Vitamin D and the Risk of Non-Melanoma Skin Cancer: A Systematic Literature Review and Meta-Analysis on Behalf of the Italian Melanoma Intergroup.

We aimed to provide a comprehensive overview of the link between vitamin D and non-melanoma skin cancer (NMSC). For this purpose, we conducted a systematic literature review (updated to 3 February 2021) and meta-analysis of the studies reporting on the association between vitamin D intake (from diet and supplements) and blood concentration, polymorphisms of the vitamin D receptor (VDR) and vitamin D binding protein (VDBP) genes, and the risk of NMSC. Random effects meta-analysis models were fitted to merge study-specific risk estimates into summary relative risk (SRR) and corresponding 95% confidence intervals (CI). Twenty-four studies altogether were included. There was a suggestive association between increasing serum/plasma vitamin D concentration and NMSC risk (SRR for highest vs. lowest concentration 1.67, 95%CI 0.61-4.56), although with large heterogeneity across studies (I2 = 91%). NMSC risk was associated with highest vitamin D intake in observational studies but not in clinical trials. Finally, there was no significant association between any polymorphism of the VDR and VDBP genes and NMSC risk. In conclusion, no strong relationship between vitamin D metabolism and NMSC risk appears to exist according to our systematic review and meta-analysis, although some findings are worthy of further investigation.

Phase 2 placebo-controlled, single-blind trial to evaluate the impact of oral ibandronate on bone mineral density in osteopenic breast cancer patients receiving adjuvant aromatase inhibitors: 5-year results of the single-centre BONADIUV trial.

AIM: We present the final results of the BONADIUV trial, a single-blind, randomised, placebo-controlled phase 2 study to evaluate the impact of ibandronate treatment on bone mineral density (BMD) in osteopenic women taking aromatase inhibitors (AI). PATIENTS AND METHODS: Between 2011 and 2014, 171 osteopenic patients were randomised in a 1:1 ratio to receive either placebo or oral monthly ibandronate (150 mg). Treatment duration was 2 years, with 6-month evaluation. Primary end-point was the 2-year lumbar spine (LS) and total hip (TH) T-score mean differences as measure of BMD variation. Secondary analyses of survival outcomes have been performed at a 5-year median follow-up. CLINICALTRIALS. GOV IDENTIFIER: NCT02616744. RESULTS: Median age of study population was 60.2 years (range 44-75). At the database cut-off time, the median follow-up was 63.3 months (range 2.7-87.3). No difference in terms of T-score was shown at baseline between arms both for TH (P = 0.61) and LS (P = 0.96). At 2-year follow up, the mean change was statistically significant in favour of ibandronate arm both at TH (P = 0.0002) and LS (P < 0.0001). No significant difference in terms of adverse events was observed between arms. At a median follow-up of 63.3 months (range 2.7-87.3), the overall survival (OS) rate was 97.5% in the placebo group and 93.0% in the ibandronate arm (P = 0.19). The invasive disease-free survival (iDFS) rates did not differ between groups (P = 0.42). CONCLUSIONS: Ibandronate compared to placebo improved BMD change in osteopenic women treated with adjuvant AI. Five-year survival analyses showed no difference between arms in terms of OS and iDFS rates.

Coffee and Tea Consumption and the Contribution of Their Added Ingredients to Total Energy and Nutrient Intakes in 10 European Countries: Benchmark Data from the Late 1990s.

BACKGROUND: Coffee and tea are among the most commonly consumed nonalcoholic beverages worldwide, but methodological differences in assessing intake often hamper comparisons across populations. We aimed to (i) describe coffee and tea intakes and (ii) assess their contribution to intakes of selected nutrients in adults across 10 European countries. METHOD: Between 1995 and 2000, a standardized 24-h dietary recall was conducted among 36,018 men and women from 27 European Prospective Investigation into Cancer and Nutrition (EPIC) study centres. Adjusted arithmetic means of intakes were estimated in grams (=volume) per day by sex and centre. Means of intake across centres were compared by sociodemographic characteristics and lifestyle factors. RESULTS: In women, the mean daily intake of coffee ranged from 94 g/day (~0.6 cups) in Greece to 781 g/day (~4.4 cups) in Aarhus (Denmark), and tea from 14 g/day (~0.1 cups) in Navarra (Spain) to 788 g/day (~4.3 cups) in the UK general population. Similar geographical patterns for mean daily intakes of both coffee and tea were observed in men. Current smokers as compared with those who reported never smoking tended to drink on average up to 500 g/day more coffee and tea combined, but with substantial variation across centres. Other individuals' characteristics such as educational attainment or age were less predictive. In all centres, coffee and tea contributed to less than 10% of the energy intake. The greatest contribution to total sugar intakes was observed in Southern European centres (up to ~20%). CONCLUSION: Coffee and tea intake and their contribution to energy and sugar intake differed greatly among European adults. Variation in consumption was mostly driven by geographical region.

Coffee, tea and melanoma risk: findings from the European Prospective Investigation into Cancer and Nutrition.

In vitro and animal studies suggest that bioactive constituents of coffee and tea may have anticarcinogenic effects against cutaneous melanoma; however, epidemiological evidence is limited to date. We examined the relationships between coffee (total, caffeinated or decaffeinated) and tea consumption and risk of melanoma in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a multicentre prospective study that enrolled over 500,000 participants aged 25-70 years from ten European countries in 1992-2000. Information on coffee and tea drinking was collected at baseline using validated country-specific dietary questionnaires. We used adjusted Cox proportional hazards regression models to calculate hazard ratios (HR) and 95% confidence intervals (95% CI) for the associations between coffee and tea consumption and melanoma risk. Overall, 2,712 melanoma cases were identified during a median follow-up of 14.9 years among 476,160 study participants. Consumption of caffeinated coffee was inversely associated with melanoma risk among men (HR for highest quartile of consumption vs. non-consumers 0.31, 95% CI 0.14-0.69) but not among women (HR 0.96, 95% CI 0.62-1.47). There were no statistically significant associations between consumption of decaffeinated coffee or tea and the risk of melanoma among both men and women. The consumption of caffeinated coffee was inversely associated with melanoma risk among men in this large cohort study. Further investigations are warranted to confirm our findings and clarify the possible role of caffeine and other coffee compounds in reducing the risk of melanoma.

Dietary flavonoid intake and colorectal cancer risk in the European prospective investigation into cancer and nutrition (EPIC) cohort.

Flavonoids have been shown to inhibit colon cancer cell proliferation in vitro and protect against colorectal carcinogenesis in animal models. However, epidemiological evidence on the potential role of flavonoid intake in colorectal cancer (CRC) development remains sparse and inconsistent. We evaluated the association between dietary intakes of total flavonoids and their subclasses and risk of development of CRC, within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. A cohort of 477,312 adult men and women were recruited in 10 European countries. At baseline, dietary intakes of total flavonoids and individual subclasses were estimated using centre-specific validated dietary questionnaires and composition data from the Phenol-Explorer database. During an average of 11 years of follow-up, 4,517 new cases of primary CRC were identified, of which 2,869 were colon (proximal = 1,298 and distal = 1,266) and 1,648 rectal tumours. No association was found between total flavonoid intake and the risk of overall CRC (HR for comparison of extreme quintiles 1.05, 95% CI 0.93-1.18; p-trend = 0.58) or any CRC subtype. No association was also observed with any intake of individual flavonoid subclasses. Similar results were observed for flavonoid intake expressed as glycosides or aglycone equivalents. Intake of total flavonoids and flavonoid subclasses, as estimated from dietary questionnaires, did not show any association with risk of CRC development.

Espresso coffee consumption and risk of coronary heart disease in a large Italian cohort.

BACKGROUND: The relationship between coffee consumption and coronary heart disease (CHD) has been investigated in several studies with discrepant results. We examined the association between Italian-style (espresso and mocha) coffee consumption and CHD risk. METHODS: We investigated 12,800 men and 30,449 women without history of cardiovascular disease recruited to the EPICOR prospective cohort study. Coffee consumption was assessed at baseline. In a random sub-cohort of 1472 subjects, plasma triglycerides, and total, LDL and HDL cholesterol were determined to investigate the effect of coffee consumption on plasma lipids. RESULTS: After a mean follow up of 10.9 years, 804 cases of CHD (500 acute events, 56 fatal events and 248 revascularizations, all first events) were identified. Multivariable adjusted hazard ratios for CHD were: 1.18 (95% CI 0.87-1.60) for drinking 1-2 cups/day, 1.37 (95% CI 1.03-1.82) for >2-4 cups/day and 1.52 (95% CI 1.11-2.07) for over 4 cups/day (P trend <0.001) compared to reference (<1 cup/day). Plasma triglycerides, and total, LDL and HDL cholesterol did not vary significantly (ANOVA) with coffee consumption. CONCLUSION: Consumption of over 2 cups/day of Italian-style coffee is associated with increased CHD risk, but coffee consumption was not associated with plasma lipid changes, so the adverse effect of consumption appears unrelated to lipid profile.

Fruit, vegetables, and olive oil and risk of coronary heart disease in Italian women: the EPICOR Study.

BACKGROUND: Many observational studies support the recommendation to eat sufficient amounts of fruit and vegetables as part of a healthy diet. OBJECTIVE: The present study aimed to investigate the association between consumption of fruit, vegetables, and olive oil and the incidence of coronary heart disease (CHD) in 29,689 women enrolled between 1993 and 1998 in 5 European Prospective Investigation into Cancer and Nutrition (EPIC) cohorts in northern (Turin and Varese), central (Florence), and southern (Naples and Ragusa) Italy. DESIGN: Baseline dietary, anthropometric, and lifestyle characteristics were collected. Major events of CHD (fatal and nonfatal myocardial infarction and coronary revascularization) were identified through a review of clinical records. Analyses were stratified by center and adjusted for hypertension, smoking, education, menopause, physical activity, anthropometric measures, nonalcohol energy, alcohol, total meat, vegetables in analyses for fruit, and fruit in analyses for vegetables. RESULTS: During a mean follow-up of 7.85 y, 144 major CHD events were identified. A strong reduction in CHD risk among women in the highest quartile of consumption of leafy vegetables (hazard ratio: 0.54; 95% CI: 0.33, 0.90; P for trend = 0.03) and olive oil (hazard ratio: 0.56; 95% CI: 0.31, 0.99; P for trend = 0.04) was found. In contrast, no association emerged between fruit consumption and CHD risk. CONCLUSION: An inverse association between increasing consumption of leafy vegetables and olive oil and CHD risk emerged in this large cohort of Italian women.

Benefit of radiation boost after whole-breast radiotherapy.

PURPOSE: To determine whether a boost to the tumor bed after breast-conserving surgery (BCS) and radiotherapy (RT) to the whole breast affects local control and disease-free survival. METHODS AND MATERIALS: A total of 1,138 patients with pT1 to pT2 breast cancer underwent adjuvant RT at the University of Florence. We analyzed only patients with a minimum follow-up of 1 year (range, 1-20 years), with negative surgical margins. The median age of the patient population was 52.0 years (+/-7.9 years). The breast cancer relapse incidence probability was estimated by the Kaplan-Meier method, and differences between patient subgroups were compared by the log rank test. Cox regression models were used to evaluate the risk of breast cancer relapse. RESULTS: On univariate survival analysis, boost to the tumor bed reduced breast cancer recurrence (p < 0.0001). Age and tamoxifen also significantly reduced breast cancer relapse (p = 0.01 and p = 0.014, respectively). On multivariate analysis, the boost and the medium age (45-60 years) were found to be inversely related to breast cancer relapse (hazard ratio [HR], 0.27; 95% confidence interval [95% CI], 0.14-0.52, and HR 0.61; 95% CI, 0.37-0.99, respectively). The effect of the boost was more evident in younger patients (HR, 0.15 and 95% CI, 0.03-0.66 for patients <45 years of age; and HR, 0.31 and 95% CI, 0.13-0.71 for patients 45-60 years) on multivariate analyses stratified by age, although it was not a significant predictor in women older than 60 years. CONCLUSION: Our results suggest that boost to the tumor bed reduces breast cancer relapse and is more effective in younger patients.

Concurrent cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy and radiotherapy for early breast carcinoma.

PURPOSE: The optimal sequencing of adjuvant chemotherapy (CT) and radiation therapy (RT) in patients with early-stage breast cancer remains unclear. PATIENTS AND METHODS: We retrospectively compared 485 patients treated with conservative breast surgery and postoperative whole-breast RT and six courses of CMF (cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2), and 5-fluorouracil 600 mg/m(2)) with 300 patients who received postoperative CMF only and with 509 patients treated with postoperative whole-breast RT only. The mean radiation dose delivered was 50 Gy (range, 46-52 Gy) with standard fractionation. The boost dose was 6-16 Gy according to resection margins and at the discretion of the radiation oncologist. Acute and late RT toxicity were scored using respectively the Radiation Therapy Oncology Group and the Late Effects in Normal Tissues Subjective, Objective, Management and Analytic scale. RESULTS: A slightly higher Grade 2 acute skin toxicity was recorded in the concurrent group (21.2% vs. 11.2% of the RT only group, p < 0.0001). RT was interrupted more frequently in the CMF/RT group respective to the RT group (8.5% vs. 4.1%; p = 0.006). There was no difference in late toxicity between the two groups. All patients in the concurrent group successfully received the planned dose of RT and CT. Local recurrence rate was 7.6% in CT/RT group and 9.8% in RT group; this difference was not statistically significant at univariate analysis (log-rank test p = 0.98). However, at multivariate analysis adjusted also for pathological tumor, pathological nodes, and age, the CT/RT group showed a statistically lower rate of local recurrence (p = 0.04). CONCLUSIONS: Whole-breast RT and concurrent CMF are a safe adjuvant treatment in terms of toxicity.

A dietary pattern rich in olive oil and raw vegetables is associated with lower mortality in Italian elderly subjects.

Dietary habits play an important role in healthy ageing. We have investigated the role of dietary patterns on overall mortality in a large series of Italian elderly, recruited in five EPIC cohorts in Northern (Varese and Turin), Central (Florence) and Southern Italy (Naples and Ragusa).A total of 5611 subjects (72.6 % women) aged 60 years or older, enrolled in 1993-1998, were prospectively followed (median 6.2 years), with 152 deaths (98 women). Four major dietary patterns were identified by using an exploratory factor analysis based on dietary information collected at enrollment. The associations between these dietary patterns and overall mortality were evaluated by Cox models adjusted for potential confounders. The 'Olive Oil & Salad' pattern, characterised by a high consumption of olive oil, raw vegetables, soups and poultry, emerged as being inversely associated with overall mortality in both crude and adjusted models. After adjustment for gender, age and caloric intake, overall mortality was reduced by approximately 50 % in the highest quartile and a significant trend emerged (P = 0.008). This association persisted after adjusting for several additional confounders (hazard ratio (HR) 0.50; 95 % CI 0.29, 0.86; P for trend = 0.02). An association of the 'Pasta & Meat' pattern (characterised by pasta, tomato sauce, red meat, processed meat, added animal fat, white bread and wine) with increased overall mortality was also suggested, but only for the highest quartile in a multivariate model. Dietary recommendations aimed at the Italian elderly population should support a dietary pattern characterised by a high consumption of olive oil, raw vegetables and poultry.

Daily consumption of a high-phenol extra-virgin olive oil reduces oxidative DNA damage in postmenopausal women.

Extra-virgin olive oils (EVOO), high in phenolic compounds with antioxidant properties, could be partly responsible for the lower mortality and incidence of cancer and CVD in the Mediterranean region. The present study aims to measure oxidative DNA damage in healthy human subjects consuming olive oils with different concentrations of natural phenols. A randomised cross-over trial of high-phenol EVOO (high-EVOO; 592 mg total phenols/kg) v. low-phenol EVOO (low-EVOO; 147 mg/kg) was conducted in ten postmenopausal women in Florence. Subjects were asked to substitute all types of fat and oils habitually consumed with the study oil (50 g/d) for 8 weeks in each period. Oxidative DNA damage was measured by the comet assay in peripheral blood lymphocytes, collected at each visit during the study period. Urine samples over 24 h were collected to measure the excretion of the olive oil phenols. The average of the four measurements of oxidative DNA damage during treatment with high-EVOO was 30 % lower than the average during the low-EVOO treatment (P=0.02). Urinary excretion of hydroxytyrosol and its metabolite homovanillyl alcohol were significantly increased in subjects consuming high-EVOO. Despite the small sample size, the present study showed a reduction of DNA damage by consumption of an EVOO rich in phenols, particularly hydroxytyrosol.

Biomarkers of dietary intake of micronutrients modulate DNA adduct levels in healthy adults.

DNA adducts, a reliable indicator of internal dose exposure to genotoxic agents and, possibly, of cancer risk, have been shown to be modulated by diet, particularly by the consumption of fresh fruit and vegetables, and by the intake of antioxidants (Palli et al., 2000, Int. J. Cancer, 87, 444-451). We have therefore investigated the association between DNA adducts in peripheral leukocytes and plasma levels of selected micronutrients, also taking into account the role of metabolic polymorphisms and smoking history, in a large independent random sample of volunteers enrolled in the prospective study EPIC-Italy (approximately 110 subjects from each of the three main geographical study areas, Northern, Central and Southern Italy). DNA adducts and five polymorphic metabolic genotypes were determined in peripheral leukocytes using the (32)P-post-labelling technique and PCR methods. Plasma levels of six carotenoids, retinol and alpha- and gamma-tocopherol were determined in the same blood sample. Among 331 subjects, 78.3% had detectable levels of DNA adducts (mean 7.46 +/- 0.48 per 10(9) nucleotides). Vitamin supplementation was reported by only a few subjects (3.9%). Strong inverse associations emerged between levels of DNA adducts and plasma retinol (P = 0.02), alpha-tocopherol (P = 0.04) and gamma-tocopherol (P = 0.03), but not carotenoids (except a borderline inverse association with beta-carotene, P = 0.08). An inverse significant association with plasma levels of retinol and gamma-tocopherol persisted in the subgroup of non-smokers, whereas a negative association with alpha-tocopherol emerged only in smokers. DNA adduct levels did not show any significant variation according to analyzed genotypes. Stratification by GSTM1 genotype, however, showed a significant negative association between DNA adduct levels and plasma levels of alpha- (P = 0.02) and beta-carotene (P = 0.02) in subjects with the GSTM1 null genotype. Our results confirm that biomarkers of dietary intake of antioxidants significantly modulate DNA adducts and suggest specific inverse associations between DNA adduct levels and antioxidant concentrations among GSTM1 null subjects and smokers.