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Cigarette smoking is the main risk factor for head and neck cancer (HNC) and many HNC patients are active smokers at diagnosis. We conducted a systematic literature review and meta-analysis to quantify the survival impact of smoking cessation at or around the time of HNC diagnosis. We searched studies published until December 31, 2021, and used random-effects meta-analysis to pool study-specific estimates into summary hazard ratio (SHR) and corresponding 95% confidence intervals (CI). Sixteen studies were published between 1983 and 2021, and over 2300 HNC patients were included. Studies were diverse in terms of design, patients, tumours and treatment characteristics, and criteria used to discriminate quitters from continued smokers. HNC patients who quit smoking at or around diagnosis had significantly better overall survival than continued smokers (SHR 0.80, 95% CI 0.70-0.91, n studies = 10). A beneficial effect of post-diagnosis smoking cessation was suggested for other survival endpoints as well, but the results were based on fewer studies (n = 5) and affected by publication bias. Cessation counselling should be offered to all smokers who start a diagnostic workup for HNC and should be considered standard multidisciplinary oncological care for HNC patients. PROSPERO registration number CRD42021245560.

BACKGROUND: To examine the associations of animal and plant protein intake with all-cause, cardiovascular and cancer mortality risk in middle-aged Italian men and women with substantially lower animal protein intake than North Americans. METHODS AND RESULTS: Food consumption was assessed by validated Epic semiquantitative FFQs. Multivariable Cox models stratified by center, age, and sex, and adjusted for confounders, estimated associations of animal and plant protein consumption with mortality for all causes, cardiovascular disease, and cancer. After a median follow-up of 15.2 years, 2,449 deaths were identified in 45,009 participants. No significant association between intake of total, animal or plant protein and mortality was found in the fully adjusted models. Substitution of plant protein for animal protein was inversely associated with cardiovascular mortality (HR, 0.47; 95% CI, 0.24–0.92) only in people with at least 1 unhealthy lifestyle risk factor and poor adherence to a Mediterranean diet. Participants in the highest quintile group of animal protein intake had higher glucose, total and LDL cholesterol levels than those in the lowest quintile. In contrast, higher plant protein intake was negatively associated with fasting insulin and cholesterol, despite higher BMI, physical inactivity and starch consumption. CONCLUSIONS: Replacing plant protein for animal protein was associated with lower cardiovascular mortality among individuals with unhealthy lifestyle risk factors. High animal but not plant protein intake is associated with impaired fasting glucose and hypercholesterolemia, despite lower calorie and carbohydrate intake, suggesting that protein source plays crucial roles in modulating cardiometabolic health independently of body weight.

To report on the anti-tumor activity of a novel combination in high-risk locally advanced head and neck squamous cell carcinoma.At a fixed dose of 1500 mg every 28 days, anti PD-L1 Durvalumab was given concomitantly to Radiotherapy and Cetuximab starting from the first week of combined treatment, followed by adjuvant Durvalumab to a maximum of 6 months after completion of radiation. The primary endpoint of the study was 2-year progression-free survival (PFS). A safety run-in was planned. Due to regulatory issues which prevented from opening multiple centers, COVID-19 pandemic and withdrawal of Durvalumab from supporting company, the study was prematurely terminated in April 2021.Between July 2019 and August 2020, 9 patients were enrolled in the study. All tumors had a PD-L1 Combined Positive Score 1. Optimal drug exposure was observed, with mean relative dose intensity of 85.5% and 87.5% for Cetuximab and Durvalumab, respectively. No radiation breaks were necessary. A grade 4 mucositis lasting for 14 days corresponded to the only dose limiting toxicity we reported. At a median follow-up of 11.5 months (IQR 7.7-16.7) all surviving patients (6 out of 9) are disease-free, with 1 and 2-year PFS rates of 77.7% and 58.3%, respectively. A selective sparing of node levels in the elective volume was performed in all cases, yielding a cumulative mean dose of 37.6 Gy (SD 8.4).Albeit limited by the small sample size, our preliminary observation of anti-tumor activity and tolerability of Durvalumab in addition to Cetuximab and radiation may warrant further investigations.

Introduction. Published evidence suggests that immunonutrition has the potential to decrease postoperative complications and reduce length of stay in patients undergoing surgery for colorectal cancer. However, only a few studies have analyzed the effects of immunonutrition on tumor microenvironment and evaluated its prognostic impact. Material and methods. This is a single center retrospective study enrolling 50 patients undergoing elective surgery for colorectal cancer managed with immunonutrition and 50 patients managed with standard nutrition for comparison. Tumor microenvironment was analyzed before (on the biopsy at the time of diagnosis) and after (on the matched surgical specimen) administration of immunonutrition. Immune function related indicators, including cytotoxic T-lymphocytes, helper T-cells, antigen presenting cells, natural killer cells, T-exhausted lymphocytes, T-regulatory cells, M1 and M2 tumor associated macrophages and PD-L1 expression were assessed by immunohistochemistry. For both groups, clinicopathological data were collected and a 5-year follow-up was available. Results. We found that immunonutrition significantly activated the T-cell response against cancer, alter tumor microenvironment phenotype towards M2 polarization and inhibits the PD1/PD-L1 axis. A lower rate of postoperative complications and a shorter length of stay (p = 0.04) were observed in the immune nutrition group. Compared to standard nutrition group, patients managed wit immune nutrition showed a higher 5-year overall survival (p = 0.001). Finally, immune nutrition allowed to reduce the hospital care costs. Conclusions. Immunonutrition modulates tumor microenvironment by improving immune function and could prolong survival in patients undergoing elective surgery for colorectal cancer. Further studies are needed to optimize IN protocols and confirm their prognostic impact.

Chronic exposure to heavy metals is of concern for its potential carcinogenic effect. An association with increased breast cancer (BC) risk was hypothesized, but literature data are conflicting and the question remains unresolved. We aimed to investigate the association between heavy metals and BC risk in a case-control study nested within the Florence section of the EPIC (European Prospective Investigation into Cancer and nutrition) cohort.We included 150 BC cases and an equal number of controls individually matched to cases by age and year of enrolment. In order to avoid confounding by smoking, the study was restricted to never smokers. Serum levels of six heavy metals (Cd, Co, Cr, Mn, Pb, and Tl) were quantified in pre-diagnostic samples using inductively coupled plasma mass spectrometry. Odds ratios (ORs) and corresponding 95 % confidence intervals (CI) were calculated via multivariable conditional logistic regression models.Serum levels of cobalt were inversely associated with BC risk (OR for the comparison of 3rd vs. 1st tertiles: 0.33, 95 % CI 0.12-0.91, p-value 0.033). None of the other heavy metals under study was significantly associated with BC risk in multivariable models. For Cd, Cr, and Tl, over half of the study participants had serum levels below the limit of quantitation.Our results do not support the hypothesis that exposure to heavy metals is associated with an increased BC risk among never smokers from the general population. The inverse association between cobalt serum levels and BC risk requires confirmation in future studies.

Mammographic breast density (MBD) is a marker of increased breast cancer (BC) risk, yet much remains to be clarified about the underlying mechanisms. We investigated whether DNA methylation patterns differ between high- vs. low-MBD women who developed BC during an 8.9-year median follow-up in the Florence section of the European Prospective Investigation into Cancer and Nutrition. We analysed 96 pairs of women with BC arising on high- vs. low-MBD breasts (BI-RADS category III–IV vs. I). DNA methylation was determined on pre-diagnostic blood samples using the Illumina Infinium MethylationEPIC BeadChip assay. The statistical analysis was conducted by performing an epigenome-wide association study (EWAS), by searching differentially methylated regions (DMRs) in gene promoters (followed by functional enrichment and gene annotation analysis); and through a “candidate pathways” approach focusing on pre-defined inflammation-related pathways. In EWAS, no single CpG site was differentially methylated between high- and low-MBD women after correction for multiple testing. A total of 140 DMRs were identified, of which 131 were hyper- and 9 hypo-methylated amongst high-MBD women. These DMRs encompassed an annotation cluster of 35 genes coding for proteins implicated in transcription regulation and DNA binding. The “apoptosis signalling” was the only inflammation-related candidate pathway differentially methylated between high- and low-MBD women. Pre-diagnostic methylation patterns differ between high- vs. low-MBD women who subsequently develop BC, particularly, in genes involved in the regulation of DNA transcription and cell apoptosis. Our study provides novel clues about the mechanisms linking MBD and BC.

Mammographic breast density (MBD) is a strong independent risk factor for breast cancer (BC). We designed a matched case–case study in the EPIC Florence cohort, to evaluate possible associations between the pre-diagnostic metabolomic profile and the risk of BC in high- versus low-MBD women who developed BC during the follow-up. A case–case design with 100 low-MBD (MBD ≤ 25%) and 100 high-MDB BC cases (MBD > 50%) was performed. Matching variables included age, year and type of mammographic examination. 1H NMR metabolomic spectra were available for 87 complete case–case sets. The conditional logistic analyses showed an inverse association between serum levels of alanine, leucine, tyrosine, valine, lactic acid, pyruvic acid, triglycerides lipid main fraction and 11 VLDL lipid subfractions and high-MBD cases. Acetic acid was directly associated with high-MBD cases. In models adjusted for confounding variables, tyrosine remained inversely associated with high-MBD cases while 3 VLDL subfractions of free cholesterol emerged as directly associated with high-MBD cases. A pathway analysis showed that the “phenylalanine, tyrosine and tryptophan pathway” emerged and persisted after applying the FDR procedure. The supervised OPLS-DA analysis revealed a slight but significant separation between high- and low-MBD cases. This case–case study suggested a possible role for pre-diagnostic levels of tyrosine in modulating the risk of BC in high- versus low-MBD women. Moreover, some differences emerged in the pre-diagnostic concentration of other metabolites as well in the metabolomic fingerprints among the two groups of patients.

Mammographic breast density (MBD) is a strong independent risk factor for breast cancer (BC). We investigated the association between volumetric MBD measures, their changes over time, and BC risk in a cohort of women participating in the FEDRA (Florence-EPIC Digital mammographic density and breast cancer Risk Assessment) study. The study was carried out among 6148 women with repeated MBD measures from full-field digital mammograms and repeated information on lifestyle habits, reproductive history, and anthropometry. The association between MBD measures (modeled as time-dependent covariates), their relative annual changes, and BC risk were evaluated by adjusted Cox models. During an average of 7.8 years of follow-up, 262 BC cases were identified. BC risk was directly associated with standard deviation increments of volumetric percent density (VPD, HR 1.37, 95%CI 1.22–1.54) and dense volume (DV, HR 1.29, 95%CI 1.18–1.41). An inverse association emerged with non-dense volume (NDV, HR 0.82, 95%CI 0.69–0.98). No significant associations emerged between annual changes in VPD, DV, NDV, and BC risk. Higher values of MBD measures, modeled as time-dependent covariates, were positively associated with increased BC risk, while an inverse association was evident for increasing NDV. No effect of annual changes in MBD emerged.

Introduction. Several studies have evaluated cardioprotective strategies to prevent myocardial dysfunction in patients who are receiving cardiotoxic therapies. Angiotensin-converting enzyme inhibitors and β-blockers are recommended first-line agents for heart failure. However, the optimal approach still represents a controversial issue. We hypothesized whether pharmacological cardioprevention could reduce subclinical heart damage in patients with breast cancer who are being treated with an anthracycline-based chemotherapy. Patients and methods. The SAFE trial was a 4-arm, randomized, phase 3, double-blind, placebo-controlled, national multicentric study conducted at eight oncology departments in Italy. The study recruitment was conducted between July 2015 and June 2020. A prespecified interim analysis on 174 women at 12 months was reported 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. Cardioprotective therapy (bisoprolol, ramipril, or both drugs compared with placebo) was administered for one 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 (5mg, once daily), ramipril (5mg, once daily), and placebo, if tolerated. The primary end point was defined as detection of any subclinical impairment (worsening 10%) in myocardial function and deformation measured at 24 months using 3-dimensional (3D) echocardiography, left ventricular ejection fraction (LVEF), and global longitudinal strain (GLS). ClinicalTrials.gov identifier: NCT2236806. Results. 262 women (median age, 48 years; range, 24-75 years) were enrolled and treated in the study. We analyzed patients who had completed the pre-planned cardiological assessment at 24 months. Baseline demographic, tumor, and cardiovascular profiles were similar between groups. All patients received an anthracycline-based chemotherapy, 215 patients received at least three cycles of anthracyclines (range 1-6), 223 patients received also a taxanes-based chemotherapy, and 84 cases were treated with adjuvant trastuzumab. Sixty patients were treated with neoadjuvant chemotherapy, 157 cases received adjuvant endocrine therapy, and 128 patients had postoperative radiation therapy. GLS worsened 10% or greater in 68% of patients enrolled in the placebo arm, 15%, 13%, and 13% in the ramipril, bisoprolol, and ramipril plus bisoprolol arms, respectively (P < 0.05). A reduction of 10% or greater in 3D-LVEF was observed in 19% in the placebo arm, 11% in the ramipril arm, 11% in the bisoprolol arm, and 7% in the ramipril plus bisoprolol arm (P < 0.05). Study drugs were well tolerated with no serious adverse events, the ramipril plus bisoprolol arm showed significantly more toxic effects and had a significantly higher rate of allocated treatment discontinuation as compared to the other arms. Conclusions. Cardioprotective pharmacological strategies in patients who were affected by breast cancer and were receiving an anthracycline-based chemotherapy are well tolerated and protect against cancer therapy–related LVEF decline and heart remodeling. Citation Format: Icro Meattini, Carlotta Becherini, Luca Visani, Calogero Saieva, Viola Salvestrini, Francesca Martella, Carlotta Bacci, Elena Molinara, Mario Airoldi, Maria Riccarda Del Bene, Domenico Amoroso, Luigi Coltelli, Isacco Desideri, Vieri Scotti, Marco Bernini, Lorenzo Orzalesi, Jacopo Nori, Simonetta Bianchi, Giuseppe Barletta, Lorenzo Livi. Beta blockers and/or ACE inhibitors as cardioprotective strategy for patients affected by nonmetastatic breast cancer who are receiving an anthracycline-based chemotherapy (SAFE - NCT02236806): final results of a randomized trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD8-03.

Germline variants of the melanocortin-1-receptor (MC1R) gene are the most common genetic trait predisposing to cutaneous melanoma (CM). Here, we performed a literature review and meta-analysis of the association between MC1R gene variants and the frequency of somatic mutations of the BRAF, NRAS, and TERT genes in CM patients. We included studies published until January 2020 in MEDLINE, EMBASE, Ovid Medline, and two grey literature databases. Random effect models were used to pool study-specific estimates into summary odds ratio (SOR) and 95% confidence intervals (CIs). Subgroup and sensitivity analyses were conducted to identify potential sources of heterogeneity and assess the robustness of pooled estimates. Twelve studies published between 2006 and 2018 (encompassing 3566 CM, mostly on nonacral sites) were included. MC1R gene variants were not significantly associated with the frequency of somatic mutations of the BRAF and NRAS genes. Only three studies focused on somatic mutations of the TERT gene promoter, all of which reported moderate-to-strong positive associations with MC1R germline variants. MC1R gene variants appear to make only moderate changes, if any, to the risk of BRAF- or NRAS-mutant CM. The association with TERT promoter mutations is suggestive, yet it warrants confirmation as it is based on a still limited number of studies.

PURPOSE To report the long-term results of external-beam accelerated partial-breast irradiation (APBI) intensity-modulated radiation therapy (IMRT) Florence phase III trial comparing whole-breast irradiation (WBI) to APBI in early-stage breast cancer. PATIENTS AND METHODS The primary end point was to determine the 5-year difference in ipsilateral breast tumor recurrence (IBTR) between 30 Gy in 5 once-daily fractions (APBI arm) and 50 Gy in 25 fractions with a tumor bed boost (WBI arm) after breast-conserving surgery. RESULTS Five hundred twenty patients, more than 90% of whom had characteristics associated with low recurrence risk, were randomly assigned (WBI, n = 260; APBI, n = 260) between 2005 and 2013. Median follow-up was 10.7 years. The 10-year cumulative incidence of IBTR was 2.5% (n = 6) in the WBI and 3.7% (n = 9) in the APBI arm (hazard ratio [HR], 1.56; 95% CI, 0.55 to 4.37; P = .40). Overall survival at 10 years was 91.9% in both arms (HR, 0.95; 95% CI, 0.50 to 1.79; P = .86). Breast cancer–specific survival at 10 years was 96.7% in the WBI and 97.8% in the APBI arm (HR, 0.65; 95% CI, 0.21 to 1.99; P = .45). The APBI arm showed significantly less acute toxicity ( P = .0001) and late toxicity ( P = .0001) and improved cosmetic outcome as evaluated by both physician ( P = .0001) and patient ( P = .0001). CONCLUSION The 10-year cumulative IBTR incidence in early breast cancer treated with external APBI using IMRT technique in 5 once-daily fractions is low and not different from that after WBI. Acute and late treatment-related toxicity and cosmesis outcomes were significantly in favor of APBI.

Adipocytokines are signaling molecules secreted by adipose tissue contributing to the control of body fat, energy expenditure and secretion of insulin and cytokines. They have been related to the development of obesity, type-2 diabetes, cardiovascular diseases and cancer. Diet and physical activity (PA) may have beneficial effects on their level. We evaluated the effects of a 24-month dietary and/or PA intervention on plasma levels of adipocytokines as a secondary analysis in the DAMA (Diet, physical Activity and Mammography) trial.The 234 study participants (healthy postmenopausal women with high breast density, 50-69 years, non-smokers, no hormone therapy) were randomised to four arms: (1) isocaloric dietary intervention mainly based on plant-foods; (2) moderate-intensity PA intervention with at least 1 h/week of supervised strenuous activity; (3) both interventions; (4) general recommendations on healthy dietary and PA patterns. Leptin, resistin and adiponectin were measured at baseline and at the end of the intervention. Analyses were performed using Tobit regression.After 24 months, women randomised to PA intervention (arms #2 + #3) showed significant lower level of leptin (37.5% lower) and resistin (65.6% lower) compared to the control group (arms #1 + #4). No significant differences emerged in adiponectin levels. No significant differences in leptin, resistin and adiponectin levels at follow-up emerged in women randomised to the dietary intervention (arms #1 + #3) in comparison with controls (arms #2 + #4).This study supports the effectiveness of PA, even at moderate intensity, in improving the leptin and resistin profile in postmenopausal women.ISRCTN28492718, date of trial registration 17/05/2012.

Epidemiologic studies have indicated that cruciferous vegetables can influence the cancer risk; therefore, we examined with a cross-sectional approach the correlation between the frequent consumption of the total cruciferous vegetables and the formation of bulky DNA damage, a biomarker of carcinogen exposure and cancer risk, in the Gen-Air study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. DNA damage measurements were performed in the peripheral blood of 696 of those apparently healthy without cancer controls, including 379 never-smokers and 317 former smokers from seven European countries by the 32P-postlabeling assay. In the Gen-Air controls, the median intake of cruciferous vegetables was 6.16 (IQR 1.16–13.66) g/day, ranging from 0.37 (IQR 0–6.00) g/day in Spain to 11.34 (IQR 6.02–16.07) g/day in the UK. Based on this information, participants were grouped into: (a) high consumers (>20 g/day), (b) medium consumers (3–20 g/day) and (c) low consumers (

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) currently represent the standard of care for the initial treatment of patients with metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer. The aim of our study is to evaluate the safety of the use of concomitant radiation therapy (RT) in a consecutive series of HR+/HER2- patients treated in two academic institutions with CDK4/6i in the metastatic setting.From September 2017 to February 2020, we retrospectively collected and analysed data on a sequential series of patients treated with CDK4/6i, receiving RT or not, at two European institutions. Primary outcome of the study was the association between RT and any adverse events (AEs) ≥ G3. Secondary outcomes were the association between RT and any AEs (any grade), CDK4/6i dose reduction rate, and CDK4/6i treatment discontinuation rate.We analysed a total of 132 consecutive women; RT was prescribed in 57 (43.2%) patients (70 irradiated lesions). The median age of the series was 52.1 years (range 32.3-78.2). Concomitant RT administration was not significantly related to higher AEs ≥ G3 (p = 0.19) and any grade AEs (p = 1.0); there was no association with RT and CDK4/6i dose reduction (p = 0.49) and discontinuation rates (p = 0.14). At a median follow-up of 18.8 months, the progression-free survival (PFS) rate was 35% and the overall survival (OS) rate was 38.7% in the whole group. The use of concomitant RT did not affect both PFS (p = 0.71) and OS rates (p = 0.55).Our data are encouraging regarding the safety of this combination, showing that concurrent RT did not increase severe toxicity and did not have an impact on systemic treatment conduction.

Background. Several studies demonstrated the prophylactic benefit of beta-blockers and angiotensin-converting enzyme (ACE) inhibitors for anthracyclines-based chemotherapy-induced cardiotoxicity. However, there is no consensus on management strategies at the time being. We present the interim analysis of the SAFE trial. Methods. The SAFE trial is a 2 × 2 factorial design randomized phase 3 study evaluating the impact of bisoprolol (B) (5 mg), ramipril (R) (5 mg), or both drugs as compared to placebo (P) on subclinical heart damage evaluated by speckle-tracking cardiac ultrasound. Enrolled patients included non-metastatic histology-proven breast cancer, treated with primary systemic therapy or adjuvant regimens based on anthracyclines with or without trastuzumab. Primary endpoint is evaluation of reduction in both systolic and diastolic, early and late subclinical cardiotoxicity measured with traditional echocardiography, pulsed tissue doppler, global linear strain (GLS), and 3-dimesional left ventricular ejection fraction (3D-LVEF). CT registry ID: NCT2236806; EudraCT number: 2015-000914-23. 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-month (-3.3%; p Citation Format: Lorenzo Livi, Icro Meattini, Francesca Martella, Calogero Saieva, Carlotta Becherini, Francesca Terziani, Isacco Desideri, Vieri Scotti, Carlotta Bacci, Mario Airoldi, Giacomo Allegrini, Domenico Amoroso, Luisa Fioretto, Giuseppe Barletta. Interim analysis of the SAFE trial (NCT2236806): A randomized phase 3 study evaluating a cardiovascular disease prevention strategy using beta-blockers and/or ACE inhibitors in non-metastatic breast cancer patients treated with anthracyclines [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-24.

107 Background: The optimal management of mCRPC in men aged ≥75 is challenging, and there is a paucity of clinical data in the literature. Although AA and E are commonly used as 1st line Rx for mCRPC, it is unclear whether use of upfront D for mCSPC may impact their clinical efficacy or safety in this elderly population. Methods: Patients aged ≥75 who started AA or E as 1st line Rx for mCRPC within January 2015 - April 2019 were identified from the IRB approved databases of 10 institutions in Europe, South and North America. Demographic and clinicopathological data were collected from available medical records, including Gleason, prior local therapy, newly diagnosed metastatic disease, disease volume, ECOG, PSA and sites of metastases. Patients were classified by use of upfront D for mCSPC. The primary endpoints were overall survival (OS) from AA/E onset and OS from ADT start and safety of AA/E. The endpoints distributions including median (95% CI) were estimated by Kaplan-Meier method. Results: Of the 337 patients selected, 24 (7.1%) received ADT+D and 313 (92.9%) ADT alone for mCSPC. Patients with ADT+D tended to be younger (78 vs 81, p=0.022) and, albeit not statistically significant, had higher rates of Gleason score >8 (81.0% vs 62.6%, p=0.10), newly diagnosed (83.3% vs 65.6%, p=0.08) and high volume disease (45.8% vs 34.6%, p=0.28), compared to those with ADT alone. Median follow-up was 18.8 months. No significant difference of OS from ADT start or from AA/E onset was observed between the 2 cohorts (see table). Despite OS from ADT start being longer in those having ADT+D, OS from AA/E start was approximately 2 years in both cohorts. Rates of adverse events (AEs) of any grade (58.3% vs 52.1%, p=0.67) and grade ≥3 (12.5% vs 15.7%, p=1.0) did not significantly differ between the 2 cohorts. Conclusions: While limited by small sample size for ADT+D and retrospective study design, patients aged ≥75 having AA/E as 1st line mCRPC Rx showed similar survival outcomes and tolerability regardless of previous use of D for mCSPC. [Table: see text]

166 Background: About 2/3 of all prostate cancer (PCa) deaths occur in patients aged ≥75, who are frequently diagnosed with advanced PCa. ARSi abiraterone acetate (AA) and enzalutamide (E) are the most common 1st line Rx for patients with mCRPC. Yet, the optimal treatment sequence for the elderly ≥75 after ARSi failure is still unclear. Methods: Using available medical records, patients aged ≥75 who started ARSi as 1st line Rx for mCRPC within January 2015 - April 2019 and, upon progression, 2nd line alternative ARSi or D were identified from the IRB approved hospital registries of 10 centers in Europe, North and South America. Patients were categorized by type of 2nd line Rx for mCRPC into cohorts AA/E and D. Primary endpoints were overall survival (OS) from 1st line AA/E start, OS and radiographic progression-free survival (rPFS) from 2nd line Rx start, and safety. The Kaplan Meier method was used to calculate endpoint distributions and medians (95% CI). Results: Of the 122 patients identified, 57 (46.7%) had AA/E and 65 (53.3%) D, as 2nd line Rx for mCRPC. Median follow-up was 26.3 months (95% CI, 23.1-27.9 months). Cohort AA/E tended to be older (81 vs 78 years; p=0.001) and with high-volume disease (45.5% vs 25.0%; p=0.022) compared to cohort D. No significant difference in OS from 1st line ARSi onset and OS or rPFS from 2nd line Rx start was found between the 2 cohorts. Cohort AA/E had longer rPFS than cohort D, albeit not significant (18.5 vs 12.0 months; p=0.13). Rates of adverse events (AEs) of any grade (42.1 vs 53.8; p=0.21) and AEs of grade ≥3 (19.3% vs 18.5%; p=1.0) did not show significant differences between the 2 cohorts. Conclusions: Within the limitations of small cohorts and retrospective design, treatment sequences with 2nd line AA/E or D after failure of 1st line alternative ARSi for mCRPC showed similar efficacy and safety in the elderly ≥75 years old.

We conducted a systematic review and meta-analysis to investigate the role of alcohol consumption with the prognosis of prostate cancer (PCa). Published reports were gathered on 15 October 2022, from PUBMED/MEDLINE and EMBASE. We found 19 independent eligible studies on the association between consumption of alcoholic beverages and the risk of fatal PCa (n = 5), PCa mortality (n = 5) in healthy subjects, and PCa patients’ survival (n = 7) or surrogates thereof (n = 2). We used random effects meta-analysis to obtain a summary risk estimate (SRE) and 95% confidence intervals (95%CI) for incidence of fatal PCa and PCa mortality. The meta-analysis revealed no association between alcohol consumption and fatal prostate cancer incidence risk in healthy subjects with an indication for publication bias, but omitting the study that mainly increased the between-study heterogeneity, the SRE becomes significant (SRE 1.33, 95%CI 1.12–1.58), and the heterogeneity disappeared (I2 = 0%) with no indication of publication bias. No association of alcohol consumption was found with mortality risk in PCa patients (SRE 0.97, 95%CI 0.92–1.03) and PCa mortality risk in healthy subjects (SRE 1.03, 95%CI 0.82–1.30). In conclusion, this study suggests that there is some evidence of an association between high alcohol consumption and an increased risk of incidence of fatal prostate cancer in healthy subjects. Given the inconsistencies this result warrants further confirmation.

Background: Androgen receptor signaling inhibitors (ARSis) abiraterone acetate (AA) plus prednisone and enzalutamide (Enza), are currently the most administered first-line treatments for metastatic castration-resistant prostate cancer (mCRPC). AA and Enza have shown similar overall survival (OS) benefits and there is no consensus upon the best option for mCRPC first-line treatment. Volume of disease may represent a useful biomarker to predict response to therapy in such patients. Objectives: In this study, we seek to evaluate the impact of volume of disease on patients treated with first-line AA versus Enza for mCRPC. Design and methods: We retrospectively evaluated a cohort of consecutive patients with mCRPC categorized by volume of disease [high volume (HV) or low volume (LV) per E3805 criteria] at ARSi onset and treatment type (AA or Enza), assessing OS and radiographic progression-free survival (rPFS), from therapy start, as co-primary endpoints. Results: Of the 420 patients selected, 170 (40.5%) had LV and received AA (LV/AA), 76 (18.1%) LV and had Enza (LV/Enza), 124 (29.5%) HV and were given AA (HV/AA), and 50 (11.9%) HV and received Enza (HV/Enza). Among patients with LV, OS was significantly longer when treated with Enza [57.2 months; 95% confidence interval (CI): 52.1–62.2 months] versus AA (51.6 months; 95% CI, 42.6–60.6 months; p = 0.003). Consistently, those with LV receiving Enza showed increased rPFS (40.3 months; 95 CI, 25.0–55.7 months) than those having AA (22.0 months; 95% CI, 18.1–26.0 months; p = 0.004). No significant difference in OS or rPFS was observed in those with HV treated with AA versus Enza ( p = 0.51 and p = 0.73, respectively). In multivariate analysis of patients with LV, treatment with Enza was independently associated with better prognosis than AA. Conclusion: Within the intrinsic limitations of a retrospective design and small population, our report suggests that volume of disease could be a useful predictive biomarker for patients starting first-line ARSi for mCRPC.

Simple Summary Malignant pleural mesothelioma (MPM) is an aggressive and still incurable cancer. There is an urgent need to identify effective and reliable tools for detecting and diagnosing the early onset of MPM. In our study, we investigated the whole miRNAs expression profile from serum extracellular vesicles to identify early changes related to MPM development. miR-11400, miR-148a-3p, and miR-409-3p levels were increased in pre-clinical MPM patients up to five years before their diagnosis. The three-miRNA pattern showed a good discrimination capacity to distinguish pre-clinical MPM from cancer-free controls. The three miRNAs also displayed high diagnostic capabilities for differentiating between MPM patients and controls. This study identified a potential EV miRNA signature in preclinical MPM up to five years before diagnosis and raises the possibility of early intervention. Malignant pleural mesothelioma (MPM) is an aggressive cancer with a dismal prognosis. Early therapeutic interventions could improve patient outcomes. We aimed to identify a pattern of microRNAs (miRNAs) as potential early non-invasive markers of MPM. In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition cohort, we screened the whole miRNome in serum extracellular vesicles (EVs) of preclinical MPM cases. In a subgroup of 20 preclinical samples collected five years prior MPM diagnosis, we observed an upregulation of miR-11400 (fold change (FC) = 2.6, adjusted p-value = 0.01), miR-148a-3p (FC = 1.5, p-value = 0.001), and miR-409-3p (FC = 1.5, p-value = 0.04) relative to matched controls. The 3-miRNA panel showed a good classification capacity with an area under the receiver operating characteristic curve (AUC) of 0.81 (specificity = 0.75, sensitivity = 0.70). The diagnostic ability of the model was also evaluated in an independent retrospective cohort, yielding a higher predictive power (AUC = 0.86). A signature of EV miRNA can be detected up to five years before MPM; moreover, the identified miRNAs could provide functional insights into the molecular changes related to the late carcinogenic process, preceding MPM development.

Background: Diet and physical activity (PA) can modulate sporadic and possibly familial breast cancer (BC) risk. The DAMA25 study is a single-arm 12-month intervention aimed to modify dietary and PA habits in healthy young Italian women with a positive BC family history, categorized as having intermediate or high genetic risk according to NICE (National Institute for Health and Cancer Excellence) guidelines. Methods: Participants, aged 25–49 years, were asked to adopt a diet mainly based on plant-based foods and to increase moderate daily activities combined with 1 h/week of more intense activity. Cooking lessons, collective walks, educational sessions, brochures, booklets and online materials were implemented. Dietary, PA habits and anthropometry were collected at baseline and at the end of the intervention. Changes on dietary, lifestyle habits and anthropometry were evaluated by GLM adjusted for weight reduction counselling aimed to participant with a BMI ≥ 25, age and baseline values of each variable. Results: Out of 237 eligible women 107 (45.2%) agreed to participate and among them 98 (91.6%) completed the intervention. The adherence rate of the intervention was 77.8%. We observed a reduction in red and processed meat (p < 0.0001) and cakes consumption (p < 0.0001). Consumption of whole grain bread (p < 0.001), leafy vegetables (p = 0.01) and olive oil (p = 0.04) increased. We observed an increase in moderate (p < 0.0001) and more intense (p < 0.0001) recreational activities, an average 1.4 kg weight loss (p = 0.005), a reduction of waist circumference (p < 0.001) and fat mass (p = 0.015). Conclusions: The DAMA25 study shows that it is feasible an intervention to improve in the short-term dietary and PA habits and anthropometry in women with high BC familial risk.

Objectives: The incidence of prostate cancer in renal transplant recipients (RTRs) is increasing, but few data are available in the literature. In this study, we reviewed the 25-year experience in the management of prostate cancer after kidney transplantation at the Florence Transplant Centre.Methods: We retrospectively reviewed the data from 617 RTR male patients who underwent renal transplantation at our institute between July 1996 and September 2016. Data regarding demographics, renal transplantation, prostate cancer and immunosuppressive treatment were analyzed. The probability of death was estimated by using the Kaplan-Meier method and differences between patients' groups were assessed by the log-rank test.Results: From July 1991 to September 2016, 617 kidney transplantations of male patients were performed at our institute. Among these, 20 patients were subsequently diagnosed with prostate cancer accounting for a cumulative incidence of 3.24%. After a median follow-up of 59 months, 10 patients underwent radical prostatectomy whereas 10 patients underwent primary radiotherapy. A biochemical recurrence was identified in five (25%) patients while a fatal event occurred in 11 (55%) patients. Univariate Cox regression showed that the basal value of PSA >10 ng/ml was the only significant factor negatively affecting the survival of patients.Conclusions: Standard treatments can be proposed to RTR with satisfactory results on both post-operative and oncological outcomes. Further studies are needed to address the issue of prostate cancer screening based on PSA levels and the optimal management of prostate cancer in RTRs.

Background. Partial breast irradiation (PBI) is a reasonable alternative for a whole breast irradiation (WBI) in selected early stage breast cancer patients. The 5-year analysis of the APBI IMRT Florence phase 3 trial showed no significant difference in terms of ipsilateral tumor recurrence (IBTR) and survival rates between the two arms. We present the 10-year follow up data. Methods. From March 2005 to June 2013, women aged more than 40 years affected by early BC, with a maximum pathological tumor size of 25 mm, were randomly assigned in a 1:1 ratio to receive either WBI using three-dimensional conformal radiotherapy (3DCRT) or accelerated PBI (APBI) using intensity-modulated radiotherapy (IMRT) technique. Patients in the APBI arm received a total dose of 30 Gy to the tumor bed in five daily fractions. The WBI arm received 50 Gy in 25 fractions, followed by a boost on the tumor bed of 10 Gy in five fractions. The primary end-point, IBTR rate is now assessed at 10 years in the ITT population, as well as secondary endpoints: overall survival (OS), breast cancer specific survival (BCSS), distant metastasis free survival (DMFS), contralateral breast cancer (CBC), and locoregional recurrences (LRR). This trial is registered with ClinicalTrials.gov, number NCT02104895. Results. Of the 520 patients, 260 were enrolled in the APBI-arm and 260 in the WBI-arm; median age was 62.8 years (63.6 in the APBI and 61.6 in the WBI arm, p=0.20). Both treatment-arms achieved a median 10-year follow-up (10.1 in APBI-arm and 10.4 in WBI-arm, p=0.39) and were comparable regarding age, tumor size, grade, tumor type, and adjuvant endocrine treatment. No significant difference in terms of IBTR rates between treatment arms was shown (log rank test p=0.58). In the group who received APBI, the 5-year IBTR was 1.96% (5 events; 95% CI: 0.3;3.7) and the 10-year IBTR was 3.74% (9 events; 95% CI: 1.5;6.3). In the group who received WBI, the 5-year IBTR rate was 1.2% (3 events; 95% CI: 0;2.5) and the 10-year IBTR was 2.5% (6 events; 95% CI: 0.7;4.5). HR for APBI patients compared with WBI patients was 1.33 (p=0.58; 95% CI: 0.49;3.56). There were no significant differences between treatment arms regarding survival outcomes. OS (log rank test p=0.33): APBI 95.4% (95% CI: 93.6;97.2) versus WBI 94.3% (95% CI: 92.3;96.3); HR for APBI patients 0.66 (p=0.33; 95% CI: 0.29;1.53). BCSS (log rank test p=0.55): APBI 98% (95% CI: 96.8;99.2) versus WBI 97.5% (95% CI: 96.2;98.8); HR for APBI patients 0.68 (P=0.55; 95% CI: 0.19;2.42). DMFS (log rank test p=0.45): APBI 97.4% (95% CI: 96.0;98.8) versus WBI 96.1% (95% CI: 94.4;97.8); HR for APBI patients 0.67 (p=0.45; 95% CI: 0.24;1.89). Cumulative incidence estimates of 10-year LRR were 3.9% (95% CI: 2.24;5.56) for APBI versus 3.0% (95% CI: 1.53;4.47) for WBI (log rank test p=0.59). CBC observed after APBI were 5 (1.9%) as compared to 9 (3.5%) after WBI (p=0.42). Conclusion. IBTR rate after 10 years in patients with early breast cancer who were treated with APBI using IMRT technique in 5 fractions is rare and not significantly different from patients treated with WBI. OS, BCSS, DMFS, and LRR control are also comparable. Thus, APBI should be considered a reasonable alternative for a WBI in early breast cancer patients. Citation Format: Icro Meattini, Calogero Saieva, Sara Lucidi, Monica lo Russo, Vieri Scotti, Isacco Desideri, Livia Marrazzo, Gabriele Simontacchi, Monica Mangoni, Carlotta Becherini, Luca Visani, Lisa Paoletti, Erica Moretti, Luca Triggiani, Marco Bernini, Lorenzo Orzalesi, Luis Sanchez, Jacopo Nori, Stefania Pallotta, Simonetta Bianchi, Lorenzo Livi. Accelerated partial breast or whole breast irradiation after breast conservation surgery for patients with early breast cancer: 10-year follow up results of the APBI IMRT Florence randomized phase 3 trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS4-06.

OBJECTIVES The aim of this study was to analyze patterns of care in elderly soft tissue sarcoma (STS) patients and their impact on clinical outcome and treatment-related toxicity. MATERIALS AND METHODS We retrospectively collected data of >65-year-old patients diagnosed with locally advanced STS between 1991 and 2017 in a single institution. RESULTS The study included 111 patients: 105 (94.6%) patients underwent surgery, associated with preoperative (n=19, 17.1%) or postoperative radiotherapy (n=72, 64.8%). Anthracycline-based chemotherapy was prescribed in 41.4% of patients (n=46). Acute grade ≥3 postoperative radiotherapy-related radiation dermatitis and all grades of chemotherapy-induced neutropenia were significantly correlated to age >80 years (P=0.02) and >70 years (P=0.045), respectively. The mean follow-up was 4.1 years (range, 0.1 to 17.7). Three-year and 5-year local recurrence-free survival were 80.3% and 75.7%, respectively; neither treatment-related nor patient-related characteristics affected local recurrence. Three-year and 5-year distant relapse-free survival were 59.6% and 44.6%, respectively. On multivariate Cox regression, undifferentiated pleomorphic sarcoma histology and Charlson Comorbidity Index >7 were independent factors associated with distant relapse-free survival (P=0.026 and P=0.0001). Overall survival was 62% and 46.6% at 3 and 5 years, respectively. On multivariate Cox regression, surgery and Charlson Comorbidity Index

Background. Several randomized trials demonstrated aromatase inhibitors (AI) superiority in terms of disease-free survival (DFS) compared to tamoxifen treatment for postmenopausal hormone receptor-positive breast cancer (BC) patients. Anyway, AI toxicity profile is a concern due to estrogen suppression. Pivotal trials demonstrated a significant bone mineral density (BMD) loss due to AI, with a consistent 5-year risk of bone fractures, thus impacting on patients' quality of life. Bisphosphonates represent an effective treatment in postmenopausal osteoporosis fractures prevention. However, an adequate patient's selection for adjuvant bisphosphonates treatment during AI endocrine therapy is still a challenge. Final results of BONADIUV trial presented at San Antonio Breast cancer Symposium in 2016 showed that treatment with ibandronate, as compared to placebo, significantly improved BMD change in osteopenic women treated with adjuvant AI, and consistently protected patients' bone loss. We present the secondary 5-year analysis on survival outcomes of the trial. Patients and methods. The BONADIUV trial is a single-blind, randomized, placebo-controlled phase 2 study designed to evaluate the impact of ibandronate treatment on BMD in osteopenic women taking AI. Between January 2011 and May 2014, 171 osteopenic patients (lumbar spine [LS] and/or trochanter -1< T-score Results. At the database cutoff time for the present analysis on May 4, 2018, median follow up was 63.3 months (mean 61.2; range 2.7-87.3) for whole series, 64.9 months (range 33.8-84.0) for the placebo arm, and 62.2 months (range 24.2-87.3) for the ibandronate arm. Ten patients in the placebo group and 17 patients in the ibandronate group withdrew the allocated arm before any follow up data collection, and so were excluded from the analysis, performed on 144 patients (72 patients per arm). At the database cutoff time, the OS rate was 97.2% in the placebo group and 100% in the ibandronate arm. We observed four loco-regional relapse (three in the placebo arm, one in the ibandronate arm; p=0.33), three distant metastases (none in the placebo arm, three in the ibandronate arm; p=0.075), and three contralateral BC (one in the placebo arm, two in the ibandronate arm; p=0.65). The number of iDFS events did not differ between groups: four in the placebo group and six in the ibandronate group (p=0.56). Up to data cutoff, two deaths have occurred; none in the placebo arm and two in the ibandronate arm (p=0.15). The OS rate did not differ between arms. Conclusions. The secondary analysis of survival outcomes showed no difference between arms in terms of OS and iDFS rates. Further large investigations and mature follow-up from the published ones are awaited. Citation Format: Meattini I, Scotti V, Desideri I, Saieva C, Visani L, Salvestrini V, Cecchini S, De Feo ML, Mariotti M, Olmetto E, Delli Paoli C, Francolini G, Bernini M, Orzalesi L, Sanchez L, Nori J, Bianchi S, Livi L. Oral ibandronate for osteopenic breast cancer patients receiving adjuvant aromatase inhibitors: secondary 5-year survival outcomes analysis of the single-center phase 2 BONADIUV trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-16-04.

Aims. To evaluate acute and late toxicity-related factors among breast cancer (BC) patients who underwent prepectoral breast reconstruction (BR). Methods. We performed a retrospective analysis of BC patients who underwent therapeutic or prophylactic mastectomy from October 2012 to May 2016 at our Center. We recorded individual patient-related features (i.e. age, body mass index [BMI], smoke-history, comorbidity, BRCA-carrier), BC-related treatments characteristics (i.e. axillary surgery, adjuvant radiotherapy [RT], adjuvant chemotherapy, primary systemic therapy [PST], endocrine therapy, and use of trastuzumab). Toxicity profile was evaluated in terms of complications related to BR; we recorded acute and late toxicity data and prosthesis/implant explant rate. Results. We analyzed 146 consecutive BC patients treated with subcutaneous BR, 117 therapeutic and 29 prophylactic mastectomies. Thirty-seven patients received postmastectomy RT. Significant factors related to acute toxicity were: previous RT (34.5% [RT] vs 8.5% [no RT]; p=0.001), BMI (31.3% [BMI ≥25] vs 8.8% [ Conclusions. In our experience prepectoral subcutaneous implant-based BR is a safe and effective approach, with low rates of acute toxicity. Major risk factors were evidenced for patients previously treated with RT or surgery, and in case of diabetes or BMI ≥25; postmastectomy RT seems not to be related to higher rate of toxicity. ALND seems to be the only factor significantly related to late toxicity. PST, and smoking exposition were significantly associated with higher rate of implant/prosthesis explant. However, further investigations and mature follow-up are warranted to confirm these encouraging results. Citation Format: Meattini I, Bernini M, Saieva C, Desideri I, Scotti V, Salvestrini V, Visani L, Mariotti M, Delli Paoli C, Olmetto E, Maragna V, Orzalesi L, Sanchez L, Nori J, Bianchi S, Livi L. Conservative breast reconstruction: Outcomes of 146 consecutive cases of prepectoral, subcutaneous implant-based breast reconstruction in a single-Institution series [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-12-07.

We conducted a meta-analysis of studies reporting on the risk of extra-ovarian malignancies among women with endometriosis. Summary relative risk (SRR) and 95% confidence intervals (CI) were calculated through random effect models. We explored causes of between-studies heterogeneity and assessed the presence of publication bias. We included 32 studies published between 1989 and 2018. We found an increased risk of endometrial (SRR 1.38, 95%CI 1.10-1.74) and thyroid cancer (SRR 1.38, 95%CI 1.17-1.63), and inverse association with cervical cancer (SRR 0.78, 95%CI 0.60-0.95). No association emerged for breast cancer (SRR 1.04, 95%CI 0.99-1.09) and melanoma (SRR 1.31, 95%CI 0.86-1.96). Between-study heterogeneity was large for breast and endometrial cancer and melanoma. Associations were generally stronger in case-control, cross-sectional, and cohort studies with internal control group, compared to cohort studies with external control group. No indication for publication bias was found. Our conclusions need to be confirmed in properly designed cohort studies with clinical confirmation of endometriosis.

Prostatectomy, radiotherapy and watchful waiting are the main therapeutic options available for local stage of prostate cancer (PCa). We report our experience on 394 patients affected by prostate cancer primarily treated with high-dose, image-guided, IMRT, focusing on gastrointestinal, genitourinary toxicities and biochemical control. From July 2003 to August 2014, 394 patients were treated with radical high-dose radiotherapy (HDRT) for prostate cancer; the mean total radiation dose was 79 Gy in standard fractions. Hormonal therapy (HT) was administered to 7.6% of low-risk patients, to 20.3% of intermediate-risk patients and to 72% of high-risk patients. Patients were evaluated for biochemical failure, local recurrence (LR) and metastases. Ninety-seven patients (26.65%) developed acute GU toxicity at the medium dose of 25.4 Gy, grade 1 (G1) or grade 2 (G2) in 94 cases. Only 16 patients (4.06%) reported chronic GU toxicity (G1 or G2), and one case developed G3 cystitis. No G3 GI acute and late toxicity were detected. Fifty-six (14.2%) patients experienced LR, 26 (6.6%) developed metastases and 70 patients (17.8%) were deceased. Gleason sum score > 7 was predictive for worse overall survival (GS = 7 was borderline) and for metastasis. No factors resulted predictive for local relapse. HT pre-RT had been demonstrated as a negative predictor for OS and DFS-DM. Data confirm the safety of HDRT for PCa. Treatment was efficient with low toxicity profile. Moreover, continued technologic advancements, as image-guided radiotherapy, could lead to further reduction in toxicity, thus increasing the therapeutic index.

Background and Objectives: The incidence of urothelial cancer in males is higher than in females; however, females have a higher risk of recurrence and progression. The aim of our study was to report the effect of gender on the oncological outcome in advanced urothelial cancer. Materials and Methods: In our retrospective study, all patients had undergone primary surgical treatment for urothelial cancer and were affected by stage IV disease at the time of chemotherapy. Response to therapy and toxicity were evaluated. Subgroups were analyzed for tumour presentation, first- and second-line treatment response, progression-free survival (PFS) and overall survival (OS). Results. Seventy-five patients, 18 (24%) females and 57 (76%) males, were considered. Investigation into the distribution of individual characteristics according to gender revealed a significant difference only for smoking, with a prevalence of smokers in women (p = 0.029). At the end of follow-up, OS was higher in females (27.5% vs. 17.4%; p = 0.047). Smoking did not significantly influence OS (p = 0.055), while univariate Cox regression analysis confirmed that males had a higher risk of death (HR = 2.28, 95% CI 0.99–129 5.25), with borderline statistical significance (p = 0.053). Men showed higher PFS than women both after first-line (p = 0.051) and second-line chemotherapy (p = 0.018), with a lower risk of progression (HR = 0.29, 95% CI 0.10–0.86; p = 0.026). No differences were found between genders with regard to toxicity. Conclusions. In our series, PFS rates following first- and second-line therapies for advanced urothelial carcinoma confirmed that females have a greater risk of progression than males.

No association between polymorphisms in CYP2E1, GSTM1, NAT1, NAT2 and the risk of gastric adenocarcinoma in the European prospective investigation into cancer and nutrition.

We re-evaluated acute and early-late toxicity-related factors among pre-pectoral immediate tissue expander/implant (TE/I) breast reconstruction (BR) unselected, first-era, cases, including previous breast radiation treatment and post-mastectomy radiation therapy (PMRT). A retrospective analysis of 146 (117 therapeutic and 29 prophylactic) pre-pectoral reconstructions, between 2012 and 2016, considered patient-related (age, body mass index [BMI], smoke-history, comorbidity, BRCA mutation), and treatment-related characteristics (previous irradiation, axillary surgery, PMRT, pre- and postoperative chemotherapy, endocrine therapy, and target-therapy). Safety was evaluated as acute and early-late complications, and TE/I failures. At multivariate analysis of the 146 cases (117 patients submitted to BR) a significant factor related to acute toxicity was: BMI ≥ 25 (31.3% [≥ 25] vs 8.8% [

Several biomarkers of healthy aging have been proposed in recent years, including the epigenetic clocks, based on DNA methylation (DNAm) measures, which are getting increasingly accurate in predicting the individual biological age. The recently developed “next‐generation clock” DNAmGrimAge outperforms “first‐generation clocks” in predicting longevity and the onset of many age‐related pathological conditions and diseases. Additionally, the total number of stochastic epigenetic mutations (SEMs), also known as the epigenetic mutation load (EML), has been proposed as a complementary DNAm‐based biomarker of healthy aging. A fundamental biological property of epigenetic, and in particular DNAm modifications, is the potential reversibility of the effect, raising questions about the possible slowdown of epigenetic aging by modifying one's lifestyle. Here, we investigated whether improved dietary habits and increased physical activity have favorable effects on aging biomarkers in healthy postmenopausal women. The study sample consists of 219 women from the “Diet, Physical Activity, and Mammography” (DAMA) study: a 24‐month randomized factorial intervention trial with DNAm measured twice, at baseline and the end of the trial. Women who participated in the dietary intervention had a significant slowing of the DNAmGrimAge clock, whereas increasing physical activity led to a significant reduction of SEMs in crucial cancer‐related pathways. Our study provides strong evidence of a causal association between lifestyle modification and slowing down of DNAm aging biomarkers. This randomized trial elucidates the causal relationship between lifestyle and healthy aging‐related epigenetic mechanisms., In a 24‐month randomized factorial intervention trial, dietary and physical activity interventions slowed down DNA methylation‐based biomarkers of aging.

Chronic low-grade inflammation plays a role in the pathogenesis of several chronic diseases including cancer. Physical activity (PA) and diet have been supposed to modulate inflammatory markers. We evaluated the effects of a 24-month dietary and/or PA intervention on plasma levels of pro-inflammatory cytokines, a secondary analysis in the DAMA factorial trial. The 234 study participants (healthy postmenopausal women with high breast density, 50–69 years, non smokers, no hormone therapy) were randomised to four arms: (1) isocaloric dietary intervention mainly based on plant-foods; (2) moderate-intensity PA intervention with at least 1 h/week of supervised strenuous activity; (3) both interventions; (4) general recommendations on healthy dietary and PA patterns. Interleukins (IL)-1α, -1β, -6, tumor necrosis factor-α and C-reactive protein were measured at baseline and at the end of the intervention. Intention-to-treat-analyses were carried out using Tobit regression. Although all cytokines tended to increase over time, after 24 months women in the PA intervention (arms 2 + 3) showed lower levels of IL-1α (exp(β) = 0.66; p = 0.04) and IL-6 (exp(β) = 0.70; p = 0.01) in comparison with women in the control group (arms 1 + 4). No effects of the dietary intervention emerged. In healthy postmenopausal women with high breast density a moderate-intensity PA appears to slow the age-related increase of pro-inflammatory cytokines.

Shared-decision making for head and neck squamous cell carcinoma (HNSCC) is challenged by the difficulty to integrate the patient perception of value within the framework of a multidisciplinary team approach. The aim of this study was to develop a questionnaire to assess the preferences of HNSCC patients with respect to the disease trajectory, expected treatment, and toxicities. In accordance with the standardized EORTC Quality of Life Group&rsquo, s methodology for the development of quality of life modules, a phase 1&ndash, 2 study was envisaged. Following a systematic review of the literature, a consolidated list of 28 issues was administered through a semi-structured interview to 111 patients from 7 institutions in 5 countries. Overall, &ldquo, cure of disease&rdquo, &ldquo, survival&rdquo, and &ldquo, trusting in health care professionals&rdquo, were the 3 most common priorities, being chosen by 87.3%, 73.6% and 59.1% of patients, respectively. When assessing the correlation with the treatment subgroup, the issue of &ldquo, being thoroughly and sincerely informed about treatments&rsquo, efficacy and survival expectation&rdquo, was highly prevalent in an independent manner (71.4%, 75% and 90% of patients in the follow-up, palliative and curative subgroups, respectively). Based on prespecified scoring criteria, a 24-item list was generated. Pending clinical applicability, further testing and validation of the questionnaire are warranted.

Purpose: To determine dose constraints that correlate with alopecia in patients treated with photon-based Volumetric Modulated Arc Therapy (VMAT) for primary brain tumors. Methods: During the treatment planning process, the scalp was drawn as a region of interest. Dose received by 0.1 cc (D0.1cc), mean dose (Dmean), absolute volumes receiving different doses (V16Gy, V20Gy, V25Gy, V30Gy, V35Gy, V40Gy, and V43Gy) were registered for the scalp. Alopecia was assessed according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Receiver operating characteristics (ROC) curve analysis was used to identify parameters associated with hair-loss. Results: One-hundred and one patients were included in this observational study. At the end of radiotherapy (RT), 5 patients did not develop alopecia (Dmean scalp 3.1 Gy). The scalp of the patients with G1 (n = 11) and G2 (n = 85) alopecia received Dmean of 10.6 Gy and 11.8 Gy, respectively. At ROC analysis, V16Gy20Gy ≥ 5.2 cc were the strongest predictors of acute alopecia risk. Chronic hair-loss assessment was available for 74 patients: median time to recovery from G2 alopecia was 5, 9 months. The actuarial rate of hair regrowth was 98.1% at 18 months after the end of RT. At ROC analysis, V40Gy43Gy ≥2.2 cc were the strongest predictors of chronic G2-alopecia risk. V20Gy, V40Gy, and D0,1cc were shown to be independent variables according to correlation coefficient r. Conclusions: V20Gy and V40Gy were the strongest predictors for acute and chronic G2 hair-loss, respectively. The low-dose bath typical of VMAT corresponds to large areas of acute but transient alopecia. However, the steep dose gradient of VMAT allows to reduce the areas of the scalp that receive higher doses, minimizing the risk of permanent alopecia. The application of our dosimetric findings for the scalp may help in reducing the alopecia risk and also in estimating the probability of hair-loss during patient counseling before starting radiotherapy.

Background: Postoperative radiation therapy after breast conserving surgery in the older adult population is a matter of debate; although radiation therapy was shown to benefit these patients concerning local disease control, the absolute benefit was small and potentially negligible. Partial breast irradiation has been introduced as an alternative treatment approach for low-risk patients. Older adult patients with early breast cancer constitute a unique population with regards to prognosis and potential comorbidities, thus minimizing treatment to maintain health-related quality of life (HRQoL) without compromising survival is extremely important. Estimates of the patient's risk of benefit and/or harm with treatment should be performed together with an assessment of baseline comorbidities, life expectancy, and care preferences. Published data suggest that radiation therapy or endocrine therapy alone resulted in excellent disease control in older women with early breast cancer, and that the combination of both treatments has less incremental benefit than expected. Conversely, the toxicity profile of endocrine therapy is well known, often significantly impacting long term HRQoL of these potentially frail patients. Methods: Patients older than 70 years receiving breast conserving surgery with T1N0, Luminal A-like tumors will be randomized to receive partial breast irradiation-alone or endocrine therapy-alone. The main objectives are to determine patient reported outcome measures in terms of HRQoL, as assessed by the EORTC QLQ-C30 using the global health status of patients, and to demonstrate a non-inferior local control rate between arms. Secondary endpoints are represented by individual scales from QLQ-C30 and module QLQ-BR45 scores; ELD14 questionnaire; geriatric COre DatasEt assessment; distant control rate, adverse events rates, breast cancer specific, and overall survival. Discussion: The EUROPA trial is a new randomized trial focused on older adults (>_70 years) affected by good prognosis primary breast cancer. Our assumption is that postoperative radiation therapy-alone avoids the long-term toxicity of endocrine therapy and favorably impacts on HRQoL in this population. In the current report we present the trial's background and methods, focusing on perspectives in the field of precision medicine. Trial registration: The trial is registered with ClinicalTrial.gov Identifier NCT04134598 / EUROPA trial. (c) 2020 Elsevier Ltd. All rights reserved.

Purpose Response assessment to definitive non-surgical treatment for head and neck squamous cell carcinoma (HNSCC) is centered on the role of 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET-CT) 12 weeks after treatment. The 5-point Hopkins score is the only qualitative system available for standardized reporting, albeit limited by suboptimal positive predictive value (PPV). The aim of our study was to explore the feasibility and assess the diagnostic accuracy of an experimental 6-point scale (“Cuneo score”). Methods We performed a retrospective, multicenter study on HNSCC patients who received a curatively-intended, radiation-based treatment. A centralized, independent qualitative evaluation of post-treatment FDG-PET/CT scans was undertaken by 3 experienced nuclear medicine physicians who were blinded to patients’ information, clinical data, and all other imaging examinations. Response to treatment was evaluated according to Hopkins, Cuneo, and Deauville criteria. The primary endpoint of the study was to evaluate the PPV of Cuneo score in assessing locoregional control (LRC). We also correlated semi-quantitative metabolic factors as included in PERCIST and EORTC criteria with disease outcome. Results Out of a total sample of 350 patients from 11 centers, 119 subjects (oropharynx, 57.1%; HPV negative, 73.1%) had baseline and post-treatment FDG-PET/CT scans fully compliant with EANM 1.0 guidelines and were therefore included in our analysis. At a median follow-up of 42 months (range 5-98), the median locoregional control was 35 months (95% CI, 32-43), with a 74.5% 3-year rate. Cuneo score had the highest diagnostic accuracy (76.5%), with a positive predictive value for primary tumor (Tref), nodal disease (Nref), and composite TNref of 42.9%, 100%, and 50%, respectively. A Cuneo score of 5-6 (indicative of residual disease) was associated with poor overall survival at multivariate analysis (HR 6.0; 95% CI, 1.88-19.18; p = 0.002). In addition, nodal progressive disease according to PERCIST criteria was associated with worse LRC (OR for LR failure, 5.65; 95% CI, 1.26-25.46; p = 0.024) and overall survival (OR for death, 4.81; 1.07-21.53; p = 0.04). Conclusions In the frame of a strictly blinded methodology for response assessment, the feasibility of Cuneo score was preliminarily validated. Prospective investigations are warranted to further evaluate its reproducibility and diagnostic accuracy.

Background Invasive triple negative apocrine carcinoma (TNAC) of the breast is a rare type of triple negative breast cancer. Several studies reported significantly distinct prognosis for TNAC when compared with most of the non-apocrine triple negative (NATN) tumors. This is a case-control study reporting onoutcomes from our long-term single-center experience. Patients and Methods We analyzed the clinicopathologic features of a series of 46 TNAC tumors treated in a 15-year period. Tumor characteristics and outcomes have been compared with a homogeneous control series of 43 NATN tumors treated during the same follow-up period. Local relapse-free survival (LRFS), distant metastases-free survival (DMFS), and overall survival (OS) have been evaluated. Results LRFS in the TNAC group was 85% and 78% at 5 and 10 years, respectively. LRFS in the NATN group was 90% and 79% at 5 and 10 years, respectively (hazard ratio [HR], 1.14; 95% confidence interval [CI], 0.41-3.19; P = .80). DMFS in the TNAC group was 85% and 85% at 5 and 10 years, respectively. DMFS in the NATN group was 85% and 75% at 5 and 10 years, respectively (HR, 0.39; 95% CI, 0.14-1.08; P = .071). OS in the TNAC group was 86% and 83% at 5 and 10 years, respectively. OS in the NATN group was 86% and 63% at 5 and 10 years, respectively. OS was significantly better in the TNAC group (HR, 0.45; 95% CI, 0.20-0.99; P = .049). Conclusions TNAC seems to represent a distinct group of triple negative breast cancer, characterized by a favorable long-term outcome when compared with NATN tumors.

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.