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Breast cancer stands as the most frequently diagnosed cancer and the primary cause of cancer-related mortality among women worldwide, including Italy. With the increasing number of survivors, many are enrolled in regular follow-up programs. However, adherence to recommendations from scientific societies (such as ASCO, ESMO, AIOM) for breast cancer follow-up management varies in daily clinical practice across different cancer centers, potentially resulting in unequal management and escalating costs. To address these concerns, the Italian Association of Multidisciplinary Oncology Groups (AIGOM) orchestrated a Consensus on early Breast Cancer follow-up utilizing the Estimate-Talk-Estimate methodology. Following the identification of 18 Items and 38 statements by a select Board, 46 out of 54 (85.1%) experts comprising a multidisciplinary and multiprofessional panel expressed their degree of consensus (Expert Panel). The Expert Panel underscores the potential for the multidisciplinary team to tailor follow-up intensity based on the individual risk of recurrence. In selected cases, the general practitioner may be recommended as the clinical lead for breast cancer follow-up, both after completion of adjuvant treatment and at early initiation of endocrine therapy in low-risk patients. Throughout follow-up, and alongside oncologic surveillance, the expert panel advises osteometabolic, cardiologic, and gynecologic surveillance for the early detection and management of early and late treatment toxicities. Moreover, preserving quality of life is emphasized, with provisions for psycho-oncologic support and encouragement to adopt protective lifestyle behaviors., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: None of the authors has any interests to report directly related to this manuscript. Outside the scope of this manuscript: Stefania Gori, Fiorenza De Rose, no conflict of interests to declare. Antonella Ferro, honoraria from Novartis, MDS, Daiichi Sankyo, Astra Zeneca, Ely Lilly, Gentili. Alessandra Fabi grants from Astra Zeneca (steering committee); consulting fees from Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead, MSD, Menarini; honoraria from Astra Zeneca, Roche, Lilly, Novartis, Gilead, Pfizer, Daiichi Sankyo Exact Sciences; travel grants from Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead, MSD, Menarini; advisory board from Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead, MSD, Menarini. Catia Angiolini, Giuseppe Azzarello, Maurizio Cancian, Michela Cinquini, Luca Arecco no conflict of interests to declare. Cynthia Aristei, grants from PRIN 2023, from the Ministry of University and Research. Project title “The microbiome in breast cancer therapy and its potential for pRobIOtics to improve treatment outcome. Acronym: BARRIO”. Daniela Bernardi, Laura Biganzoli, Anna Cariello no conflict of interests to declare. Laura Cortesi, report grants from Astra Zeneca, MSD, Pfizer; consulting fees and honoraria from Astra Zeneca, Gilead, MSD, Roche, Pfizer, Daijchii Sanchio, Novartis; travel grants from Gilead, Pfizer, Daijchi Sanchio; Advisory Board from Astra Zeneca, MSD, Novartis. Elisabetta Cretella no conflict of interests to declare. Carmen Criscitiello, grants from Seagen, Gilead; consulting fees and honoraria from Pfizer, Novartis, Lilly, MSD; Seagen, Daiichi Sankyo, Gilead, AstraZeneca, Roche. Ugo De Giorgi consulting fees from Amgen, Astellas Pharma, Astrazeneca, Bayer, Bristol-Myers Squibb, Eisai, Ipsen, Janssen, Merck KGaA, MSD, Novartis, Pfizer; travel grants from Pfizer, Ipsen, Astrazeneca. Maria Carmen De Santis, Giuseppe Deledda, Massimo Dessena, Sara Donati, Arianna Dri, Gianluigi Ferretti no conflict of interests to declare. Jennifer Foglietta, honoraria from Novartis; travel grants from Roche, Sophos, Pfizer; Advisory Board from Menarini Stem Line. Davide Franceschini, Pierfrancesco Franco, Alessio Schirone no conflict of interests to declare. Daniele Generali, grants from LILT, University of Trieste, Novartis, Roche; consulting fees from Lilly, Novartis, Pfizer, Roche, Accord, Daiichi Dankyo; honoraria from Lilly, Novartis, Pfizer, Roche, Accord, Daiichi Dankyo, Astrazeneca, Istituto Gentili; travel grants from Roche, Menarini; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from Mednote. Lorenzo Gianni, travel grants from Novartis, Lilly, Pfizer; Advisory Board from Astra Zeneca, Novartis, Seagen. Stefano Giordani, Giovanni Grandi, Maria Cristina Leonardi, Stefano Magno, no conflict of interests to declare. Luca Malorni, consulting fees from Menarini, Pfizer, Lilly, Novartis, Roche; travel grants from Roche, Menarini, Celgene, IT Health Fusion; Advisory Board from Novartis. Carlotta Mantoan no conflict of interests to declare. Federica Martorana honoraria from Lilly, Daychii-Sankyo, Pfizer, Astra-Zeneca, Novartis; travel grants from Gilead, Roche, Pfizer, Lilly; advisory board from Amgen. Icro Meattini consulting fees from Pfizer, Astra Zeneca, Daiichi Sankyo, Novartis, Eli Lilly, Seagen, Gilead, Menarini StemLine. Bruno Meduri, Laura Merlini, Federica Miglietta, Alessandra Modena, Fabrizio Nicolis, Isabella Palumbo, no conflict of interests to declare. Pietro Panizza honoraria and travel grants from Bayer AG. Francesca Angela Rovera, Piermario Salvini, Armando Santoro, Mario Taffurelli, no conflict of interests to declare. Angela Toss consulting fees and grants from Lilly, Pfizer, Novartis, MSD, Astrazeneca, Gilead, Seagen, Daiichi Sankyo; travel grants from Gilead, Daiichi Sankyo, Menarini, Astrazeneca. Paolo Tralongo, Monica Turazza, Matteo Valerio, Matteo Verzè no conflict of interests to declare. Patrizia Vici consulting fees from Lilly, Daiichi-Sankyo, Pfizer, MSD, Novartis; honoraria from EISAI, Daiichi-Sankyo, Lilly, Novartis, Pfizer; travel grants from Roche, Pfizer, Daiichi-Sankyo, Novartis, IPSEN; advisory board from Pfizer, Novartis. Claudio Zamagni no conflict of interests to declare. Giuseppe Curigliano advisory board from Roche, Novartis, Lilly, Pfizer, Astra Zeneca, Daichii Sankyo, Ellipsis, Veracyte, Exact Science, Celcuity, Merck, BMS, Gilead, Sanofi, Menarini. Giovanni Pappagallo no conflict of interests to declare. Alberto Zambelli consulting fees Pfizer, Lilly, Novartis, Roche, AstraZeneca, DaiichiSankyo, Seagen, ExactSciences, MSD, Gentili, Gilead; travel grants from Roche, DaiichiSankyo, AstraZeneca, Novartis; advisory board from Roche., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Paraoxonase-2 (PON2) is an intracellular protein, that exerts a protective role against cell oxidative stress and apoptosis. Genetic and environmental factors (i.e. dietary factors, cigarette smoke, drugs) are able to modulate cellular PON2 levels. The effect of ultraviolet A radiation (UVA), the oxidizing component of sunlight, on PON2 in human dermal fibroblasts (HuDe) has not been previously explored. Excessive UVA radiation is known to cause direct and indirect skin damage by influencing intracellular signalling pathways through oxidative stress mediated by reactive oxygen species (ROS) that modulate the expression of downstream genes involved in different processes, e.g. skin photoaging and cancer. The aim of this study was, therefore, to investigate the modulation of PON2 in terms of protein expression and enzyme activity in HuDe exposed to UVA (270 kJ/m 2 ). Our results show that PON2 is up-regulated immediately after UVA exposure and that its levels and activity decrease in the post-exposure phase, in a time-dependent manner (2-24 h). The trend in PON2 levels mirror the time-course study of UVA-induced ROS. To confirm this, experiments were also performed in the presence of a SPF30 sunscreen used as shielding agent to revert modulation of PON2 at 0 and 2 h post-UVA exposure where other markers of photo-oxidative stress were also examined (NF-KB, γH2AX, advanced glycation end products). Overall, our results show that the upregulation of PON2 might be related to the increase in intracellular ROS and may play an important role in mitigation of UVA-mediated damage and in the prevention of the consequences of UV exposure, thus representing a new marker of early-response to UVA-induced damage in skin fibroblasts., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Previous studies have inconsistently reported associations between refractory ceramic fibers (RCFs) or mineral wool fibers (MWFs) and the presence of pleural plaques. All these studies were based on chest radiographs, known to be associated with a poor sensitivity for the diagnosis of pleural plaques., Research Question: Does the risk of pleural plaques increase with cumulative exposure to RCFs, MWFs, and silica? If the risk does increase, do these dose-response relationships depend on the co-exposure to asbestos or, conversely, are the dose-response relationships for asbestos modified by co-exposure to RCFs, MWFs, and silica?, Study Design and Methods: Volunteer workers were invited to participate in a CT scan screening program for asbestos-related diseases in France. Asbestos exposure was assessed by industrial hygienists, and exposure to RCFs, MWFs, and silica was determined by using job-exposure matrices. A cumulative exposure index (CEI) was then calculated for each subject and separately for each of the four mineral particle exposures. All available CT scans were submitted to randomized double reading by a panel of radiologists., Results: In this cohort of 5,457 subjects, significant dose-response relationships were determined after adjustment for asbestos exposure between CEI to RCF or MWF and the risk of PPs (ORs of 1.29 [95% CI, 1.00-1.67] and 1.84 [95% CI, 1.49-2.27] for the highest CEI quartile, respectively). Significant interactions were found between asbestos on one hand and MWF or RCF on the other., Interpretation: This study suggests the existence of a significant association between exposure to RCFs and MWFs and the presence of pleural plaques in a large population previously exposed to asbestos and screened by using CT scans., (Copyright © 2023. Published by Elsevier Inc.)

Invasive alien species are among the main global drivers of biodiversity loss posing major challenges to nature conservation and to managers of protected areas. The present study applied a methodological framework that combined invasive Species Distribution Models, based on propagule pressure, abiotic and biotic factors for 14 invasive alien plants of Union concern in Italy, with the local interpretable model-agnostic explanation analysis aiming to map, evaluate and analyse the risk of plant invasions across the country, inside and outside the network of protected areas. Using a hierarchical invasive Species Distribution Model, we explored the combined effect of propagule pressure, abiotic and biotic factors on shaping invasive alien plant occurrence across three biogeographic regions (Alpine, Continental, and Mediterranean) and realms (terrestrial and aquatic) in Italy. We disentangled the role of propagule pressure, abiotic and biotic factors on invasive alien plant distribution and projected invasion risk maps. We compared the risk posed by invasive alien plants inside and outside protected areas. Invasive alien plant distribution varied across biogeographic regions and realms and unevenly threatens protected areas. As an alien's occurrence and risk on a national scale are linked with abiotic factors followed by propagule pressure, their local distribution in protected areas is shaped by propagule pressure and biotic filters. The proposed modelling framework for the assessment of the risk posed by invasive alien plants across spatial scales and under different protection regimes represents an attempt to fill the gap between theory and practice in conservation planning helping to identify scale, site, and species-specific priorities of management, monitoring and control actions. Based on solid theory and on free geographic information, it has great potential for application to wider networks of protected areas in the world and to any invasive alien plant, aiding improved management strategies claimed by the environmental legislation and national and global strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Epidemiological studies suggest associations between diabetes mellitus (DM) andbladder cancer. Several potential mechanisms may explain the increased bladdercancer burden in DM patients. Hyperglycaemia is associated with dysregulation of cellintracellular metabolism and alterations of lipoprotein metabolism and oxidative stress. Dysfunctional HDL including glycated and oxidized HDL are described in DM. Weevaluated the effect of normal HDL (N-HDL) and glycated HDL (G-HDL) on cellproliferation and oxidative stress of J82 bladder cancer cells. We also studied the effectof HDL on cholesterol influx and efflux. In addition, the levels of proteins involvedin cholesterol transport (ABCA1, SRB1, ABCG1) by western blot analysis were studied.Our results demonstrate that N-HDL and G-HDL promote cell proliferation and increase intracellular reactive oxygen species (ROS) levels triggered by incubation of tert-butylhydroperoxide. The increase of intracellular ROS in cells preincubated with G-HDL was associated to higher levels of TBARS in cells compared to N-HDL. Cholesterol efflux wasincreased, on the contrary cholesterol influx was significantly decreased in cellsincubated with G-HDL with respect to cells incubated with N-HDL. Levels of SR-B1 and ABCG1 was increased in cells incubated with G-HDL, suggestingthat dysfunctional HDL could affect cholesterol homeostasis in J82 cells. These resultssuggest that HDL-based treatments should be considered for treatment of urinary bladder cancer., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Stage III NSCLC comprises a heterogeneous population. Different treatment strategies are available, including surgery, radiotherapy, and chemotherapy. The PACIFIC trial results represented a significant change and improvement in the therapeutic strategy for these patients. We aimed to compare the different treatment strategies employed in Stage III NSCLC patients within our institution., Methods: All Stage III NSCLC patients discussed during the weekly thoracic oncology multidisciplinary team meetings at the University hospital Grenoble Alpes (France) between January 2010 and January 2017 were included. Patients' overall survival (OS) according to treatment strategies along with their respective changes were compared., Results: Overall, 476 patients were identified. Among patients initially scheduled to receive neoadjuvant chemotherapy followed by surgery (n = 60), only 37 (62%) actually underwent surgery. Median OS of the cohort was 21.3 months [IQR 25%-75%: 9.6-48.3]. Patients who received neoadjuvant chemotherapy followed by surgery displayed better survival than those treated by CT-RT: 53.2 months [IQR 25%-75%: 16.1-87.3] versus 23.9 [IQR 25%-75%, 13.3-48.1]. Survival was slightly superior for patients treated by upfront CT-RT than for those planned for neoadjuvant chemotherapy followed by surgery who eventually converted to CT-RT (concurrent or sequential): 23.9 months [IQR 25%-75%: 13.3-48.1] versus 20.4 [IQR 25%-75%:10.8-36], respectively., Conclusion: While patients who underwent neoadjuvant chemotherapy followed by surgery displayed a better survival than those treated using CT-RT, switch from surgery to CT-RT actually shortened survival. These results stress the relevance of the tumor board in deciding which is the best therapeutic strategy for Stage III disease patients., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Neuromuscular impairment (NMI) affects almost half of critically ill patients. The purpose was to investigate the role of neuromuscular electrical stimulation (NMES) to gain more insight into the nature of the NMI associated with ICU admission. To this aim, we analyzed the strength-duration (S-D) curves of the rectus femoris muscles of ICU patients compared to healthy volunteers., Methods: S-D curves were recorded from 44 healthy volunteers and 29 ICU patients. Three electrophysiological parameters were used to classify the neuromuscular function, from grade 0 (normal function), to grade 3 (no evocable muscle contraction). ICU patients underwent electroneurographic peroneal nerve testing (PENT) to analyze NMI by electroneurography (ENG)., Results: Three patients were classified as Grade 0; nine as mild NMI (Grade 1), 13 as Grade 2, and four showed unexcitable muscles (Grade 3). Mean CMAP amplitudes were 6.1, 3.4, 2.9 and 0.81 mV from Grade 0 to Grade 3, respectively. CMAP was inversely correlated to NMI grade (-1.7 mV, R 2  = 0.946, p < 0.05)., Conclusions: The normative parameters of the S-D curves obtained by NMES in healthy volunteers allowed identification of NMI in ICU patients. NMES was an affordable tool to evaluate NMI in ICU patients, providing additional information to that obtained by ENG., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: p53 and antiapoptotic B-cell leukemia/lymphoma 2 (BLC2) have been proposed as prognostic markers for early breast cancer (BC), although their relationship with conventional parameters and patient prognosis, as well as their distribution within the molecular BC subtypes remains uncertain., Patients and Methods: In this observational study, we analyzed the immunohistochemical expression of p53 and BLC2 in 1099 early BC patients surgically treated between 2000 and 2006 and followed for at least 5 years, also considering their association with pathologic factors and molecular subtypes, as well as their influence on disease-free survival., Results: p53 and BLC2 are distributed differently across molecular subtypes (P < .0001); in particular, p53 positivity and BLC2 negativity seems to be associated with more aggressive conventional tumor phenotypes. Moreover, BLC2 negativity seems to be a significant discriminating factor for disease-free survival (P = .003) according to Kaplan-Meier analysis, while p53 seems to have no discriminating effect. Among patients with discordant p53/BLC2 phenotype, the combination p53 + BLC2 - seems to be associated with the worst outcomes (P = .007) and significantly influenced the clinical course of node-negative patients treated only with hormone therapy (P = .004)., Conclusion: These two biomarkers, in addition to conventional pathologic factors and molecular subtype, could help define the risk and outcome of BC., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: BRAF mutations occurring in 1%-5% of patients with non-small-cell lung cancer (NSCLC) are therapeutic targets for these cancers but the impact of the exact mutation on clinical activity is unclear. The French National Cancer Institute (INCA) launched the AcSé vemurafenib trial to assess the efficacy and safety of vemurafenib in cancers with various BRAF mutations. We herein report the results of the NSCLC cohort., Patients and Methods: Tumour samples were screened for BRAF mutations in INCA-certified molecular genetic centres. Patients with BRAF-mutated tumours progressing after ≥1 line of treatment were proposed vemurafenib 960 mg twice daily. Between October 2014 and July 2018, 118 patients were enrolled in the NSCLC cohort. The primary outcome was the objective response rate (ORR) assessed every 8 weeks (RECIST v1.1). A sequential Bayesian approach was planned with an inefficacy bound of 10% for ORR. If no early stopping occurred, the treatment was of interest if the estimated ORR was ≥30% with a 90% probability. Secondary outcomes were tolerance, response duration, progression-free survival (PFS), and overall survival (OS)., Results: Of the 118 patients enrolled, 101 presented with a BRAF V600 mutation and 17 with BRAF nonV600 mutations; the median follow-up was 23.9 months. In the BRAF nonV600 cohort, no objective response was observed and this cohort was stopped. In the BRAF V600 cohort, 43/96 patients had objective responses. The mean Bayesian estimated success rate was 44.9% [95% confidence intervals (CI) 35.2%-54.8%]. The ORR had a 99.9% probability of being ≥30%. Median response duration was 6.4 months, median PFS was 5.2 months (95% CI 3.8-6.8), and OS was 10 months (95% CI 6.8-15.7). The vemurafenib safety profile was consistent with previous publications., Conclusion: Routine biomarker screening of NSCLC should include BRAF V600 mutations. Vemurafenib monotherapy is effective for treating patients with BRAF V600 -mutated NSCLC but not those with BRAF nonV600 mutations., Trial Registration: ClinicalTrials.gov identifier: NCT02304809., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In 2013, the French National Cancer Institute initiated the AcSé program to provide patients with secure access to targeted therapies outside of their marketed approvals. Efficacy and safety was then assessed using a two-stage Simon phase II trial design. When the study design was designed, crizotinib was approved only as monotherapy for adults with anaplastic lymphoma kinase plus non-small-cell lung cancers (NSCLC)., Patients and Methods: Advanced NSCLC patients with c-MET ≥6 copies, c-MET-mutated, or ROS-1-translocated tumours were enrolled in one of the three cohorts. Patients were treated with crizotinib 250 mg twice daily. Efficacy was assessed using the objective response rate (ORR) after two cycles of crizotinib as primary outcome. Secondary outcomes included disease control rate at four cycles, best ORR, progression-free survival, overall survival, and drug tolerance., Results: From August 2013 to March 2018, 5606 patients had their tumour tested for crizotinib targeted molecular alterations: 252 patients had c-MET ≥6 copies, 74 c-MET-mutation, and 78 ROS-1-translocated tumour. Finally, 25 patients in the c-MET ≥6 copies cohort, 28 in the c-MET-mutation cohort, and 37 in the ROS-1-translocation cohort were treated in the phase II trial. The ORR was 16% in the c-MET ≥6 copies cohort, 10.7% in the mutated, and 47.2% in the ROS-1 cohort. The best ORR during treatment was 32% in the c-MET-≥6 copies cohort, 36% in the c-MET-mutated, and 69.4% in the ROS-1-translocation cohort. Safety data were consistent with that previously reported., Conclusions: Crizotinib activity in patients with ROS1-translocated tumours was confirmed. In the c-MET-mutation and c-MET ≥6 copies cohorts, despite insufficient ORR after two cycles of crizotinib, there are signs of late response not sufficient to justify the development of crizotinib in this indication. The continued targeting of c-MET with innovative therapies appears justified., Clinical Trial Number: NCT02034981., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: We reported the results of an Italian large retrospective analysis that evaluated the effectiveness and safety of T-DM1 in 'field-practice' breast cancer patients. We performed a sub-analysis to investigate the clinical activity of T-DM1 in patients with brain metastases (BMs)., Methods: The records of 87 adult women with HER2-positive breast cancer and BMs treated with T-DM1 were reviewed. Their clinical outcomes were compared with those of 216 patients without central nervous system (CNS) involvement., Results: Response to T-DM1 treatment in BMs was available for 53 patients in the BM group (60.9%): two patients reported a complete response (3.8%), 11 patients obtained partial response (20.7%; overall response rate: 24.5%), 16 patients had a stable disease (30.1%). Regarding extracranial disease, a total of 77 and 191 patients were evaluable for response in BM group and non-BM group, respectively. The overall response rate was 35.1% in the BM group and 38.3% in the non-BM group; disease control rate was 53.3% and 66.6%, respectively. At a median follow-up of 16 months (range: 1-55), median cumulative progression-free survival (PFS) was 7 months (95% CI: 5.4-8.6) in the BM group and 8 months (95% CI: 5.7-10.3) in the non-BM group. In the second-line setting, PFS was 5 (95% CI: 3.1-6.9) versus 11 (95% CI: 7.1-14.9) months (p = 0.01). Overall survival was 14 months (95% CI: 12.2-15.8) in the BM group and 32 months (95% CI: 24.4-39.6) in the non-BM group (p < 0.0001)., Conclusions: T-DM1 is active in breast cancer patients with BMs., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Beta-sympathomimetic compounds are widely used in therapy because of the bronchodilator, smooth muscle-relaxant and tocolytic properties. However, their growth promoting and performance enhancing effects are often subject to illegal use. The present work describes the development of a fast and reliable analytical multiresidue method for the confirmation 20 β-agonist compounds in animal hair. The procedure is based on alkaline digestion, LLE with organic solvents, SPE clean up and liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis, and is suitable for the public Official control of β-agonist residues in hair sample. Validation was performed according to Commission Decision 2002/657/EC requirements. Independent samples spiked with the investigated compounds in the range 0.2-10.0μgkg -1 are showing intra-day and inter-day precision (RSD) lower than 17.8% and 19.7%, respectively. Linearity, measured in the range of 0.1-10.0μgkg -1 , resulted with a Pearson's r>0.996. The decision limits (CCα) for the all investigated beta agonists resulted in the range 0.2-1.0μgkg -1 . Furthermore, the method was tested on real hair samples obtained from cattle, known as positive to clenbuterol, in order to check its effectiveness and the β-agonists stability., (Published by Elsevier B.V.)

The beneficial effects of statin therapy in reducing cardiovascular morbidity and mortality is not merely explained by the lipid-modulating effects. Although adipokines levels have been associated with cardiometabolic disorders, a few studies have explored the effect of statin on resistin and visfatin. We aimed to evaluate the impact of statin therapy on levels of resistin and visfatin through a meta-analysis of published studies. A systematic literature search in Medline and SCOPUS databases was conducted up to January 2015 to identify controlled trials assessing changes in plasma concentrations of visfatin and resistin during treatment with statins. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference (WMD) and 95% confidence interval (CI) as summary statistics. 12 eligible studies with 14 treatment arms were included. Overall, 844 participants were studied. No significant change in plasma resistin concentrations was observed following statin therapy (WMD: -0.11ng/mL, CI: -1.94,1.73, p=0.909). This effect was robust and not affected by statin type, treatment duration and LDL-cholesterol concentrations. With respect to visfatin concentrations, there was a marginally significant reduction following statin therapy (WMD: -2.40ng/mL, CI: -4.79,-0.002, p=0.050). However, this effect size was weak and sensitive to three of the trials included in the analysis. This meta-analysis did not suggest any effect of statin therapy on plasma resistin levels, while a slight reduction in visfatin levels was found. The effect of statins on visfatin levels may represent a novel pleiotropic characteristic of these drugs., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Vitamin E is one of the most important natural antioxidants, and its plasma levels are inversely associated with the progression of atherosclerosis. There have been reports suggesting a potential negative effect of statin therapy on plasma vitamin E levels. The aim of this meta-analysis was to determine the impact of statin therapy on plasma vitamin E concentrations., Methods: PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases were searched to identify randomized placebo-controlled trials evaluating the impact of statins on plasma vitamin E concentrations from inception to February 27, 2015. A systematic assessment of bias in the included studies was performed using the Cochrane criteria. A random-effects model (using DerSimonian-Laird method) and the generic inverse variance method were used to examine the effect of statins on plasma vitamin E concentrations. Heterogeneity was quantitatively assessed using the I(2) index. Sensitivity analysis was conducted using the leave-one-out method., Results: A meta-analysis of data from 8 randomized treatment arms including 504 participants indicated a significant reduction in plasma vitamin E concentrations following statin treatment (WMD: -16.30%, 95% CI: -16.93, -15.98, p < 0.001). However, cholesterol-adjusted vitamin E concentrations (defined as vitamin E:total cholesterol ratio) were found to be improved by statin therapy (WMD: 29.35%, 95% CI: 24.98, 33.72, p < 0.001). Statin therapy was not associated with any significant alteration in LDL vitamin E content (SMD: 0.003, 95% CI: -0.90, 0.90, p = 0.995)., Conclusion: Findings of the present study suggest that statin therapy has no negative impact on plasma vitamin E concentrations or LDL vitamin E content., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Many low-income parent/caregivers do not understand the importance of cavity-free primary (baby) teeth and the chronic nature of dental caries (tooth decay). As a consequence, dental preventive and treatment utilization is low even when children are screened in schools and referred for care. This study aims to test a referral letter and Dental Information Guide (DIG) designed using the Common-Sense Model of Self-Regulation (CSM) framework to improve caregivers' illness perception of dental caries and increase utilization of care by children with restorative dental needs., Methods: A multi-site randomized controlled trial with caregivers of Kindergarten to 4th grade children in urban Ohio and rural Washington State will compare five arms: (1) CSM referral letter alone; (2) CSM referral letter+DIG; (3) reduced CSM referral letter alone; (4) reduced CSM referral letter+DIG; and (5) standard (control) referral. At baseline, children will be screened at school to determine restorative dental needs. If in need of treatment, caregivers will be randomized to study arms and an intervention packet will be sent home. The primary outcome will be dental care based on a change in oral health status by clinical examination 7 months post-screening (ICDAS sealant codes 1 and 2; restoration codes 3-8; extraction). Enrollment commenced summer 2015 with results in summer 2016., Conclusion: This study uses the CSM framework to develop and test behavioral interventions to increase dental utilization among low-income caregivers. If effective this simple intervention has broad applicability in clinical and community-based settings., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background and Aim: Oxidative stress is associated with insulin resistance pathogenesis, insulin secretion deficiency, and complication onset. Fermented papaya preparation (FPP), a dietary supplement obtained by fermentation of the papaya fruit, may be used as an antioxidant in the prevention of diabetic complications., Methods and Results: Platelets from 30 patients with type 2 diabetes mellitus (DM 2) and 15 healthy subjects were analyzed to evaluate the in vitro effects of FPP incubation. Na(+)/K(+)-adenosine triphosphatase (ATPase) activity, membrane fluidity, total antioxidant capacity (TAC), superoxide dismutase (SOD) activity, and conjugated diene levels were determined. In vitro FPP incubation improved platelet function, by enhancing Na(+)/K(+)-ATPase activity and membrane fluidity, and ameliorated the antioxidant system functionality, through an increase in TAC and SOD activity and a parallel decrease in conjugated diene levels in patients with DM 2., Conclusion: Our data suggest that the incubation with FPP may have a protective effect on platelets from patients with DM 2, by preventing the progression of oxidative damage associated with diabetes and its complications., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Despite advances in cancer therapy, mortality is still high except in early-stage tumors, and screening remains a challenge. The randomized National Lung Screening Trial (NLST), comparing annual low-dose computed tomography (LDCT) and chest X-rays, revealed a 20% decrease in lung-cancer-specific mortality. These results raised numerous questions. The French intergroup for thoracic oncology and the French-speaking oncology group convened an expert group to provide a coherent outlook on screening modalities in France., Methods: A literature review was carried out and transmitted to the expert group, which was divided into three workshops to tackle specific questions, with responses presented in a plenary session. A writing committee drafted this article., Results: The multidisciplinary group favored individual screening in France, when carried out as outlined in this article and after informing subjects of the benefits and risks. The target population involves subjects aged 55-74 years, who are smokers or have a 30 pack-year smoking history. Subjects should be informed about the benefits of quitting. Screening should involve LDCT scanning with specific modalities. Criteria for CT positivity and management algorithms for positive examinations are given., Conclusions: Individual screening requires rigorous assessment and precise research in order to potentially develop a lung-cancer screening policy.

Central nervous system involvement is an uncommon though potentially a severe complication during influenza infection; the pathogenic mechanisms of the neurological syndromes described in humans are largely unknown. We describe a case of a 51-year-old man who presented with fever and behavioral changes but no focal neurological deficits. The next day, the condition rapidly evolved into a severe neurological syndrome with recurrent focal motor seizures with secondary generalization. At the brain MRI, FLAIR disclosed a slight area of increased signal in the left mesial frontal cortex extending to the frontopolar area and insula. At DWI, a mild hyperintensity was evident in the mesial-frontopolar cortex, with normal ADC values. MR perfusion was indicative of severe hypoperfusion. Fungal, bacterial and viral cultures in CSF, blood and urine were negative. The nasopharyngeal swab PCR was positive for the H1N1-influenza A virus. The patient was thus treated and by day five the neurological examination results had returned to normal. A follow-up MRI, performed two weeks later, only revealed a residual slight hyperintensity in the left medial frontal cortex. The onset of a rapidly evolving encephalopathy syndrome, its close association with a MRI brain pattern of acute vasogenic edema and favorable outcome support a diagnosis of PRES during influenza A infection. However, the topographic characteristics of the cerebral lesion seem to define a PRES with an atypical pattern., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Aims: Aim of the paper was to summarize the literature about the effect of dietary lipids on activity of paraoxonase-1 (PON1), a multifunctional enzyme associated with high density lipoprotein (HDL). PON1 exerts a protective effect against oxidative damage of cells and lipoproteins and modulates the susceptibility of HDL and LDL to atherogenic modifications such as homocysteinylation., Data Synthesis: The present review shows evidence that the amount and the composition of dietary lipids are key factors in the modulation of PON1. The effect of dietary lipids is also modulated by PON1 polymorphisms. The molecular mechanisms involved include an effect on PON1 hepatic synthesis or secretion and/or modification of PON1 interactions with HDL. Changes of PON1 activity could also be related to dietary intake of oxidized lipids that behave as PON1 inhibitors., Conclusion: Dietary fatty acids by the modulation of PON1 gene expression and activity could constitute an useful approach for the prevention of human diseases associated with oxidative damage., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Human plasma low density lipoproteins (LDL) and high density lipoproteins (HDL) are involved in the transport of lipids, modulate membrane lipid composition and regulate signal transduction. HDL-like lipoproteins have been shown also in human cerebrospinal fluid and it has been hypothesized that they could have a role in lipid transport in central nervous system. After synthesis, lipoproteins are susceptible to lipid peroxidation triggered by reactive oxygen species (ROS and RNS) produced by peripheral and brain cells. Aim of the paper has been to review the scientific literature on the role of lipid peroxidation of LDL and HDL in the molecular mechanisms of multiple sclerosis (MS). Several studies have demonstrated a significant increase in lipid peroxidation products in brain, plasma and cerebrospinal fluid of MS patients. The increase of antibodies against ox-LDL in plasma and the presence of ox-LDL in demyelinating plaques in MS brain suggests that the disease is associated with oxidative damage of lipoproteins. The impairment of antioxidant systems or an increase in the production of ROS and RNS could contribute to lipoprotein peroxidation in MS. Oxidized lipoproteins show several alterations of their functions, they are neurotoxic and have pro-inflammatory properties. Therefore lipoprotein lipid peroxidation products could be involved in demyelination and axonal injury in MS., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Avermectines are antiparasitic agents widely used as veterinary drugs for food producing animals. The European Community, due to their side effects, limited the use of these molecules establishing maximum residue limits (MRLs) in some foods. A validated qualitative and quantitative high performance liquid chromatography method with fluorescence detection (HPLC-FL) is presented for the simultaneous determination of ivermectin (IVM), abemectin (ABA), moxidectin (MOX), eprinomectin (EPR), doramectin (DOR) and emamectin (EMA) in foodstuffs (muscle, eggs and milk). Samples were extracted with acetonitrile, purified with liquid-liquid extraction (LLE), and analysed by HLPC-FL previous derivatization with trifluoroacetic anhydride (TFAA) in presence of 1-methyl-imidazole (MI) and acetic acid. To date, the presented method is the first validated for the matrix eggs, and in accordance with the requirements set by Commission Decision 2002/657/EC. Recoveries of the methods, calculated spiking the samples in the range 5.0-100.0 μg kg(-1), were 64-83% for muscle, 65-89% for milk and 63-84% for eggs. The precision (CV) ranged between 9.2 and 17.1% for muscle, 9.9 and 16.6% for milk and from 9.4 to 17.4% for eggs. Linearity for the six analytes was calculated from 5.0 to 200.0 μg kg(-1). The main advantages of the presented method are its rapidity, the specificity, the good precision and recovery that make it very suitable to the detection and determination of avermectines., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Organizing pneumonia (OP), or bronchiolitis obliterans organizing pneumonia (BOOP), is rare, particularly in children. It affects the small airways and belongs to the group of interstitial lung diseases. Approximately 20 cases in children have been reported, the lack of knowledge of this disease making the diagnosis less likely. Contrary to the findings in adults, where the cryptogenic form is widely present, OP in pediatrics often occurs after a definite cause (infection, transplant, etc.) or in a specific context (dysimmune disease). We report on a teenager who presented with OP in the context of celiac disease, the first case of this association described in the literature., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Background: Bevacizumab (BVZ) combined with platinum-based therapy is registered for first-line treatment of nonsquamous non-small-cell lung cancer (NSCLC). Patients with centrally located tumors are stated ineligible for BVZ treatment. The goal of this study was to assess the consistency in evaluating eligibility of patients with central tumors for BVZ treatment., Materials and Methods: The study group was composed of 150 NSCLC patients with centrally located tumors. Eligibility for BVZ was assessed by chest computed tomography (CT) scan. Eligibility was assessed independently using CT images reviewed on workstations. Inter- and intraobserver variations on 50 randomly extracted patients were estimated through a statistical modeling (multiple correspondence analysis)., Results: Discordance in eligibility was found for 82 patients (55%). The interobserver strength of agreement was fair to moderate (average kappa = 0.40). Contrarily, the intraobserver strength of agreement was good to very good (average kappa = 0.74). At multivariate analysis, the risk of discrepancy was essentially related to the assessment of the contact between the tumor and the vessels (odds ratio = 13.3, 95% confidence interval 2.8-62.6, P = 0.001)., Conclusions: The consistency in evaluating eligibility of patients with central tumors for BVZ treatment is weak. The study group indicated more stringent criteria to help physicians in taking the best treatment choice that need however to be prospectively validated.

Tumors of the trachea and central bronchi can be benign or malignant. Clinical presentation may be confusing, particularly in benign tumors that can be misdiagnosed as asthma or chronic bronchitis. Chest radiography has many limitations and is often considered unremarkable in patients with tumors of the central airways; therefore, multidetector CT (MDCT) has become the most useful noninvasive method for diagnosing and assessing the central airways. The purpose of this article is to provide a review of imaging of the tumors of the trachea and central bronchi. We emphasize the crucial role of MDCT and postprocessing techniques in assessing neoplasms of the central airways.

Though preclinical evidence supports the protracted use of trastuzumab to reach sustained anti-tumor activity, the activity of trastuzumab beyond disease progression remains controversial in HER-2 over-expressing (HER-2+) metastatic breast cancer (MBC) patients. We retrospectively evaluated a total of 59 patients with HER-2 + MBC treated at our institution with trastuzumab-based therapies. Our results were added to those obtained in similar observational studies and summary estimates for overall response (OR) and clinical benefit (CB) to first and second trastuzumab-based lines were calculated. In our series of patients we observed an OR of 59.3% and 27% for first and second trastuzumab-based lines, respectively, with a corresponding CB of 83% and 62.2%, respectively. Time to first and second progression were 9.5 months and 6.7 months, respectively. The combined analysis showed an OR of 50% for first trastuzumab-based regimen and 21.2% for second trastuzumab-based line. The corresponding values for CB were 77.6% and 42.6%, respectively. A second trastuzumab-containing regimen beyond progression yields a considerable rate of OR and CB in HER-2 + MBC patients. Randomized trials are warranted.

A new LC-MS/MS method for the separation, identification and quantification of residues of 17alpha-estradiol (17alpha-E2) and 17beta-estradiol (17beta-E2) in bovine serum is reported. Deuterium-labelled 17beta-estradiol was used as internal standard. The method was in-house validated in accordance with European Union criteria and adopted in a proficiency study organised by the Community Reference Laboratory (CRL-RIVM, Bilthoven, The Netherlands). The analytes were extracted from serum using acetate buffer, purified by C18 solid-phase extraction (SPE) and chromatographed on a C18 LC column. They were then ionized in a heated nebulizer (HN) interface operating in negative ion mode, where only intact deprotonated molecules, [M-H](-), were generated at m/z 271 and 274 for 17alpha/17beta-E2 and 17beta-E2-d(3), respectively. The decision limits obtained (CCalpha, i.e., critical concentration alpha) were 0.06 ng/mL and 0.03 ng/mL, respectively for 17alpha-E2 and 17beta-E2. Detection capability (CCbeta, i.e., critical concentration beta) values were 0.08 ng/mL and 0.04 ng/mL, respectively, for 17alpha-E2 and 17beta-E2. Precision, accuracy and specificity were satisfactory, recovery ranged from 86.3% to 93.2% and the method resulted sensitive for the required purposes. This method is currently in use for Official Control purposes.

The residue profiles of boldenone (17beta-Bol), its epimer (17alpha-Bol) and the related compound androsta-1,4-diene-3,17-dione (ADD), were investigated by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in urine of male calves orally treated with boldenone, boldenone esters, and/or ADD. In all the experiments with the administered steroids residues of 17alpha-Bol decreased rapidly after end of treatment; detectable amounts of 17alpha-Bol were however noticed along the withdrawal observation period after end of treatment. Differently, residues of 17beta-Bol were detectable only shortly after administration. This in vivo research concerning oral treatments of cattle with boldenone related substances proves ADD to be a very active boldenone precursor in bovine animals.

The residue profiles of 17alpha-/17beta-boldenone conjugated (17alpha/beta-Bol) and ADD were investigated by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in urine of male veal calves fed two commercial milk replacers, with different content of cholesterol and phytosterols. The urine samples were collected within 4 h after feeding and further from all the animals. Detectable amounts of 17alpha-Bol conjugated were measured in urine collected from all calves, but the concentrations of 17alpha-Bol were higher in urine from calves receiving the milk replacer with the greater amount of phytosterols. During the whole experiment, 17beta-Bol and ADD were never detected in urine samples collected.

Purposes: To evaluate whether the incidence of recurrent venous thromboembolism (VTE) events after therapy differs for patients treated with long-term low-molecular-weight heparin (LMWH) or oral anticoagulant therapy (OAT)., Methods: All randomized studies were searched through computerized queries of MEDLINE, the Cochrane Controlled Trials Register, the American Society of Hematology abstract database, and the American Society of Clinical Oncology abstract database., Results: Eleven studies including 2,907 patients were identified. Seven studies evaluated a period of 3 to 9 months after cessation of the allocated treatment: 5.4% of patients in the LMWH group vs 4% in the arm allocated to OAT had an episode of recurrent symptomatic VTE. Combined analysis showed a nonsignificant trend in lowering recurrent symptomatic VTE in favor of OAT (relative risk [RR], 1.29; 95% confidence interval [CI], 0.82 to 2.02; p = 0.27). By contrast, during active treatment, a statistically significant reduction of the risk of recurrent symptomatic VTE in favor of LMWH over OAT was registered (RR, 0.63; 95% CI, 0.47 to 0.83; p = 0.001). Regarding cancer patients only, 37 of 569 patients (6.5%) in the LMWH group had recurrent symptomatic VTE vs 69 of 546 patients (12.6%) in the OAT group, with a statistically significant reduction of the risk of recurrent symptomatic VTE in favor of LMWH (RR, 0.52; 95% CI, 0.35 to 0.76; p = 0.001)., Conclusions: Despite the significant reduction of the risk of recurrent symptomatic VTE in favor of LMWH over OAT during treatment, patients treated with long-term LMWH do not seem to have more frequently recurrent VTE events compared with OAT after cessation of therapy. The significant difference favoring LMWH over OAT among all patients receiving treatment comes mostly from studies enrolling cancer patients.

Aims: The aim of this study was to evaluate the sensitivity, specificity and accuracy of axillary ultrasonography (US) and (99m)Tc-sestamibi scintimammography (SSM) in patients with breast cancer (BC) undergoing curative surgery., Methods: A series of 77 consecutive women (median age 54 years, range 36-70) with primary BC underwent both US and SSM from 2 to 15 (median 4) days prior to curative surgery. The results of imaging studies were compared against the final pathology. Breast-conserving surgery with axillary node (AN) dissection was performed in 49 (63.6%) patients, and modified radical mastectomy in 28 (36.4%) patients, according to the tumour staging., Results: Final pathology showed 5 pT1bN0, 1 pT1bN1, 28 pT1cN0, 19 pT1cN1, 7 pT2N0, and 17 pT2N1 BC. Overall, 719 AN were removed of which 106 (14.7%) were metastatized nodes (median 3, range 1-5 per patient). The sensitivity, specificity and accuracy were 67.6%, 80.0%, and 74.0% for US, 78.4%, 85.0%, and 81.8% for SSM, and 91.9%, 92.5%, and 92.2% for US and SSM together, respectively. There was a significant difference (p<0.05) in the number of metastatized AN between patients with metastases correctly detected and undetected by both US (3.1+/-1.3 vs. 2.0+/-0.7) and SSM (3.2+/-1.3 vs. 1.7+/-0.7)., Conclusions: Although the results of each diagnostic tests are strictly dependent on the number of the metastatized AN, the combination of axillary US and SSM is a sensitive low-cost procedure that should be suggested in all patients with BC, when a preoperative evaluation of the AN status is required.

Insulin resistance induces nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH). We used a high-fat, high-calorie solid diet (HFD) to create a model of insulin resistance and NASH in nongenetically modified rats and to study the relationship between visceral adipose tissue and liver. Obesity and insulin resistance occurred in HFD rats, accompanied by a progressive increase in visceral adipose tissue tumor necrosis factor (TNF)-alpha mRNA and in circulating free fatty acids. HFD also decreased adiponectin mRNA and peroxisome proliferator-activated receptor (PPAR)-alpha expression in the visceral adipose tissue and the liver, respectively, and induced hepatic insulin resistance through TNF-alpha-mediated c-Jun N-terminal kinase (JNK)-dependent insulin receptor substrate-1Ser307 phosphorylation. These modifications lead to hepatic steatosis accompanied by oxidative stress phenomena, necroinflammation, and hepatocyte apoptosis at 4 weeks and by pericentral fibrosis at 6 months. Supplementation of n-3 polyunsaturated fatty acid, a PPARalpha ligand, to HFD-treated animals restored hepatic adiponectin and PPARalpha expression, reduced TNF-alpha hepatic levels, and ameliorated fatty liver and the degree of liver injury. Thus, our model mimics the most common features of NASH in humans and provides an ideal tool to study the role of individual pathogenetic events (as for PPARalpha down-regulation) and to define any future experimental therapy, such as n-3 polyunsaturated fatty acid, which ameliorated the degree of liver injury.

This paper reports the assembly of a disposable immunosensor based on the direct competitive enzyme-linked immunosorbent assay (ELISA), for simple and fast measurement of 17beta-estradiol (17beta-E2) in bovine serum, using screen-printed electrodes (SPEs) and a Palm-Sens portable electrochemical detector. The immunosensor strip was assembled immobilising, by passive adsorption, anti-rabbit IgG onto the surface of the working SPE electrode. After the interaction between anti-rabbit IgG and rabbit anti-17beta-E2 polyclonal antibodies (PAb), the competition was performed using 17beta-estradiol-alkaline phosphatase conjugate (17beta-E2-AP) synthesised in our laboratory. The enzymatic substrate used for signal generation was 1-naphthylphosphate and its conversion to an electroactive product (1-naphthol) was measured using differential pulse voltammetry (DPV). To develop a prototype for field measurements, the entire competitive protocol has been optimised directly in a blank non-extracted bovine serum. According to the new EU criteria established by the Commission Decision 2002/657/EC for qualitative and quantitative screening methods, the detection capability (CCbeta), was determined. The CCbeta value resulted below the action limit (40 pg mL(-1)) fixed for 17beta-E2) Spiked and real samples were analysed using the electrochemical immunostrips obtaining precision values (relative standard deviation, R.S.D.%) ranging from 8.6 to 17.0% and a recovery (R%) from 88.2 to 120.0%. Results obtained on real samples were confirmed by liquid chromatography coupled on-line with tandem mass spectrometry (LC-MS/MS) using an atmospheric pressure chemical ionisation (APCI) source and a heated nebulizer (HN) interface; this is the method currently used to confirm illegal hormone administration for regulatory purposes. The disposable immunosensor appears suitable as a screening tool for field analysis of bovine serum estradiol.

Purpose: To observe whether in pretreated metastatic breast cancer patients with HER2-positive disease vinorelbine plus trastuzumab can produce different overall response rate (ORR), time to progression (TTP), and overall survival (OS) from women with HER2-negative tumors treated with vinorelbine alone., Methods: Between June 2000 and January 2004, 68 consecutive women were enrolled: 33 patients received vinorelbine (V) alone, while 35 patients were given trastuzumab plus vinorelbine (T+V) according to HER2 expression determined by immunohistochemistry. In tumors scored +2, HER2 gene amplification was determined by fluorescence in situ hybridization., Results: In patients treated with V (HER2-negative tumors) the ORR was 27.3%, while in those given T+V (HER2 positive tumors) the ORR was 51.4%. The median duration of response was 8 months for women treated with V and 10 months for those who received T+V. Patients given T+V had a longer TTP (9 months) and OS (27 months) than those receiving V alone (6 months and 22 months respectively). Toxicity was mild in both groups. Concerning cardiotoxicity in T+V group, 7 patients (20%) had left ventricular systolic disfunction., Conclusion: Our data suggest that trastuzumab can change the natural history of HER2-positive metastatic breast cancer. In fact, when treated with trastuzumab, women with HER2-positive disease had better prognosis than patients with HER2-negative tumors. Conducting a formal phase III trial comparing vinorelbine alone vs vinorelbine plus trastuzumab in HER2-positive metastatic breast cancer women could be debatable.

Recent evidence suggests that young women with estrogen receptor (ER)-positive breast cancer (BC) require additional treatment because of the inadequacy of cyclophosphamide, methotrexate fluorouracil (CMF) alone. Herein we report our findings from 368 premenopausal patients given adjuvant anthracycline alone. Overall, patients had a significantly increasing risk of relapse and dying with decreasing age at diagnosis and ER-negative disease. Interestingly, ER expression was not a negative prognostic factor, even among women <35 years, the 5-year disease-free survival (DFS) tending to be higher in patients with ER-positive rather than -negative BC. The potential of combining anthracyclines and endocrine therapies is reviewed and discussed.

High density lipoproteins (HDL) are susceptible to structural modifications mediated by various mechanisms including oxidation, glycation, homocysteinylation or enzymatic degradation. Structural alterations of HDL may affect their functional and atheroprotective properties. Oxidants, such as hypochlorous acid, peroxyl radicals, metal ions, peroxynitrite, lipoxygenases and smoke extracts, can alter both surface and core components of HDL. The formation of lipid peroxidation derivatives, such as thiobarbituric acid reactive substances, conjugated dienes, lipid hydroperoxides and aldehydes, is associated with changes of physical properties (fluidity, molecular order) and of apoprotein conformation. Non-enzymatic glycation, generally associated with lipoxidation, leads to form irreversible complexes called advanced glycation end products. These HDL modifications are accompanied with altered biological activities of HDL and associated enzymes, including paraoxonase, CETP and LCAT. Homocysteine-induced modification of HDL is mediated by homocysteine-thiolactone, and can be prevented by a calcium-dependent thiolactonase/paraoxonase. Tyrosylation of HDL induces the formation of dimers and trimers of apo AI, and alters cholesterol efflux. Phospholipases and proteolytic enzymes can also modify HDL lipid and apoprotein structure. HDL modification induces generally the loss of their anti-inflammatory and cytoprotective properties. This could play a role in the pathogenesis of atherosclerosis and neurodegenerative diseases such as Alzheimer's disease.