Wilcoxon test. RESULTS: CDKN2A mutation carriers with 1 MC1R variant showed a double melanoma risk as compared to CDKN2A mutation carriers without MC1R variants (Summary OR; 95%CI: 2.2; 1.1-4.5). MC1R heterozygous subjects had no significantly higher melanoma risk than wild-type subjects (1.6; 0.5-5.4) while carriers of multiple MC1R variants had a more than four-times higher melanoma risk (4.6; 1.3-16.4). Carriers of red hair colour (RHC) variants showed an increased melanoma risk with a Summary OR of 3.5 (95%CI: 1.3-9.9). CDKN2A mutation carriers with MC1R variants had a statistically significant lower median age at melanoma diagnosis than CDKN2A mutation carriers with no MC1R variants (37years versus 47years, p-value<0.0001). CONCLUSION: MC1R variants significantly increase penetrance of CDKN2A mutations in melanoma-prone families, especially with respect to multiple MC1R variants and to RHC variants. A significant anticipation of melanoma diagnosis is observed in CDKN2A mutation carriers with MC1R variants. [ABSTRACT FROM AUTHOR]

Several epidemiological, pre-clinical and clinical studies support Vitamin D as a preventive and therapeutic cancer agent. Background Vitamin D and cancer: calcitriol, the biologically active form of vitamin D (1,25(OH)D), exerts its effects mainly through binding to nuclear vitamin D receptor (VDR). Calcitriol has been shown to be an anti-proliferative, pro-differentiation, pro-apoptotic agent and an inhibitor of cell migration. Animal and human in vitro studies strongly indicate that vitamin D may have benefits for many forms of cancer. Inadequate levels of circulating 25-hydroxy-vitamin D (25(OH)D) are associated with an increased risk and poor prognosis of several types of cancer. Vitamin D and melanoma: cutaneous malignant melanoma (CMM) represents a major public health issue: rates in Italy have almost doubled in the last decade and CMM is frequent among young adults. For resected stage II melanoma no standard adjuvant treatment exists and five-year overall survival is about 70%. Cultured melanoma cells can synthesize calcitriol from 25(OH)D and express the VDR. Moreover, 1,25(OH)D has anti-proliferative and pro-differentiation effects in human melanoma cells. 1,25(OH)D has been shown to induce apoptosis in human melanoma cell lines and has an inhibitory effect on the spreading of melanoma cells in vitro. Preliminary results on vitamin D: epidemiological data indicate that vitamin D deficiency is relatively common in Europe. In an Italian study, we found that 85% of the participants had insufficient levels of 25(OH)D. We have shown through a meta-analysis of randomized trials that vitamin D supplementation is associated with a significant reduction (7%) in total mortality in healthy subjects and an association between VDR and 25(OH)D and CMM progression has also been demonstrated. We have also reported significant associations between VDR polymorphisms and incidence of skin cancer. In early supplementation trials, the lack of effect on cancer incidence has been attributed to insufficient vitamin D supplementation, stressing the need to better study vitamin D bioavailability. In fact, a recent IARC report highlighted the need for new randomized trials, based on results from our meta-analyses on 25(OH)D serum levels and cancer risk. Clinical trial and biomarkers studies: in order to assess whether vitamin D supplementation could improve prognosis of CMM, an Italian multi-centre trial in stage II resected melanoma patients was planned to monitor changes in 25(OH)D. The study will address two important questions regarding the relationship between the biology of VDR and (1) vitamin D metabolism, and (2) CMM prognosis. This will involve investigating the association between VDR polymorphisms and Breslow thickness, the most important prognostic factor of CMM, and between 25(OH)D serum level, vitamin D supplementation and VDR. We will also evaluate at baseline whether VDR polymorphisms are associated with Breslow thickness and whether we obtain signi ficant increase in 25(OH)D serum levels during the first year of supplementation. We will quantify the percentages of patients who have desirable levels of 25(OH)D and, if they don't, the mean time to reach that level. The findings from this study will be of great interest because vitamin D could have anti-cancer benefits for a wide spectrum of cancers. [ABSTRACT FROM AUTHOR]

Background: Results of a clinical trial recently completed in the United States indicate that administration of tamoxifen (20 mg/day) to women at risk can reduce breast cancer incidence by approximately 50% but is associated with an increased risk of developing endometrial cancer and venous thromboembolic events. Since these adverse effects may be dose related, we investigated the effect of tamoxifen on several biomarkers when the drug was given at doses lower than those currently in use.Methods: In two sequential experiments, 127 healthy hysterectomized women aged 35-70 years were randomly assigned to one of the following four treatment arms: placebo (n = 31) or tamoxifen at 20 mg/day (n = 30) (first experiment); or tamoxifen at 10 mg/day (n = 34) or tamoxifen at 10 mg/ alternate days (n = 32) (second experiment). Baseline and 2-month measurements of the following parameters were compared: 1) total cholesterol (primary end point) and other surrogate markers of cardiovascular disease, e.g., low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and lipoprotein(a); 2) blood cell count; 3) fibrinogen; 4) antithrombin III; 5) osteocalcin; and, 6) in a subgroup of 103 women, insulin-like growth factor-I (IGF-I), a possible surrogate marker for breast cancer.Results: After adjustment for the baseline values, there were reductions in circulating levels of total cholesterol and IGF-I of the same magnitude in all three tamoxifen treatment arms. A similar pattern was observed for most of the other parameters. In the placebo arm, fibrinogen level, which showed a decrease, was the only parameter exhibiting change.Conclusions: Up to a 75% reduction in the conventional dose of tamoxifen (i.e., 20 mg/day) does not affect the activity of the drug on a large number of biomarkers, most of which are surrogate markers of cardiovascular disease. This study was hypothesis generating, and larger studies are warranted to assess the efficacy of tamoxifen at low doses. [ABSTRACT FROM AUTHOR]

The effect of dopamine infusion on basal and pentagastrin-stimulated gastric secretion, on basal and secretin-CCK-PZ-stimulated pancreatic secretion, and on basal and meal-induced gastrin release has been evaluated in healthy volunteers. Both basal and stimulated gastric acid secretion were significantly inhibited during dopamine infusion with a significant rebound to pre-infusion values after discontinuing dopamine. These effects were prevented by pretreatment with the antidopaminergic drug, metoclopramide. A slight but now significant decrease in amylase and bicarbonate outputs was also observed during dopamine infusion, while gastrin release did not change. These data suggest the existence of dopaminergic mechanisms in the regulation of gastric acid secretion in man. [ABSTRACT FROM PUBLISHER]

Acknowledgements section was missing [ABSTRACT FROM AUTHOR]

To report toxicity and efficacy outcome of moderately hypofractionated image-guided external-beam radiotherapy in a large series of patients treated for prostate cancer (PCa). Between 10/2006 and 12/2015, 572 T1-T3N0M0 PCa patients received 70.2 Gy in 26 fractions at 2.7 Gy/fraction: 344 patients (60%) with three-dimensional conformal radiotherapy (3D-CRT) and 228 (40%) with intensity-modulated radiotherapy (IMRT). Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria and Houston definition (nadir + 2) were used for toxicity and biochemical failure evaluation, respectively. Median age was 74 years (interquartile range 69-77). Compared with 3D-CRT, in IMRT group more high-risk patients (29% vs 18%; P = 0.002) and more high-volume target (75% vs 60%; P < 0.001) were included. Acute gastro-intestinal (GI) toxicity G > 1 were registered in 8% and in 11% IMRT and 3D-CRT patients, respectively, whereas late GI G > 1 were observed in 2% and 16% IMRT and 3D-CRT patients, respectively. Acute genito-urinary (GU) toxicity G > 1 were registered in 26% and 40% IMRT and 3D-CRT patients, respectively, whereas late GU G > 1 occurred in 5% IMRT and 15% 3D-CRT patients. Multivariate proportional hazard Cox models confirmed significantly greater risk of late toxicity with 3D-CRT compared to IMRT for GU > 1 (P = 0.004) and for GI > 1 (P < 0.001). With a median 4-year follow-up, overall survival (OS), clinical progression-free survival (cPFS) and biochemical PFS (bPFS) for the whole series were 91%, 92% and 91%, respectively. cPFS and bPFS were significantly different by risk groups. Multivariate Cox models for bPFS and cPFS showed no difference between irradiation techniques and a significant impact of risk group and initial PSA. Moderately hypofractionated radiotherapy is a viable treatment option for localized PCa with excellent tumour control and satisfactory toxicity profile. IMRT seems associated with a reduction in toxicity, whereas tumour control was equal between IMRT and 3D-CRT patients and depended mainly on the risk category. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Recent skin self-examination and doctor visits in relaxation to melanoma risk and tumour depth" in the previous issue.

Background: Window-of-opportunity (WOP), presurgical models often use Ki-67 labeling index (LI) as the main surrogate biomarker for screening therapeutic activity of candidate agents and characterize their mechanism of action. Ki-67 LI in the placebo arm has been frequently reported to be higher at surgery than at baseline biopsy in WOP studies, a finding that has been ascribed to the higher proliferative activity in the tumor edge of surgical specimens that cannot be detected in the baseline core biopsy. Since this observation has important implications in sample size calculation and effect interpretation, we investigated which factors affected the changes of Ki-67 LI in a series of patients allocated to the placebo arms of a number of WOP trials carried out at IEO. Methods: Data from 181 patients with pT1-2 invasive breast cancer from the placebo arms of three WOP randomized trials were pooled with those of 98 untreated patients, who had a diagnostic core biopsy preceding surgery but declined participation to the study or were ineligible for histological characteristics. Ki-67 LI was measured by evaluating the prevalence of neoplastic cells showing any definite nuclear immunostaining with the Mib-1 monoclonal antibody, in the whole invasive component of baseline core biopsies and in at least 2000 invasive neoplastic cells of surgical samples, in accordance to the recently licensed international recommendations. Results: We collected data of 273 breast cancer patients with information on the changes in Ki -67 LI: 46 (17%) were Luminal A, 85 (31%) Luminal B/HER2-, 24 (9%) Luminal B/HER2+, 38 (14%) HER2+ and 81 (30%) Triple Negative (TN). Median (IQR) Ki-67LI at baseline in each molecular subtype was 10% (7-11), 20% (16-29), 28% (22-35), 30% (25-45) and 50% (32-75) in the Luminal A, Luminal B/HER2-, Luminal B/HER2+, HER2+ and TN, respectively. Median (IQR) age was 50 years (44-60), median BMI was 24 (22-27), 50% were post-menopausal. The median (range) time elapsed from biopsy to surgery was 41 days (33-48). Overall, the median change in Ki-67 LI between baseline biopsies and surgical samples was 0 (IQR, -2, 5). Results from multivariate analysis showed that none of the factors investigated, including patient and tumor characteristics, time elapsed from biopsy to surgery and circulating biomarkers (IGF-I, SHBG and ultrasensitive CRP) were associated with the Ki-67 LI change except for the immunohistochemically defined molecular subtype, which explained most of the variability of the changes (p = 0.004). As a matter of fact, we observed a 5%, significant increase of Ki-67 LI both in HER2+ and TN tumors, after adjustment for baseline values. Conclusions: We reported a significant increase in Ki-67 LI between baseline biopsy and endpoint surgery in the placebo arms of HER2+ and TN tumors. This association suggests a real biological increase in proliferation rather than an analytical artifact, and should be taken into account in designing future WOP studies. [ABSTRACT FROM AUTHOR]

Abstract Background For complex diseases like cancer, pooled-analysis of individual data represents a powerful tool to investigate the joint contribution of genetic, phenotypic and environmental factors to the development of a disease. Pooled-analysis of epidemiological studies has many advantages over meta-analysis, and preliminary results may be obtained faster and with lower costs than with prospective consortia. Design and methods Based on our experience with the study design of the Melanocortin-1 receptor (MC1R) gene, SKin cancer and Phenotypic characteristics (M-SKIP) project, we describe the most important steps in planning and conducting a pooled-analysis of genetic epidemiological studies. We then present the statistical analysis plan that we are going to apply, giving particular attention to methods of analysis recently proposed to account for between-study heterogeneity and to explore the joint contribution of genetic, phenotypic and environmental factors in the development of a disease. Within the M-SKIP project, data on 10,959 skin cancer cases and 14,785 controls from 31 international investigators were checked for quality and recoded for standardization. We first proposed to fit the aggregated data with random-effects logistic regression models. However, for the M-SKIP project, a two-stage analysis will be preferred to overcome the problem regarding the availability of different study covariates. The joint contribution of MC1R variants and phenotypic characteristics to skin cancer development will be studied via logic regression modeling. Discussion Methodological guidelines to correctly design and conduct pooled-analyses are needed to facilitate application of such methods, thus providing a better summary of the actual findings on specific fields.

Background: Surgical procedure for breast cancer is not without its side effects and one such side effect is axillary web syndrome (AWS), characterized by palpable fibrotic-like cords in the operated arm. As physical evaluation is the only gold standard method used, our study aims to assess the incidence and early detection of AWS with a self-assessment questionnaire.Methods: From July 2013 to July 2014, 370 breast cancer patients were enrolled. AWS incidence was 51.1%, with 94.1% onset in the first 4 weeks after surgery; 43.5% of the patients did not recover in the first 8 weeks. Univariate analysis showed that BMI (P < 0.001), age (P < 0.001), educational level (P = 0.01), and exercise frequency in the eighth week of follow-up (P < 0.001) were significantly associated with the AWS detection, and multivariate analyses confirmed that younger patients (age < 50) have significantly higher AWS detection (OR = 2.38 (95%CI 1.53, 3.71) and that BMI is associated with AWS, with normal weight patients (BMI ≤ 25) having a significantly greater AWS detection with an odds ratio of 2.11 (95%CI 1.33, 3.36).Conclusion: Our findings indicated that the incidence of AWS is high in breast cancer patients, particularly in the first month after surgery. Not all patients achieved recovery during our 8 week follow-up, suggesting that evaluation and treatment should be longer. Double AWS detection was found for patients who were younger (age < 50) and with normal weight. [ABSTRACT FROM AUTHOR]