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Aim Male breast cancer (MBC) is a rare disease and recommendations for its clinical management are often extrapolated from those for female breast cancer, even if breast cancer (BC) has different characteristics in the two sexes. The purpose of this study was to assess the influence of several individual characteristics including clinico-pathological, lifestyle and genetic factors on overall survival (OS) of a relatively large and well characterized population-based series of 166 MBCs enrolled in Tuscany. Methods We genotyped MBC cases at BRCA1/2 genes and at 9 candidate BC susceptibility SNPs. Kaplan-Meier method and multivariate Cox regression, adjusted for several individual characteristics were used. To reduce a possible selection bias related to the interval between diagnosis and enrolment of MBC cases into the study, we used the date of blood donation as the date of the start of observation for survival analysis. Results Only smoking habits had a significant effect on OS at 10 years (for current smokers, HR: 3.34; 95% CI 1.45–7.68; p = 0.004), while lymph node status fell short of reaching statistical significance (for pN positive, HR: 2.07; 95% CI 0.93–4.55; p = 0.07). In the same multivariate analysis we found a significantly higher OS in cases with FGFR2 rs2981582 variant in the dominant transmission model (HR: 0.29; 95% CI: 0.13–0.62; p = 0.028). A sensitivity analysis with left truncation showed similar results. Conclusions Our results may contribute to shed light on factors influencing MBC survival suggesting an important role for cigarette smoking and FGFR2 rs2981582 variant, and provide clues for better patient management.

Introduction: This retrospective study analyzes the safety and feasibility of concurrent chemoradiotherapy (CRT) in adjuvant treatment of soft tissue sarcoma (STS). Methods: A total of 158 patients with STS were retrospectively analyzed. Anthracycline-based computed tomography was performed in high-risk patients. Acute radiotherapy toxicity and chemotherapy-related toxicity were assessed according to the Common Terminology Criteria for Adverse Events 4.0; late radiotherapy toxicity was recorded according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. Results: Fifty-four (34.2%) patients received CRT. Mean follow up was 5.4 years (range .2–21.1 years). Local DFS–recurrence-free survival, distant DFS–relapse-free survival, and overall survival were 79.1%, 76.4%, and 64.6%, respectively, at last follow-up. Leukopenia occurred in 11.4% of patients. Skin acute toxicity developed in 60.1% of patients and determined interruption of radiotherapy treatment in 19 (12%) patients. Nineteen patients (12%) experienced moderate fibrosis (grade 2). Mild and moderate joint stiffness was recorded in 16 (10.1%) patients. Size ≥5 cm was the only predictor of local recurrence at multivariate analysis (hazard ratio [HR] 9.65, 95% confidence interval [CI] 1.28–72.83, p = .028). Age and stage resulted as independent distant relapse predictors (HR 4.77, 95% CI 1.81–12.58, p = .002 and HR 4.83, CI 1.41–16.57, p = .012, respectively). At Cox regression univariate analysis, Karnofsky Performance Status, size, and stage were significant survival predictors (HR 2.23, 95% CI 1.02–4.87, p = .045; HR 2.88, 95% CI 1.10–7.52, p = .031; HR 2.59, 95% CI 1.11–6.04, p = .028). Conclusions: Concurrent CRT is a well-tolerated treatment option with no additional toxicity compared to exclusive radiotherapy or sequential CRT.

Several studies in recent years have investigated the relationship between alcohol intake and melanoma risk, with conflicting results. To help clarify this issue, we conducted a literature review and dose–response meta-analysis of studies published until June 30th, 2017, that examined the association between alcohol intake (overall and by beverage type) and melanoma risk. We used random effect models with maximum likelihood estimation to calculate summary relative risk (SRR) and 95% confidence intervals (95%CI). We included 20 independent studies (encompassing 10,555 melanoma cases and over 1.6 million non-cases/controls) published during 1986–2016, of which six had a prospective cohort study design. Adjustment for phenotypic characteristics and sunlight exposure was performed in 11 and nine studies, respectively. Alcohol intake was moderately associated with melanoma risk: the SRR were 1.29 (95% CI 1.14–1.45) for those in the highest vs. lowest category of current alcohol intake, and 1.96 (95% CI 1.02–3.76, I2 = 0%) for cumulative intake. In the dose–response analysis, the increase in risk associated with a 10 g increment in daily alcohol intake was 1.07 (95% CI 1.03–1.11). Risk estimates did not differ by gender, study design and adjustment for confounders; between-studies heterogeneity was acceptable, and there was no evidence of publication bias. Our findings suggest that alcohol drinking may be moderately associated with increased melanoma risk, although residual confounding and bias cannot be ruled out. Further research is needed to confirm these findings, clarify the role of the different alcohol sources, and investigate the interaction with known melanoma risk factors.

IMPORTANCE: Several studies have evaluated cardioprotective strategies to prevent myocardial dysfunction in patients who are receiving cardiotoxic therapies. However, the optimal approach still represents a controversial issue. OBJECTIVE: To determine whether pharmacological cardioprevention could reduce subclinical heart damage in patients with breast cancer who are being treated with anthracycline-based chemotherapy. DESIGN, SETTING, AND PARTICIPANTS: The SAFE trial was a 4-arm, randomized, phase 3, double-blind, placebo-controlled, national multicentric study conducted at 8 oncology departments in Italy. It was a prespecified interim analysis on the first 174 patients who had completed cardiac assessment at 12 months. The study recruitment was conducted between July 2015 and June 2020. The interim analysis was performed in 2020. Patients were eligible for trial inclusion if they had indication to receive primary or postoperative systemic therapy using an anthracycline-based regimen. Patients with a prior diagnosis of cardiovascular disease were excluded. INTERVENTIONS: Cardioprotective therapy (bisoprolol, ramipril, or both drugs compared with placebo) was administered for 1 year from the initiation of chemotherapy or until the end of trastuzumab therapy in case of ERBB2-positive patients. Doses for all groups were systematically up-titrated up to the daily target dose of bisoprolol (5 mg, once daily), ramipril (5 mg, once daily), and placebo, if tolerated. MAIN OUTCOMES AND MEASURES: The primary end point was defined as detection of any subclinical impairment (worsening ≥10%) in myocardial function and deformation measured with standard and 3-dimensional (3D) echocardiography, left ventricular ejection fraction (LVEF), and global longitudinal strain (GLS). RESULTS: The analysis was performed on 174 women (median age, 48 years; range, 24-75 years) who had completed a cardiological assessment at 12 months and reached the end of treatment. At 12 months, 3D-LVEF worsened by 4.4% in placebo arm and 3.0%, 1.9%, 1.3% in the ramipril, bisoprolol, ramipril plus bisoprolol arms, respectively (P = .01). Global longitudinal strain worsened by 6.0% in placebo arm and 1.5% and 0.6% in the ramipril and bisoprolol arms, respectively, whereas it was unchanged (0.1% improvement) in the ramipril plus bisoprolol arm (P

Simple Summary Vitamin D has been extensively studied in relation to cancer risk at several body sites, but its relationship with non-melanoma skin cancer (NMSC), the most frequent malignancy in humans, is still unclear. Here, we performed a systematic literature search and meta-analysis of published studies and did not find convincing evidence that a causal association exists between vitamin D intake (from foods and supplements), vitamin D blood concentration, or polymorphisms of the genes coding for the vitamin D receptor and binding protein, and NMSC risk. Abstract 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.

Background and aim: Over the last decades, the incidence of melanoma has been steadily growing, with 4.2% of the population worldwide affected by cutaneous melanoma (CM) in 2020 and with a higher incidence and mortality in men than in women. We investigated both the risk factors for CM development and the prognostic and predictive factors for survival, stratifying for both sex and gender. Methods: We conducted a systematic review of studies indexed in PUB-MED, EMBASE, and Scopus until 4 February 2021. We included reviews, meta-analyses, and pooled analyses investigating differences between women and men in CM risk factors and in prognostic and predictive factors for CM survival. Data synthesis: Twenty-four studies were included, and relevant data extracted. Of these, 13 studies concerned potential risk factors, six concerned predictive factors, and five addressed prognostic factors of melanoma. Discussion: The systematic review revealed no significant differences in genetic predisposition to CM between males and females, while there appear to be several gender disparities regarding CM risk factors, partly attributable to different lifestyles and behavioral habits between men and women. There is currently no clear evidence of whether the mutational landscapes of CM differ by sex/gender. Prognosis is justified by a complex combination of phenotypes and immune functions, while reported differences between genders in predicting the effectiveness of new treatments are inconsistent. Overall, the results emerging from the literature reveal the importance of considering the sex/gender variable in all studies and pave the way for including it towards precision medicine. Conclusions: Men and women differ genetically, biologically, and by social construct. Our systematic review shows that, although fundamental, the variable sex/gender is not among the ones collected and analyzed.

Background and aims The relevant role of physical activity (PA) in cardiovascular risk prevention is widely agreed. We aimed to evaluate, in a large Mediterranean population, the influence of PA on systolic (SBP) and diastolic blood pressure (DBP), taking into account individual characteristics and lifestyle habits. Methods and results In the Florence section of the European Prospective Investigation into Cancer and Nutrition 10,163 individuals, 35–64 years, without a previous diagnosis of hypertension were recruited. Information on occupational and leisure-time PA and blood pressure were collected at recruitment, together with data on lifestyle, dietary habits and anthropometry. Multivariate regression models were applied to evaluate the effect of total, occupational and leisure-time PA on SBP and DBP. Mean values of SBP and DBP in the study subjects were 124.4 (SD 15.6) and 79.7 mmHg (SD 9.4), respectively. Overall, a total PA index and an index including cycling, fitness and occupational PA (Cambridge index) were inversely associated with DBP (beta −0.87, p -value 0.02 actives vs inactives, p for trend 0.02 and beta −0.84, p value 0.003 actives vs inactives, p for trend 0.002, respectively), while SBP was associated only with the latter index (beta −1.14, p -value 0.01 actives vs inactives, p for trend 0.006). An inverse association emerged between manual/heavy manual occupation and DBP ( p 0.02, ref sedentary/standing occupation) and between increasing cycling activity and SBP ( p for trend 0.04). Conclusions In this large cohort of Mediterranean adults without a diagnosis of hypertension we confirm the role of overall PA in modulating SBP and DBP values. Cycling and manual occupations were associated with lower DBP values.

Ductal carcinoma in situ (DCIS) is a heterogeneous disease, for which the best adjuvant treatment is still uncertain. Many attempts of risk-groups stratification have been made over time, developing prognostic scores to predict risk of local recurrence (LR) on the basis of features such as age, final surgical margins (FSM) status, grade, and tumor size. The aim of our analysis was to evaluate the patterns of recurrence from a two large-institutional retrospective series.We collected data on 457 patients treated with BCS and adjuvant RT between 1990 and 2012. Final analysis was performed on 278 patients, due to missing data about hormonal status (HS). Patients were treated at the Radiation Oncology Unit of the University of Florence (n = 195), and S. Maria Annunziata Hospital (n = 83) (Florence, Italy).At a median follow up time of 10.8 years (range 3-25), we observed 20 LR (7.2%). The 5-year and 10-year LR rates were 4.9% and 10.2%, respectively. At Cox regression univariate analysis, estrogen receptor (ER) positive status (p = 0.001), HS positive (p = 0.003), and FSM1 mm (p = 0.0001) significantly impacted on LR. At Cox regression multivariate analysis positive ER status maintained a protective role (p = 0.003), and FSM status1 mm its negative impact (p = 0.0001) on LR rate.Our experience confirmed the wide heterogeneity of DCIS. Inadequate FSM and negative ER status negatively influenced LR rates. Tumor biology should be integrated in adjuvant treatment decision-making process.

Background Alcohol-use disorders (AUDs), including alcohol dependence and alcohol abuse defined according to specific DSM-IV and ICD-X criteria, can be potentially lethal, since they are associated with several medical and psychiatric conditions. This study aims to describe the causes of hospitalization of a large cohort of subjects with alcohol dependence (alcoholics) enrolled in Florence (Italy) over a 5-year follow-up period and to evaluate the effect of hospitalization on overall survival. Methods Eleven-hundred-thirty (1,130) alcoholics, newly diagnosed from 1997-2001, were linked to the Regional Mortality Registry for update of vital status as of December 31, 2006 and to the Hospital Discharge electronic archives of the Regional Health System of Tuscany to verify hospital admissions during the 5-year post cohort enrollment follow-up. Kaplan-Meier survival and Cox regression analyses were performed to evaluate any association of hospital admission with overall survival. Results A total of 3,916 new hospitalizations occurred during the 5-year follow-up. Most alcoholics (70.6%) reported at least 1 new hospitalization, with a first hospitalization rate of 61.7 per 100 person-years in the first year of follow-up. The mean number of hospitalizations per admitted subject was 4.87 (SD:7.4) and mean length of hospital stay was 8.5 days (SD:11.3). The main causes of hospitalization were mental disorders and diseases of the digestive system, as well as accidents or violence. Among those alcoholics alive after 1 year of follow-up, a significantly increased risk of dying in the following years could be predicted by early hospitalization in the 12 months preceding (HR 1.73; 95% CI 1.15-2.60) or following (HR 3.59; 95% CI 2.31-5.61) enrollment in the cohort. Conclusions Our results confirm the association of AUDs with several serious medical conditions. This fact may be responsible for a high impact on health resource utilization and high social costs. Early hospitalization significantly predicts vital status at 5 years. This article is protected by copyright. All rights reserved.

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.

Background. Accelerated partial breast irradiation (APBI) represents a valid option for selected early breast cancer (BC); potential advantages of APBI include shorter treatment time, improved safety profile, and a cost reduction compared with standard fractionation. We reported the final analysis of quality of life (QOL) results from a phase 3 randomized trial comparing standard adjuvant radiotherapy (50 Gy in 25 fractions, plus 10 Gy boost) to APBI using IMRT technique (30 Gy in 5 daily fractions). The 5-year results have been recently published showing equivalence in terms of local control (ClinicalTrials.gov, NCT02104895). Methods. Overall 205 patients (105 APBI and 100 WBI) fully completed the given questionnaires at time 0 (RT start), time 1 (RT end), and time 2 (2-year follow up). Patients were asked to compile two specific questionnaires on QOL, the EORTC QLQ-C30 as a reliable and valid measure of the QOL of cancer patients in multicultural clinical research settings, and the BR23 module as a supplementary questionnaire for assessing QOL issues relevant to patients with BC. The statistical software SPSS (SPSS Inc, Chicago, IL, USA) for Windows (version 22), and STATA (StataCorp LP, College Station TX77845, USA) for Windows (version 12) were used. Chi-squared test or Mann Whitney U test were used to compare the individual characteristics of the patients between two arms. Mean and standard deviations (SD) were calculated for all QOL domains, and all scores were compared between APBI and WBI arms using the Mann Whitney test due to non-parametric distribution of data. The Kruskal-Wallis test was used to compare the scores between age groups. Results. Mean values (and SD) of QLQ-C30 scores according to arm in the series of 205 BC patients at time 2 (time 0 vs time 2), showed significant improvement in favor of APBI in terms of global health status (mean 75.5 vs 59.5, SD range 13.3-22.0; p Conclusions. Women treated with APBI reported a significantly better QOL outcome as compared with women treated using WBI. QOL improvement was evidenced in terms of functional, symptoms, and global health status/QOL scales, both at the end of radiation and at a 2-year follow-up time. Citation Format: Meattini I, Saieva C, Desideri I, Miccinesi G, Francolini G, Meacci F, Muntoni C, Scotti V, De Luca Cardillo C, Marrazzo L, Simontacchi G, Pallotta S, Sanchez L, Casella D, Bernini M, Orzalesi L, Nori J, Bianchi S, Livi L. Accelerated partial breast irradiation versus whole breast irradiation: Health-related quality of life analysis from a phase 3 trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-10-04.

Background. Several randomized trials demonstrated aromatase inhibitors (AI) superiority in terms of disease-free survival compared to tamoxifen treatment for postmenopausal hormone receptor-positive breast cancer (BC) patients. Anyway AI toxicity profile due to estrogen suppression is a concern. Pivotal trials demonstrated a significant bone mineral density (BMD) loss due to AI, with a consistent risk of fractures, thus impacting on patients' quality of life. Bisphosphonates represent an effective treatment in postmenopausal osteoporosis fractures prevention. Several studies demonstrated that upfront bisphosphonates therapy prevents bone loss in postmenopausal women receiving adjuvant AI for early-stage BC. However an adequate patients selection for adjuvant bisphosphonates treatment during AI endocrine therapy is still a challenge. We present the final results of the BONADIUV trial, a single-blind, randomized, placebo-controlled phase 2 study designed to evaluate the impact of ibandronate treatment on BMD in osteopenic women taking AI. Methods. Between January 2011 and May 2014, 561 patients underwent a baseline BMD assessment before starting AI as planned adjuvant treatment. Overall 171 osteopenic patients (lumbar spine [LS] and/or trochanter -1< T-score Results. A total of 171 patients were randomized in the study. Overall 27 patients (15.8%) withdrew the protocol (17 ibandronate vs 10 placebo arm): the final analysis was performed on 144 patients (72 patients per arm). P-value from Wilcoxon test showed no significant difference between arms at baseline both for LS (p=0.94) and trochanter (p=0.83). At 2-year, osteopenic patients treated with ibandronate gained +18.7% and +15.5% at the LS and trochanter BMD, respectively. Patients treated with placebo lost -13.3% at the LS, and gained +2.9% at the trochanter. Trochanter p-value from covariance analysis showed a mean BMD change significantly in favor of ibandronate arm at 1-year (p=0.012), and borderline at 2-year (p=0.087). Concerning LS, the mean BMD change was significantly in favor of ibandronate arm both at 1-year (p=0.002) and 2-year (p Conclusions. Final results of our study showed that treatment with ibandronate, as compared to placebo, improved BMD change in osteopenic women treated with adjuvant AI, and consistently protected patients' bone loss. Citation Format: Livi L, Saieva C, Desideri I, Scotti V, De Luca Cardillo C, Carta G, Cecchini S, Orzalesi L, Sanchez LJ, Casella D, Bernini M, Nori J, Bianchi S, De Feo ML, Meattini I. A single-blind, randomized, placebo-controlled phase II study to evaluate the impact of oral ibandronate on bone mineral density in osteopenic breast cancer patients receiving adjuvant aromatase inhibitors: Final results of the single-center BONADIUV trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-09-12.

Radiosurgery (RS) is a well-established treatment in selected patients with brain metastasis. The aim of this study is to compare the differences between CyberKnife (CK) and TomoTherapy (HT) treatment plans of RS of single brain metastasis (BM) to define when HT should be used in cases beyond Cyberknife—when both systems are readily available for the radiation oncologist. Nineteen patients with single brain metastasis treated with CK were re-planned for radiosurgery using TomoTherapy Hi-ART system. Two planning approaches have been used for TomoTherapy plans: the classical one (HT) and the improved conformity (icHT) that produces dose distributions more similar to those of RS plans. PTV coverage, Conformity Index (CI), Paddick Conformity Index (nCI), Homogeneity Index (HI), Gradient Index (GI), and beam on time of CK, HT, and icHT plans were evaluated and compared. A good coverage was found for CK, HT, and icHT plans. A difference between mean HI of CK and icHT plans was observed (p = 0.007). Better dose gradients compared to both icHT and HT modalities were observed in CK plans. icHT modality showed improved mean CI respect to HT modality, similar to that obtained in CK plans. CK plans show higher conformity and lower GI than icHT and HT plans. TomoTherapy demonstrates the advantage of being a device capable to reach different clinical objectives depending on the different planning modality employed. CyberKnife and TomoTherapy are both optimal RS devices, the choice to use one over another has to be clinically guided.

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Background: For decades, conventional fractionated whole breast irradiation (CF-WBI) was used after breast conserving surgery (BCS). Pivotal phase-3 trials on hypofractionated-WBI (HF-WBI) showed i...

Aims: The hypothesis of ‘metabolically healthy obesity’ implies that, in the absence of metabolic dysfunction, individuals with excess adiposity are not at greater cardiovascular risk. We tested this hypothesis in a large pan-European prospective study. Methods and results: We conducted a case-cohort analysis in the 520 000-person European Prospective Investigation into Cancer and Nutrition study (‘EPIC-CVD’). During a median follow-up of 12.2 years, we recorded 7637 incident coronary heart disease (CHD) cases. Using cut-offs recommended by guidelines, we defined obesity and overweight using body mass index (BMI), and metabolic dysfunction (‘unhealthy’) as >_ 3 of elevated blood pressure, hypertriglyceridaemia, low HDL-cholesterol, hyperglycaemia, and elevated waist circumference. We calculated hazard ratios (HRs) and 95% confidence intervals (95% CI) within each country using Prentice-weighted Cox proportional hazard regressions, accounting for age, sex, centre, education, smoking, diet, and physical activity. Compared with metabolically healthy normal weight people (reference), HRs were 2.15 (95% CI: 1.79; 2.57) for unhealthy normal weight, 2.33 (1.97; 2.76) for unhealthy overweight, and 2.54 (2.21; 2.92) for unhealthy obese people. Compared with the reference group, HRs were 1.26 (1.14; 1.40) and 1.28 (1.03; 1.58) for metabolically healthy overweight and obese people, respectively. These results were robust to various sensitivity analyses. Conclusion: Irrespective of BMI, metabolically unhealthy individuals had higher CHD risk than their healthy counterparts. Conversely, irrespective of metabolic health, overweight and obese people had higher CHD risk than lean people. These findings challenge the concept of ‘metabolically healthy obesity’, encouraging population-wide strategies to tackle obesity., European Union (EU) HEALTH-F2-2012-279233, European Research Council (ERC) 268834, Medical Research Council UK (MRC) G0800270 MR/L003120/1 MR/M012190/1, British Heart Foundation SP/09/002 RG/08/014 RG13/13/30194, National Institute for Health Research (NIHR), Regional Government of Asturias, Hellenic Health Foundation, German Cancer Aid, German Cancer Research Centre, German Federal Ministry of Education and Research, Cancer Research UK 570/A16491, Regione Sicilia, Associazione Iblea per la Ricerca Epidemiologica (A.I.R.E.) - ONLUS Ragusa, Associazione Volontari Italiani Sangue AVIS Ragusa, Compagnia di San Paolo, Human Genetics Foundation-Torino (HuGeF), British Heart Foundation RG/13/13/30194 RG/08/014/24067, Cancer Research UK 16491, Medical Research Council UK (MRC) MR/L003120/1 G0800270 MC_UU_12015/1, National Institute for Health Research (NIHR) NF-SI-0512-10135 NF-SI-0512-10165, Novo Nordisk Foundation NNF17OC0026936

Background: Lead exposure, even at low levels, is associated with adverse health effects in humans. We investigated the determinants of individual lead levels in a general population-based sample of adults from Florence, Italy. Methods: Erythrocyte lead levels were measured (using inductively coupled plasma-mass spectrometry) in 454 subjects enrolled in the Florence cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC) study in 1992&ndash, 1998. Multiple linear regression models were used to study the association between demographics, education and working history, lifestyle, dietary habits, anthropometry, residential history, and (among women) menstrual and reproductive history and use of exogenous sex hormones, and erythrocyte lead levels. Results: Median lead levels were 86.1 &mu, g/L (inter-quartile range 65.5&ndash, 111.9 &mu, g/L). Male gender, older age, cigarette smoking and number of pack-years, alcohol intake, and residing in urban areas were positively associated with higher erythrocyte lead levels, while performing professional/managerial or administrative work or being retired was inversely associated with lead levels. Among women, lead levels were higher for those already in menopause, and lower among those who ever used hormone replacement therapy. Conclusions: Avoidable risk factors contribute to the lead body burden among adults, which could therefore be lowered through targeted public health measures.

BACKGROUND AND PURPOSE Breast-conserving surgery (BCS) and whole breast radiation (RT) with or without endocrine therapy (ET) represent the standard of care for ductal carcinoma in situ (DCIS). The use of adjuvant treatments after surgery is still controversial in this setting. We performed a retrospective multicenter analysis on a series of DCIS patients treated with BCS and adjuvant RT. MATERIALS AND METHODS We collected clinical data from nine Italian centers on 1072 women having a diagnosis of DCIS and treated between 1997 and 2012. We reported on the 5- and 10-year local recurrence (LR) rates, overall survival, and breast cancer specific survival (BCSS) employing the Kaplan-Meier method. RESULTS At a median follow-up of 8.4 years, 67 LR (6.3%) and 47 deaths (4.4%) were observed. LR rates at 5 and 10 years were 3.4% and 7.6%, respectively. BCSS rates at 5 and 10 years were 99.7% and 99.1%, respectively. At univariate regression analysis, postmenopausal state (p = 0.009), estrogen receptor (ER) (p = 0.0001) and progesterone receptor (p = 0.018) positivity and ET (p = 0.006) were inversely correlated with LR. Final surgical margins (FSM) status

Background There is no consensus on the leading causes of death among inflammatory bowel diseases (IBD) patients. Aim We present the results of an extended follow-up of the population-based Florence IBD cohort, including 689 ulcerative colitis and 231 Crohn's disease patients. Methods The causes of death of cohort members were determined through linkage with the local mortality registry. We calculated standardized mortality ratios (SMR) and 95% confidence intervals (95%CI) by applying gender-, age- and calendar time–death rates to person-years at risk. Results Ulcerative colitis patients had overall mortality comparable to the general population (SMR 0.99, 95%CI 0.85–1.14), though being at increased risk of dying from Hodgkin's disease (SMR 11.74, 95%CI 2.94–46.94), rectal cancer (SMR 3.69, 95%CI 1.66–8.22) and Alzheimer's disease (2.40, 95%CI 1.00–5.76). Crohn's disease patients had an increased overall mortality (SMR 1.79, 95%CI 1.39–2.27) and were at higher risk of dying from cancer (SMR 2.57, 95%CI 1.28–5.13) and non-cancer diseases of the respiratory system (SMR 2.51, 95%CI 1.05–6.04), brain cancer (SMR 6.26, 95%CI 1.57–25.02) and non-cancer diseases of the genitourinary system (SMR 4.38, 95%CI 1.10–17.52). Conclusions IBD patients should be offered counselling on risk reduction strategies, as much of their mortality excess is potentially avoidable.

Objectives To present our experience with a sigmoid orthotopic neobladder. Methods We retrospectively evaluated the functional and oncological outcomes of 160 patients who underwent orthotopic neobladder reconstruction using a detubularized 20–25-cm sigmoid segment at our institution. Each patient was evaluated every 3 months the first year, every 6 months for the next 4 years and annually thereafter. Urodynamic studies of all consenting patients were carried out after 6 months, and 2, 5 and 10 years. We carried out the log–rank test, and used Cox regression models and Kaplan–Meier survival analysis. The anova test was used to compare urodynamic findings over time. Results Mean follow up was 6.8 years (range 0.65–21.7 years). Overall survival was 58.1% at 5 years, and 47.1% at 10 years. Early complications occurred in 36 patients (22.6%); late complications in 40 (25%). Stage V chronic kidney disease developed in two patients (1.3%). Complete (daytime and night-time) continence, defined as no need for pads or condom devices, was achieved by 45% of patients at 5 years, daytime continence was achieved by just 36% of patients; both were unchanged at 10 years. A significant difference emerged in maximal neobladder capacity and post-void residual values between 6 months and 2 years, and between 2 and 5 years (P < 0.01 and P = 0.03, respectively). Conclusions Sigmoid neobladder continence and capacity significantly improve over the first 5 years, and they remain stable over the long term. Upper urinary tract function is not affected by endoluminal pressure, and the rate of metabolic imbalance is negligible.

Aim: This study analyzes our single-center, retrospective experience on 63 premenopausal breast cancer patients treated with monthly triptorelin and concomitant chemotherapy. Patients & methods: Concomitant chemotherapy and triptorelin were adopted as part of premature ovarian failure prevention strategy. Results: Age at diagnosis was the main factor influencing fertility preservation (p = 0.002). Compared with patients aged 41–45 years, the probability of menses resumption was almost threefold than for women aged 35–40 years, and significantly higher for women aged

Introduction. Accelerated partial breast irradiation (APBI) represents a valid option for selected early breast cancer (BC); potential advantages of APBI include shorter treatment time, improved safety profile, and a cost reduction compared with standard fractionation. We recently published the 5-years results of a phase 3 randomized trial (NCT02104895), showing a very low rate of disease failure. A significant impact on patients compliance in terms of acute and late toxicity was shown. The purpose of the present analysis is to compare the quality of life (QoL) of women with BC treated with either APBI or whole breast irradiation (WBI). Methods. Eligible patients were women aged more than 40 years with early BC suitable for breast conserving surgery. At the end of radiotherapy, patients were asked to compile the EORTC QLQ-C30 as a reliable and valid measure for cancer patients in multicultural clinical research settings, and the BR23 module as a supplementary questionnaire for issues relevant to patients with BC. Overall 205 patients (105 APBI and 100 WBI) fully completed the given questionnaires. Results. The scores of the functional and symptom scales of QLQ-C30 are reported in Table 1 and Table 2, respectively. Significant differences between the two arms emerged by global health status (p=0.0001) and most functional and symptom scales, with better outcomes in the APBI arm. Women treated with APBI reported a significantly better QoL in terms of physical, role, emotional and social functioning. We also found in the APBI arm better outcomes in term of symptoms (fatigue, pain, dyspnoea, insomnia, appetite loss). Concerning the functional and symptom scales of BR23 module, the body image perception and the future perspective were significantly better in the APBI group; no significant difference emerged for sexual functioning. Significant differences emerged also for symptom scales (breast and arm symptoms), with better scores for APBI group. Conclusion. Overall, women treated with APBI reported a significantly better short-term QoL outcome as compared with women treated using WBI. QLQ-C30 functional scale scores in the series: difference between arms and p-value from Mann Whitney U testDomainAPBISDWBISDScore Differencep-valueQL2, mean66.418.849.718.1+16.70.0001PF2, mean86.215.277.717.3+8.50.0001RF2, mean88.519.276.821.6+11.70.0001EF, mean78.617.666.324.3+12.30.0001CF, mean86.818.281.717.8+5.10.014SF, mean88.919.482.319.5+6.60.003QL2, global health status; PF2, physical functioning; RF2, role functioning; EF, emotional functioning; CF, cognitive functioning; SF, social functioning QLQ-C30 symptom scale scores in the series: difference between arms and p-value from Mann Whitney U testDomainAPBISDWBISDScore Differencep-valueFA, mean21.618.735.821.2-14.20.0001NV, mean5.29.68.011.2-2.80.047PA, mean13.219.323.719.6-10.50.0001DY, mean12.421.320.323.6-7.90.006SL, mean19.724.828.725.1-9.00.004AP, mean5.713.420.024.2-14.30.0001CO, mean13.020.420.723.6-7.70.01DI, mean4.814.95.014.5-0.20.88FI, mean14.931.08.014.3+6.90.67FA, fatigue; NV, nausea-vomiting; PA, pain; DY, dyspnoea; SL, insomnia; AP, appetite loss; CO, constipation; DI, diarrhoea; FI, financial difficulties Citation Format: Meattini I, Miccinesi G, Saieva C, Desideri I, Di Brina L, Francolini G, Scotti V, De Luca Cardillo C, Livi L. Accelerated partial breast irradiation versus whole breast irradiation: short term quality of life results from a phase 3 trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-12-24.

566 Background: The impact of age on local recurrence rate of patients affected by early breast cancer is still unclear. The standard of care for older adult largely varies depending on patient- and tumor-related features, but also on national guidelines. We recently presented the 10 years median follow update of the APBI-IMRT Florence phase III trial. The primary aim of the present analysis is to identify the potential relationship between age and ipsilateral breast tumor recurrence (IBTR) in this setting of patients. Methods: This retrospective analysis was performed on the whole series of 520 patients who were enrolled in the trial after breast conserving surgery and randomized to receive APBI or whole breast irradiation. We analyzed patients stratified by age (70+ vs 40-69 years). Results: At a median follow up time of 10.7 years, we recorded 15 IBTR events. Four hundred and three patients (77.5%) were aged less than 70 years old (11 IBTR) and 117 patients (22.5%) were aged 70 years or older (4 IBTR). At the univariate analysis the age (70+ vs 40-69 years) was not significantly correlated with IBTR occurrence (HR 1.33, 95% CI 0.42-4.17; p=0.63). The only significant prognostic factor was adjuvant endocrine therapy, also at the multivariable analysis (HR 0.26, 95% CI 0.07-0.94; p=0.041). Main results are summarized in the table. Within the luminal-like patients (n=437; 12 IBTR events), the age did not impact on the IBTR rate (HR 0.91, 95% CI 0.19-4.31; p=0.91) and adjuvant endocrine therapy lost its significance (HR 0.32, 95% CI 0.09-1.11; p=0.072). Conclusions: Our trial subanalysis did not demonstrate a significant effect of age on IBTR rate for early breast cancer patients receiving a breast conserving therapy. Due to the low number of events, the benefit of adjuvant endocrine therapy is unclear and calls for further investigations. Clinical trial information: NCT02104895 . [Table: see text]

To report on the safety and clinical benefit of robotic stereotactic radiotherapy (SBRT) for liver oligometastatic colorectal cancer (CRC). Robotic SBRT was applied to oligometastatic CRC patients, defined as having 1–4 liver metastases and absent or controlled extrahepatic disease. The intended prescription dose was 37.5 Gy in three fractions. Treatment efficacy was estimated by clinical benefit rate (CBR), progression-free survival (PFS) and overall survival (OS). Toxicity was graded according to CTC-AE scale, v. 4.03. Regression analysis was performed to search for the presence of any predictive factors. Between 2012 and 2017, 38 patients (66 lesions) were irradiated. The median delivered biological effective maximum dose (maxBED10) was 142 Gy. At a median follow-up of 11.8 months (range 3.2–58.8), the 1- and 2-year OS were 67.3% and 44.1%, respectively. Actuarial LC rates for all patients at 6 and 12 months were 64.2% and 60.4%, respectively. Local or distant progression occurred in 28 (77.8%) patients, with a 1- and 2-year PFS of 19.3% and 12.2%, respectively. The CBR was 71.4%, with no significant association with maxBED10. At multivariate analysis, the presence of extrahepatic disease had a detrimental impact on PFS (HR 3.98, 95% CI 1.77–8.93; p

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).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.NCT02616744.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).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.

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&rsquo, 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.

Background Cadmium bioaccumulates in the body and causes several adverse health effects. Understanding the primary sources of exposure is critical in order to implement effective prevention measures. Methods We included 454 adults enrolled in the Florence cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC) during 1992–98. At enrolment, information was collected on demographics, lifestyle and dietary habits using validated questionnaires; anthropometric measures were taken; and a blood sample was collected from each study participant. Information on the residential and occupational history prior to enrolment was reconstructed by phone interviews. Cadmium levels were measured in erythrocytes using inductively coupled plasma-mass spectrometry. We used multiple linear regression models to investigate the main determinants of cadmium levels. Results Median erythrocyte cadmium levels were 0.66 μg/L (inter-quartile range 0.43–1.07 μg/L). Cadmium levels were lowest in never smokers (0.50 μg/L) and highest in current smokers (1.38 μg/L). Smoking status and the number of pack-years were the strongest predictors of cadmium levels in multivariable analysis, together with erythrocyte levels of lead, and biking to work, while an inverse association emerged with consumption of red meat and dairy products and physical activity levels. Cadmium levels were higher among women than men (0.66 vs. 0.58 μg/L), and, among the former, positively associated with late menopause, nulliparity, and use of hormones for menopause. The predictors included in the multivariable model explained >40% of the variability in erythrocyte cadmium levels. Conclusions Smoking was the most important determinant of erythrocyte cadmium levels, which were also affected by dietary habits, physical activity levels, biking, and (among women) hormone-related variables. Our results are important to inform public health actions aimed at reducing the impact of potentially modifiable sources of exposure to cadmium.

Liposarcoma (LPS) is rare tumor deriving from adipocytes. LPS is classified into histological subtypes: well-differentiated (WDLPS), dedifferentiated (DDLPS), myxoid (MLPS) and pleomorphic (PLPS). A tailored approach taking into account the specificity of disease subtype and age at presentation could be helpful in delineating therapeutic management of liposarcoma. In this paper, we report a retrospective series of a single-institution cohort of patients with LPS, undergoing surgery and radiotherapy and/or chemotherapy. The aim of this study is to evaluate whether clinical characteristics, tumor- and treatment-related features affect clinical outcome in patients treated with curative intent for non-metastatic liposarcoma.Data of patients with locally advanced, non-metastatic liposarcoma treated between 1990 and 2015 were retrospectively reviewed. Data about patient, tumor and treatment features were collected. Two patients subgroups were identified according to age (cutoff: age 65 years or 65 years). Statistical analysis was performed to assess correlation between the above-cited variables and local recurrence-free survival (DFS-LR), distant metastasis-free survival, overall survival (OS) and disease-specific survival (DSS); moreover, differences in clinical outcome between the two age groups were identified.Data of 186 patients were collected. At diagnosis, 27.4% of patients were 65 years or older. At a median follow-up of 8.6 years (range 0.1-27.3 years), Kaplan-Meier (KM) survival analysis showed that LR, DM, OS and DSS were 75.5%, 76.6%, 48.1% and 72.1%, respectively. KM analysis showed that age 65, DDLPS and lower limb localization were related to LR (p = 0.001, p = 0.0001 and p = 0.0001, respectively). Association between LR, age and DDLPS persisted both at univariate (p = 0.003 and p = 0.0001, respectively) and multivariate Cox regression (CR) analysis (p = 0.024 and p = 0.002). Age, tumor depth and grading influenced distant recurrence, both at KM (p = 0.023, p = 0.026 and p = 0.016) and univariate CR (p = 0.026, p = 0.042 and p = 0.012). Age and grading were confirmed at multivariate analysis (p = 0.009 and p = 0.017). Patients with WDLPS and wide excision had significantly better OS (p = 0.001 and p = 0.03, respectively), while histological G3 and age 65 were related with worse OS (p = 0.008 and p = 0.0001, respectively). Age, DDLPS and grade were related to OS at univariate (p = 0.0001, p = 0.0001 and p = 0.03, respectively) and multivariate CR analysis (p = 0.031, p = 0.0001 and p = 0.001, respectively). However, analyzing the specific causes of death, female died less often for tumor-related causes, with a DSS of 91.0% compared to 57.4% of male counterpart (p = 0.005). At Kaplan-Meier analysis, postoperative radiotherapy resulted in a statistically significant better disease-specific survival than postoperative radiotherapy (82.9% vs. 46.2%, p = 0.045). High grade correlated with poorer disease-specific survival (59.3%) than intermediate and low grade (73.4% and 91.6%, respectively) (p = 0.008). Association between DSS, sex and grade persisted both at univariate (p = 0.008 and p = 0.022, respectively) and multivariate Cox regression (CR) analysis (p = 0.014 and p = 0.038). Histotype-driven schedules of treatment should be developed to take into account biological heterogeneity of this disease. Further studies are needed to stratify patients subgroup and develop tailored treatment strategies (i.e., altered fractionations and different chemotherapy regimens in aggressive subtypes), in particular more prospective trials are needed to develop treatment guidelines in elderly STS, taking into account the frailty and the peculiarity of this subgroup.

Several foods and nutrients have been independently associated with systolic (SBP) and diastolic (DBP) blood pressure values. This study aimed to evaluate the effects of combined dietary habits on SBP and DBP values in a large cohort of healthy adults, with a cross-sectional design. Adherence of participants to four a priori dietary patterns was considered: the Healthy Eating Index 2010 (HEI-2010); the Dietary Approaches to Stop Hypertension (DASH); the Greek Mediterranean Diet Score (MDS); and the Italian Mediterranean Index (IMI). Overall, 13,597 volunteers (35–64 years) were enrolled in 1993–1998 in the EPIC-Florence cohort. Information on dietary habits, anthropometry, smoking status, education, physical activity habits, previous diagnosis of hypertension and SBP and DBP measurements were collected at baseline. Multivariate regression models were performed on 10,163 individuals (7551 women) after excluding subjects with prevalent hypertension. IMI, DASH and HEI-2010 were significantly and inversely associated with SBP and DBP values in the total population. The strongest association emerged between IMI and SBP (β − 1.80 excellent adherence vs low adherence, 95% CI − 2.99; − 0.61, p trend 0.001) and DBP (β − 1.12, 95% CI − 1.869; − 0.39, p trend 0.001) values. In sub-group analyses, an inverse association also emerged between IMI and SBP and DBP values among females and between DASH and DBP among males. MDS was not associated with SBP or DBP. Overall, this study, carried out in a large cohort of healthy adults from Tuscany (Central Italy), showed inverse significant associations between specific a priori dietary patterns, identifying general models of health-conscious diet, and blood pressure values.

OBJECTIVE:To investigate the association between alcohol consumption (at baseline and over lifetime) and non-fatal and fatal coronary heart disease (CHD) and stroke. DESIGN:Multicentre case-cohort study. SETTING:A study of cardiovascular disease (CVD) determinants within the European Prospective Investigation into Cancer and nutrition cohort (EPIC-CVD) from eight European countries. PARTICIPANTS:32 549 participants without baseline CVD, comprised of incident CVD cases and a subcohort for comparison. MAIN OUTCOME MEASURES:Non-fatal and fatal CHD and stroke (including ischaemic and haemorrhagic stroke). RESULTS:There were 9307 non-fatal CHD events, 1699 fatal CHD, 5855 non-fatal stroke, and 733 fatal stroke. Baseline alcohol intake was inversely associated with non-fatal CHD, with a hazard ratio of 0.94 (95% confidence interval 0.92 to 0.96) per 12 g/day higher intake. There was a J shaped association between baseline alcohol intake and risk of fatal CHD. The hazard ratios were 0.83 (0.70 to 0.98), 0.65 (0.53 to 0.81), and 0.82 (0.65 to 1.03) for categories 5.0-14.9 g/day, 15.0-29.9 g/day, and 30.0-59.9 g/day of total alcohol intake, respectively, compared with 0.1-4.9 g/day. In contrast, hazard ratios for non-fatal and fatal stroke risk were 1.04 (1.02 to 1.07), and 1.05 (0.98 to 1.13) per 12 g/day increase in baseline alcohol intake, respectively, including broadly similar findings for ischaemic and haemorrhagic stroke. Associations with cardiovascular outcomes were broadly similar with average lifetime alcohol consumption as for baseline alcohol intake, and across the eight countries studied. There was no strong evidence for interactions of alcohol consumption with smoking status on the risk of CVD events. CONCLUSIONS:Alcohol intake was inversely associated with non-fatal CHD risk but positively associated with the risk of different stroke subtypes. This highlights the opposing associations of alcohol intake with different CVD types and strengthens the evidence for policies to reduce alcohol consumption.

Background For decades, conventionally fractionated whole breast irradiation (CF-WBI) was used after breast conserving surgery (BCS). Pivotal phase 3 trials on hypofractionated-WBI (HF-WBI) showed its non-inferiority as compared to CF-WBI. However, younger patients ( Methods Between 2010 and 2016, a total of 786 patients aged less than 60 years old with early stage breast cancer were treated with postoperative WBI after BCS in three breast cancer centers: 340 underwent HF-WBI while 446 were treated with CF-WBI. Acute toxicity was evaluated at the end of WBI. Late toxicity was evaluated at 6, 12, 24, and 36 months. Results At univariate logistic analysis, hypofractionation showed a significant protective effect in terms of acute edema (p = 0.0001), acute wet desquamation (p = 0.009), chronic edema (p = 0.0001), chronic erythema/pigmentation (p = 0.0001), and breast fibrosis (p = 0.0002). At multivariate logistic analysis, hypofractionation was independent significant factor for acute edema (OR 0.09, 95% CI 0.02 to 0.48; p = 0.005), acute wet desquamation (OR 0.07, 95% CI 0.009 to 0.59; p = 0.014), and chronic edema (OR 0.18, 95% CI 0.04 to 0.75; p = 0.018). Significant association between individual characteristics and toxicity (grade 2 or more) are summarized in Table. Table . 215P Toxicity N Protective factor p-value OR (95%CI) Risk factor p-value OR (95%CI) Acute edema 43 Hypofractionation Dmax/Prescribed dose° 0.0001 0.001 0.09 (0.03-0.30) 0.16 (0.06-0.46) Chemotherapy 0.002 2.63 (1.42-4.90) Chronic edema 50 Hypofractionation Dmax/Prescribed dose° 0.0001 0.003 0.20 (0.09-0.44) 0.31 (0.14-0.66) EIC presence Boost dose >10 Gy Breast size >492 cc 0.0001 0.032 0.003 3.0 (1.66-5.46) 9.02 (1.21-67.45) 2.67 (1.41-5.05) Acute erythema/ pigmentation 163 HER2 positive status Trastuzumab 0.002 0.022 0.30 (0.14-0.63) 0.39 (0.18-0.87) Smoking habits Boost dose >10 Gy Breast size >492 cc 0.001 0.038 0.002 2.14 (1.37-3.32) 2.60 (1.06-6.41) 1.78 (1.24-2.54) Chronic erythema/ pigmentation 110 Hypofractionation Dmax/Prescribed dose° 0.0001 0.001 0.40 (0.25-0.63) 0.45 (0.28-0.73) EIC presence Positive FSM Boost dose >10 Gy Breast size >492 cc 0.0001 0.002 0.007 0.034 2.39 (1.54-3.71) 3.47 (1.56-7.71) 15.43 (2.08-114.3) 1.58 (1.04-2.41) Acute wet desquamation 20 Hypofractionation Dmax/Prescribed dose° 0.009 0.047 0.14 (0.03-0.61) 0.29 (0.08-0.99) - - - Breast fibrosis 117 Hypofractionation Tumor grade Ki67 index Dmax/Prescribed dose° 0.0002 0.022 0.023 0.017 0.44 (0.29-0.68) 0.53 (0.31-0.92) 0.60 (0.38-0.93) 0.58 (0.37-0.91) EIC presence Boost dose >10 Gy Breast size >492 cc 0.0001 0.022 0.0001 3.03 (1.99-4.62) 6.76 (2.04-22.45) 2.84 (1.83-4.41) Conclusions HF-WBI showed significantly improved toxicity outcomes in terms of both acute skin edema and wet desquamation, and chronic skin edema. HF-WBI after BCS should replace CF-WBI independently of age. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Perturbations in levels of amino acids (AA) and their derivatives are observed in hepatocellular carcinoma (HCC). Yet, it is unclear whether these alterations precede or are a consequence of the disease, nor whether they pertain to anatomically related cancers of the intrahepatic bile duct (IHBC), and gallbladder and extrahepatic biliary tract (GBTC). Circulating standard AA, biogenic amines and hexoses were measured (Biocrates AbsoluteIDQ-p180Kit) in a case-control study nested within a large prospective cohort (147 HCC, 43 IHBC and 134 GBTC cases). Liver function and hepatitis status biomarkers were determined separately. Multivariable conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (OR; 95%CI) for log-transformed standardised (mean = 0, SD = 1) serum metabolite levels and relevant ratios in relation to HCC, IHBC or GBTC risk. Fourteen metabolites were significantly associated with HCC risk, of which seven metabolites and four ratios were the strongest predictors in continuous models. Leucine, lysine, glutamine and the ratio of branched chain to aromatic AA (Fischer's ratio) were inversely, while phenylalanine, tyrosine and their ratio, glutamate, glutamate/glutamine ratio, kynurenine and its ratio to tryptophan were positively associated with HCC risk. Confounding by hepatitis status and liver enzyme levels was observed. For the other cancers no significant associations were observed. In conclusion, imbalances of specific AA and biogenic amines may be involved in HCC development.

Although it appears biologically plausible for iron to be associated with gastric carcinogenesis, the evidence is insufficient to lead to any conclusions. To further investigate the relationship between body iron status and gastric cancer risk, we conducted a nested case-control study in the multicentric European Prospective Investigation into Cancer and Nutrition (EPIC) study. The study included 456 primary incident gastric adenocarcinoma cases and 900 matched controls that occurred during an average of 11 years of follow-up. We measured prediagnostic serum iron, ferritin, transferrin and C-reactive protein, and further estimated total iron-binding capacity (TIBC) and transferrin saturation (TS). Odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of gastric cancer by iron metrics were estimated from multivariable conditional logistic regression models. After adjusting for relevant confounders, we observed a statistically significant inverse association between gastric cancer and ferritin and TS indices (ORlog2 = 0.80, 95% CI = 0.72-0.88; OR10%increment = 0.87, 95% CI = 0.78-0.97, respectively). These associations appear to be restricted to noncardia gastric cancer (ferritin showed a p for heterogeneity = 0.04 and TS had a p for heterogeneity = 0.02), and no differences were found by histological type. TIBC increased risk of overall gastric cancer (OR50 µg/dl = 1.13, 95% CI = 1.02-1.2) and also with noncardia gastric cancer (p for heterogeneity = 0.04). Additional analysis suggests that time between blood draw and gastric cancer diagnosis could modify these findings. In conclusion, our results showed a decreased risk of gastric cancer related to higher body iron stores as measured by serum iron and ferritin. Further investigation is needed to clarify the role of iron in gastric carcinogenesis.

Epidemiologic studies have reported that moderate alcohol consumption is inversely associated with the risk of renal cancer. However, there is no information available on the associations in renal cancer subsites. From 1992 through to 2010, 477,325 men and women in the European Prospective Investigation into Cancer and Nutrition cohort were followed for incident renal cancers (n=931). Baseline and lifetime alcohol consumption was assessed by country-specific, validated dietary questionnaires. Information on past alcohol consumption was collected by lifestyle questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from Cox proportional hazard models. In multivariate analysis, total alcohol consumption at baseline was inversely associated with renal cancer; the HR and 95% CI for the increasing categories of total alcohol consumption at recruitment versus the light drinkers category were 0.78 (0.62-0.99), 0.82 (0.64-1.04), 0.70 (0.55-0.90), 0.91 (0.63-1.30), respectively, (p(trend)=0.001). A similar relationship was observed for average lifetime alcohol consumption and for all renal cancer subsites combined or for renal parenchyma subsite. The trend was not observed in hypertensive individuals and not significant in smokers. In conclusion, moderate alcohol consumption was associated with a decreased risk of renal cancer. What's new? Previous studies have indicated that environmental or lifestyle factors may be involved in the etiology of renal cancer, and that moderate alcohol consumption may reduce the risk of this type of cancer. In this very large European study (nearly 500,000 subjects), the authors found that, indeed, total alcohol consumption was inversely associated with renal cancer overall (for all subsites combined), and also with cancers of the renal parenchyma.

Thyroid cancer has a higher incidence in women than in men, and it has been hypothesized that hormonal factors may explain such disparity. We performed a meta-analysis of observational prospective studies to investigate the association between menstrual and reproductive variables and exogenous hormone use and the risk of thyroid cancer among women.We calculated summary relative risks and 95% confidence intervals (95% CI) using random effect models.Overall, 5,434 thyroid cancer cases from twenty-four papers were included. Increasing age at first pregnancy/birth (SRR 1.56, 95% CI 1.01-2.42) and hysterectomy (SRR 1.43, 95% CI 1.15-1.78) were associated with thyroid cancer risk. Women that were in menopause at enrolment had a reduced thyroid cancer risk (SRR 0.79, 95% CI 0.62-1.01). No other menstrual, reproductive, and hormonal variable was associated with thyroid cancer risk.Menstrual and reproductive factors may play a role in the etiology of thyroid cancer, possibly through the mediation of estrogen receptors.

General obesity, as reflected by BMI, is an established risk factor for esophageal adenocarcinoma (EAC), a suspected risk factor for gastric cardia adenocarcinoma (GCC) and appears unrelated to gastric non-cardia adenocarcinoma (GNCC). How abdominal obesity, as commonly measured by waist circumference (WC), relates to these cancers remains largely unexplored. Using measured anthropometric data from 391,456 individuals from the European Prospective Investigation into Cancer and Nutrition (EPIC) study and 11 years of follow-up, we comprehensively assessed the association of anthropometric measures with risk of EAC, GCC and GNCC using multivariable proportional hazards regression. One hundred twenty-four incident EAC, 193 GCC and 224 GNCC were accrued. After mutual adjustment, BMI was unrelated to EAC, while WC showed a strong positive association (highest vs. lowest quintile HR = 1.19; 95% CI, 0.63-2.22 and HR = 3.76; 1.72-8.22, respectively). Hip circumference (HC) was inversely related to EAC after controlling for WC, while WC remained positively associated (HR = 0.35; 0.18-0.68, and HR=4.10; 1.94-8.63, respectively). BMI was not associated with GCC or GNCC. WC was related to higher risks of GCC after adjustment for BMI and more strongly after adjustment for HC (highest vs. lowest quintile HR = 1.91; 1.09-3.37, and HR = 2.23; 1.28-3.90, respectively). Our study demonstrates that abdominal, rather than general, obesity is an indisputable risk factor for EAC and also provides evidence for a protective effect of gluteofemoral (subcutaneous) adipose tissue in EAC. Our study further shows that general obesity is not a risk factor for GCC and GNCC, while the role of abdominal obesity in GCC needs further investigation.

Aim The aim of this study was to identify a subgroup of breast cancer patients in whom it is possible to avoid axillary lymph node dissection (ALND) when the sentinel lymph node (SLN) is positive. Methods A series of 292 patients treated with breast-conserving surgery or mastectomy underwent ALND after positive SLN detection. To correlate SLN metastasis with the chances of finding additional metastasis in non-SLNs we evaluated the main clinicopathological characteristics. No patients received adjuvant radiotherapy to the axillary region. Results Fifty-six patients (35.4%) with positive SLNs for macrometastases (n = 158) had additional metastases upon completion ALND compared with 7 patients (5.2%) with micrometastases in the SLN (n = 132). Cases with a higher number of positive axillary lymph nodes tended to have higher pT stage (p = 0.004). In multivariate analysis, pT was confirmed as an independent predictor of non-SLN metastases (OR = 2.40; 95% CI = 1.16-4.99). No patients with micrometastases in SLN and cancer Conclusions Our results, in agreement with the major published studies, suggest that ALND can be avoided in selected patients without the need for additional treatment to the axillary region.

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 multi-centre 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., In France, the E3N study was financially supported by the Mutuelle Générale de l'Education Nationale (MGEN), the European Community, the French League Against Cancer (LNCC); Gustave Roussy; and the French Institute of Health and Medical research (INSERM). EPIC-Greece was supported by the Hellenic Health Foundation. Support for EPIC Norfolk is from Medical Research Council UK and Cancer Research UK. EPIC-Italy was supported by the Italian Association for Cancer Research (AIRC).

Objectives: The effect of modifiable stroke risk factors in terms of prevented cases remains unclear due to sex-specific disease rate and risk factors prevalence. Our aim was to estimate their impact on stroke by gender through population-attributable fraction (PAF), preventive fraction (PF) and their combination in EPIC-Italian cohort. Methods: 43,976 participants, age 34–75, and free of cardiovascular disease at baseline (1993–1998) were followed up for almost 11 years. Adjusted hazard ratios and PAF were estimated using Cox models. Results: We identified 386 cases. In males, the burden for stroke was 17% (95% CI 4–28%) for smoking and 14% (95% CI 5–22%) for alcohol consumption. In females, hypertension was carrying the biggest burden with 18% (95% CI 9–26%) followed by smoking 15% (95% CI 7–22%). Their combination was 46% (95% CI 32–58%) in males and 48% (95% CI 35–59%) in females. PF for current smokers was gender unequal [males 21% (95% CI 15–27%) females 9% (95% CI 1–17%)]. Conclusions: Half of strokes are attributable to potentially modifiable factors. The proportion of prevented cases is gender unbalanced, encouraging sex-specific intervention.

Breast cancer (BC) is the most frequent cancer among women in developed countries. Physical activity (PA), body mass index (BMI), and alcohol intake have been identified as relevant lifestyle modifiable risk factors for post-menopausal BC. We aimed to evaluate the role of these factors in modulating post-menopausal BC risk and to estimate the proportion of BC cases attributable to low PA, high BMI, and alcohol taking into account non-modifiable factors. In the Italian section of the EPIC study, 15,010 post-menopausal women were recruited and provided information about dietary and lifestyle habits including PA, smoking, reproductive history, and anthropometric measurements. During 14.8 years of median follow-up, 672 incident BC cases (607 invasive and 65 in situ) were identified. In multivariate models, inverse associations with BC risk emerged for increasing level of total (p trend 0.02), leisure time (p trend 0.04), and occupational (p trend 0.007) PA. High BMI (HR 1.21; 95% CI 1.02–1.43 and HR 1.33; 95% CI 1.06–1.65 for overweight and obesity, respectively) and alcohol consumption higher than 10 g/day (HR 1.30; 95% CI 1.09–1.54) were associated with BC risk. We estimated that 30% (95% CI 8–50%) of post-menopausal BC cases would be avoided through an increase of leisure time PA, a BMI below 25.0, and consuming no more than one drink/day. This large study carried out in Mediterranean women confirms the role of PA, BMI, and alcohol consumption in modulating post-menopausal BC risk and supports the potential benefits obtainable by modifying these lifestyle factors.

Neoadjuvant chemotherapy (NAC) is widely used in locally advanced breast cancer (BC) treatment. The role of postmastectomy radiotherapy (PMRT) after NAC is strongly debated. The aim of our analysis was to identify major prognostic factors in a single-center series, with emphasis on PMRT. From 1997 to 2011, 170 patients were treated with NAC and mastectomy at our center; 98 cases (57.6%) underwent PMRT and 72 cases (42.4%) did not receive radiation. At a median follow-up period of 7.7 years (range 2–16) for the whole cohort, median time to locoregional recurrence (LRR) was 3.3 years (range 0.7–12.4). The 5-year and 10-year actuarial LRR rate were 14.5% and 15.9%, respectively. At the multivariate analysis the factors that significantly correlated with survival outcome were ≥4 positive nodes (HR 5.0, 1.51–16.52;P=0.035), extracapsular extension (HR 2.18, 1.37–3.46;P=0.009), and estrogen receptor positive disease (HR 0.57, 0.36–0.90;P=0.003). Concerning LRR according to use of radiation, PMRT reduced LRR for patient with clinical T3 staged disease (P=0.015). Our experience confirmed the impact of pathological nodal involvement on survival outcome. PMRT was found to improve local control in patients presenting with clinical T3 tumors, regardless of the response to chemotherapy.

The 11-gauge (11G) stereotactic vacuum-assisted breast biopsy (VABB) showed a better profile than 14G-VABB in terms of feasibility, safety, microcalcification sampling, and accuracy. Underestimation rates were significantly lower with 11G-VABB than with 14G-VABB. Thus, the introduction of an even larger needle at the VABB procedure could reduce this rate further. The purpose of this study was to compare the overall performance of stereotactic VABB with 8G and 11G needles.Four hundred and three VABBs performed between July 2012 and February 2015 at the Breast Diagnostic Unit of Careggi Hospital in Florence were retrospectively analyzed; 197 were performed with 11G-VABB and 206 with 8G-VABB. Lesions were classified according to mammographical patterns in microcalcifications, architectural distortions, or opacities, and all biopsy targets were classified according to BIRADS classification as BIRADS III, IV or V. Data were collected on radiological classification of targets, imaging presentation, procedure time, number of specimens per procedure, and microcalcification retrieval on histological findings. Surgery was always performed when high-risk or malignant lesions (B3 or B5) were detected; the final diagnosis was made on surgical pathology.Compared to VABB with an 11G needle, 8G-VABB allows a reduction in the time needed to complete the procedure (20.6 versus 27.4, P 0.00001) and the number of specimens collected per lesion (21.6 versus 12.2, P 0.00001). Moreover, 8G-VABB resulted in the same diagnostic accuracy, and the underestimation rates were comparable between the two groups for both B3 and DCIS lesions.The 8G needle should be considered as a valid alternative option in VABB for breast lesions.

Background SAFE trial (NCT2236806) is a phase 3 study comparing the effect on subclinical heart damage of bisoprolol (B), ramipril (R), or both drugs (R+B), as compared to placebo (P), in breast cancer treated with (neo)adjuvant anthracyclines +/- trastuzumab. Methods Primary endpoint is subclinical cardiotoxicity measured with echocardiography and global linear strain (GLS). This interim analysis was pre-specified on the first 120 patients who had completed cardiological assessments at 12-mos. Stopping rules per arm were: dose reduction >15%, study withdraw rate >5%, and no significant impact on 3D-left ventricular ejection fraction (3D-LVEF) as compared to T0 at 12-mos assessment. Results A total of 191 out of 480 patients have been enrolled; overall 123 patients were available for the analysis (P = 34; R = 28; B = 31; R+B=30). 3D-LVEF decreased at 3-mos (-3.3%; p Conclusions Following the stopping rules, the closure of the R arm is required and the study will continue with 3 arms. At the interim analysis, a cardioprevention strategy significantly impact on subclinical heart damage. Clinical trial identification NCT2236806. Legal entity responsible for the study University of Florence. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Meningiomas account for up to 20 % of all primary intracranial neoplasms; although the majority of these have a benign course, as many as 5–10 % can display more aggressive behavior and a higher incidence of disease progression. The benefit of immediate adjuvant radiotherapy is still being debated for atypical and malignant meningiomas. This study aimed to retrospectively assess prognostic factors and outcome in 68 patients with atypical and malignant meningiomas. Sixty-eight meningioma patients were treated with radiotherapy after initial resection or for recurrence, between January 1993 and December 2011. Surgery was macroscopically complete in 80 % of the patients; histology was atypical and malignant in 51 patients and 17 patients, respectively. Mean dose of radiotherapy was 54.6 Gy. Fifty-six percent of all patients received radiotherapy after surgical resection, 26 % at the first relapse, and 18 % at the second relapse. Median follow-up was 6.7 years, (range 1.5–19.9 years). The 5- and 10-year actuarial overall survival (OS) rates were 74.1 and 45.6 %, respectively. At univariate analysis age >60 years, radiotherapy dose >52 Gy showed statistical significance, (p = 0.04 and p = 0.03, respectively). At the multivariate analysis radiotherapy dose >52 Gy maintained the statistical significance, (p = 0.037). OS of patients treated with radiotherapy at diagnosis was longer than the survival of patients treated with salvage radiotherapy; however this difference did not reach statistical significance when tested for the entire series or for the subgroups of grade 2 and grade 3 patients. The 5- and 10-year disease-free survival (DFS) rates were 76.5 and 69.5 %, respectively, and were significantly influenced by size >5 cm (p = 0.04) and grading (p = 0.003) on univariate analysis. At multivariate analysis, size and grading both remained significant prognostic factors, p = 0.044 and p = 0.0006, respectively. Grade ≤ 2 acute side effects were seen during radiotherapy treatment in 16 % of the patients, with no ≥ grade 3 acute toxicity, based on the Common Terminology Criteria for Adverse Events. In this mono-institutional retrospective study, age and radiotherapy dose were associated with a longer OS, while preoperative size and grading of the tumor influenced DFS. Although there were some advantages in terms of OS for patients treated with postoperative radiotherapy, the benefit did not reach the significance. Multicenter prospective studies are necessary to clarify the management and the correct timing of radiotherapy in such a rare disease.

Background Hormone therapy is the most prescribed systemic therapy for patients with breast cancer (BC). Some patients fail to respond to tamoxifen; one pathway seems to involve human epidermal growth factor receptor 2 (HER2) overexpression. To better understand this matter, we reviewed our single-center experience of premenopausal patients who were chemotherapy naive and treated with 5 years of tamoxifen for early-stage BC by focusing on estrogen receptor (ER), progesterone receptor, HER2 status, and Ki-67 proliferative index. Patients and Methods We reviewed 425 patients treated with tamoxifen for early-stage BC. Previous solid tumors, age less than 18 years, BC recurrences or contralateral tumor, tamoxifen discontinuation, adjuvant chemotherapy, and a follow-up shorter than 6 months were considered exclusions criteria of the study. Results At a mean follow-up of 8.1 years, the mean (SD) time to local relapse was 6.7 ± 3.6 years; range, 2.0-10.7 years), whereas the mean (SD) time to distant metastases was 4.7 ± 2.3 years; range, 2.2-8.8 years). HER2 status did not influence local relapse–free survival (log-rank test, 0.40), distant metastases–free survival (log-rank test, 0.72), and overall survival rate (log-rank test, 0.87). Conclusions Resistance to tamoxifen is a complex trait, and its pathway is still unclear; in patients with BC, a multidisciplinary approach is highly recommended. In our experience, we did not find a statistically significant difference in tamoxifen treatment efficacy according to HER2 status.