Search

Objective BRCA carriers are recommended to undergo prophylactic risk-reducing salpingo-oophorectomy (RRSO). Possible adverse health impacts of RRSO, particularly when done before natural menopause, can reduce the long-term satisfaction with this risk-reducing strategy. The aim of this study was to prospectively evaluate the level of satisfaction of women undergoing RRSO, also in relation to some specific characteristics at RRSO. Methods A prospective cohort study was performed in the Modena Family Cancer Clinic of the University Hospital of Modena (Italy). All BRCA1/2 confirmed mutation carriers who decided to undergo RRSO were recruited between 2016 and 2019. Results Fifty-five women (29 BRCA1 and 26 BRCA2) (mean age: 50.4 ± 7.7 years [range 35-79]) were included with a mean follow-up after RRSO of 660.9 days (1.8 years) (range 35-1,688 days) (median: 549 days). No intraepithelial (Serous Tubal Intraepithelial Carcinoma)/invasive cancers were found (0%) at RRSO. No vasomotor symptoms at 1 month after surgery were reported by 11/22 (50%) premenopausal women at RRSO. All women (100%) with new "RRSO-caused" vasomotor symptoms with no previous breast cancer initiated postmenopausal hormone therapy. At the final follow-up the satisfaction rate (0-100 visual analog scale points) of the participants was 96.4 ± 8.6 points (range 62-100). To the question "Would you undergo RRSO again if it was proposed today? (0-100 visual analog scale points)" the answer was 99.4 ± 3.2 points (range 79-100). These scores were in general very high and did not change in the different groups according to pre/postmenopausal status at RRSO, cancer survivors versus healthy women at RRSO, BRCA status, hormone therapy users/nonusers after RRSO, "RRSO-caused" symptoms versus not RRSO-caused (P > 0.05). Conclusions Findings from this prospective study suggest that satisfaction with RRSO is very high and little dependent on the participants' characteristics at surgery. Women at high risk for ovarian cancer are very satisfied with their choice of risk-reduction strategy.

Objective: As prostate cancer (PrC) shows a BRCA mutation rate as high as 30%, it becomes crucial to find the optimal selectioncriteria for genetic testing. The primary objective of this study was to evaluate the BRCA mutation rate in families with PrC associatedwith breast and/or ovarian cancers; secondary aims were to compare the characteristics of families and BRCA-related PrC outcomeamong BRCA1 and BRCA2 carriers. Methods: Following the Modena criteria for the BRCA test, we evaluated the mutation rate in families with breast and/or ovariancancer with a Gleason score ≥7 PrCs, by testing breast or ovarian cases and inferring the mutation in the prostate cases. Thecharacteristics of families and BRCA-related PrC outcomes were measured using the chi-square (χ2) test and Kaplan–Meier methods,respectively. Results: Among 6,591 families, 580 (8.8%) with a Gleason score ≥ 7 PrCs were identified, of which 332 (57.2%) met the Modenaselection criteria for BRCA testing. Overall, 215 breast or ovarian cancer probands (64.8%) were tested, of which 41 resulted positivefor BRCA and one for CHEK2 genes (19.5%). No statistically significant differences were found in BRCA-related PrC prognosis andin the characteristics of families among BRCA1, BRCA2 and non-tested patients. Ten of 23 (44%) mutations in the BRCA2 gene fellin the prostate cancer cluster region (PCCR) at the 3′ terminal of the 7914 codon. Conclusions: It appears the Modena criteria are very useful for BRCA testing selection in families with breast and/or ovarian cancerand PrC. A trend toward a worse prognosis has been found in BRCA2 carriers.

Background Healthy lifestyle, including caloric restriction, balanced diet and physical activity, is important in primary and secondary prevention of breast cancer (BC). It is known that Mediterranean diet reduces metabolic syndrome and insulin resistance that are associated with increased risk of BC onset and recurrence. Physical activity decreases BMI, blood concentrations of testosterone, estrogens, insulin, its resistance and strengthens anti-inflammatory pathways against tumor cells. Since January 2014, at our Institution we promoted a project named “Lifestyle Program” for high risk BC patients underwent to primary surgery. Here we presented the results of 12 months of “Lifestyle Program”. Patients and methods Since January 2014 we have prospectively enrolled all high risk patients between 18 and 70 years treated to our department for invasive early-stage breast cancer (stage I-III). High risk has been defined by one or more of the following inclusion criteria: body mass index (BMI) > 25, diagnosis of metabolic syndrome, increased level of blood testosterone and/or insulin. All high risk patients receive a periodical personalized educational intervention by a physiatrist for physical activity and by a nutritionist for a mediterranean diet low in animals fat and enriched of fibers, fruits and vegetables. All patients underwent to screening for anxiety and depression through HADS questionnaire scores. All data were analyzed by Chi-square test assuming statistical significance at p25 in 94.9% of pts at baseline vs 63.2% after 12 months of lifestyle; p=110 mg/dl in 23.5% of pts at baseline vs 10.2% at 12 months; p=27 uU/ml in 20.6% of pts at baseline vs 2.9% after 12 months; p1,2 ng/ml in 17.6% of pts at baseline vs 4.1% at 12 months; p200 mg/dl in 46.9% of pts at baseline vs 35.7% at 12 months; p170 mg/dl in 13.3% of pts at baseline vs 10.2% at 12 months; p Citation Format: Mirco Pistelli, Valentina Natalucci, Lucia Bastianelli, Laura Scortichini, Veronica Agostinelli, Filippo Merloni, Agnese Savini, Marianna Capecci, Maria Gabriella Ceravolo, Roberta Serrani, Maurizio Ricci, Marina Taus, Albano Nicolai, Elena Barbieri, Rossana Berardi. Assessing the impact of 12 months lifestyle interventions on breast cancer secondary prevention: A modeling approach [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD11-03.

The standard first-line for endocrine sensitive metastatic breast cancer (BC) is represented by endocrine therapy. Several phase III clinical trials searched for more effective endocrine strategies. Nevertheless, the use of combinations for the first-line treatment of bone-only disease (BoD) is widely discussed, due to its indolent course. Our meta-analysis aims to explore the role of new endocrine strategies in BoD. A systematic review of electronic databases was conducted to identify the phase III clinical trials comparing the standard AI to novel experimental strategies. The hazard ratios (HR) for PFS were pooled in a meta-analysis. The heterogeneity of the data was evaluated by Chi-square Q test and I2 statistic. 8 studies were included in the analyses. 4 trials explored the role of CDK4/6 inhibitors (Monaleesa2 and 7, Monarch3 and Paloma2), 2 trials analyzed Fulvestrant + AI (SWOG and FACT), one trial studied Fulvestrant monotherapy (FALCON), while one trial evaluated the association between Bevacizumab and Letrozole (ALLIANCE). 6 trials reported data regarding the BoD, while 2 trials included the BoD in the non-visceral disease. Overall, the meta-analyses showed a PFS advantage for the experimental arms [HR 0.70 p 0.012], with a significant moderate/high heterogeneity [I2 66.48% p 0.004]. Only the FALCON and Paloma2 showed a significant improvement in PFS, respectively for Fulvestrant and Palbociclib + Letrozole. Considering only trials reporting data for BoD, the experimental arms significantly improved the PFS [HR 0.66 p 0.005], with a low/moderate non-significant heterogeneity [I2 44.95% p 0.106]. The novel strategies showed to be able to improve the PFS of BoD. Nonetheless, only Palbociclib + Letrozole provided statistically significant data of advantage in this setting. In clinical trials, BoD is often included in the non-visceral disease subgroup. Future clinical trials should take into account the differences in natural history and better prognosis of BoD, in order to define the best approach to these patients. Citation Format: Toss A, Venturelli M, Sperduti I, Isca C, Molinaro E, Barbieri E, Piacentini F, Omarini C, Cortesi L, Cascinu S, Moscetti L. First-line treatment for endocrine sensitive bone-only metastatic breast cancer: Is more always better? [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 P1-18-06.

Given the benefits of physical activity for breast cancer survivals, this pilot study aims to assess the feasibility of the MOTIVE program at achieving and maintaining the recommended physical activity level in women diagnosed and treated breast cancer, over 16 weeks. We conduct a pilot-controlled study of 20 women diagnosed with breast cancer stage I, II or IIIa. In this study, women of Intervention Arm (n = 10) received the MOTIVE program. This group was compared to women of Control Arm (n = 10) who received only counselling. Health-related fitness measures, and quality of life were assessed at baseline (t0) and after 4 (t1), 8 (t2) and 16 (t3) weeks. Intervention Arm women reached the recommended physical activity guidelines at t1 and t2 (eff.size = 1.9 [1.0–3.1]), and 90% continued to be active, autonomously, at t3 (eff.size = 1.12 [0.21–2.12]). Intervention Arm participants’ arm strength, fitness levels and quality of life also improved over time. No significant improvements in outcome measures were observed in Control Arm participants. These results are encouraging and suggest that the MOTIVE program may be a viable, well tolerated and effective option to help breast cancer women reaching a stable physical activity level over time, which meets prevention-related goals., Physical activity; Adherence; Breast cancer; Aerobic exercise; Strength training; Secondary/tertiary prevention; Lifestyle; Public health.

This study aimed to evaluate the cardiometabolic effects of a home-based lifestyle intervention (LI) in breast cancer survivors (BCSs) during the COVID-19 lockdown. In total, 30 BCSs (women, stages 0–II, non-metastatic, aged 53.5 ± 7.6 years, non-physically active, normal left ventricular systolic function) with a risk factor for recurrence underwent a 3-month LI based on nutrition and exercise. Anthropometrics, Mediterranean diet adherence, physical activity level (PAL), cardiorespiratory fitness (VO2max), echocardiographic parameters, heart rate variability (average standard deviation of NN intervals (ASDNN/5 min) and 24 h very- (24 hVLF) and low-frequency (24 hLF)), and metabolic, endocrine, and inflammatory serum biomarkers (glycemia, insulin resistance, progesterone, testosterone, and high-sensitivity C-reactive protein (hs-CRP)) were evaluated before (T0) and after (T1) the LI. After the LI, there were improvements in: body mass index (kg/m2: T0 = 26.0 ± 5.0, T1 = 25.5 ± 4.7, p = 0.035), diet (Mediet score: T0 = 6.9 ± 2.3, T1 = 8.8 ± 2.2, p &lt, 0.001), PAL (MET-min/week: T0 = 647 ± 547, T1 = 1043 ± 564, VO2max (mL·min−1·kg−1: T0 = 30.5 ± 5.8, T1 = 33.4 ± 6.8, signs of diastolic dysfunction (participants: T0 = 15, T1 = 10, p = 0.007), AS-DNN/5 min (ms: T0 = 50.6 ± 14.4, T1 = 55.3 ± 16.7, p = 0.032), 24 hLF (ms2: T0 = 589 ± 391, T1 = 732 ± 542, p = 0.014), glycemia (mg/dL: T0 = 100.8 ± 11.4, T1 = 91.7 ± 11.0, insulin resistance (HOMA-IR score: T0 = 2.07 ± 1.54, T1 = 1.53 ± 1.11, p = 0.005), testosterone (ng/mL: T0 = 0.34 ± 0.27, T1 = 0.24 ± 0.20, p = 0.003), hs-CRP (mg/L: T0 = 2.18 ± 2.14, T1 = 1.75 ± 1.74, p = 0.027). The other parameters did not change. Despite the home-confinement, LI based on exercise and nutrition improved cardiometabolic health in BCSs.

Objectives The Next Generation Sequencing (NGS) based mutational study of hereditary cancer genes is crucial to design tailored prevention strategies in subjects with different hereditary cancer risk. The ease of amplicon-based NGS library construction protocols contrasts with the greater uniformity of enrichment provided by capture-based protocols and so with greater chances for detecting larger genomic rearrangements and copy-number variations. Capture-based protocols, however, are characterized by a higher level of complexity of sample handling, extremely susceptible to human bias. Robotics platforms may definitely help dealing with these limits, reducing hands-on time, limiting random errors and guaranteeing process standardization. Methods We implemented the automation of the CE-IVD SOPHiA Hereditary Cancer Solution™ (HCS) libraries preparation workflow by SOPHiA GENETICS on the Hamilton’s STARlet platform. We present the comparison of results between this automated approach, used for more than 1,000 DNA patients’ samples, and the performances of the manual protocol evaluated by SOPHiA GENETICS onto 240 samples summarized in their HCS evaluation study. Results We demonstrate that this automated workflow achieved the same expected goals of manual setup in terms of coverages and reads uniformity, with extremely lower standard deviations among samples considering the sequencing reads mapped onto the regions of interest. Conclusions This automated solution offers same reliable and affordable NGS data, but with the essential advantages of a flexible, automated and integrated framework, minimizing possible human errors and depicting a laboratory’s walk-away scenario.

Background: Achilles tendinopathy (AT) affects ca. 10 million recreational runners in Europe, the practice of hyaluronic acid (HA) infiltration is being increasingly adopted. The aim of this pilot study was to monitor the effects of a three-local time-spaced injections regimen of HA in the treatment of AT in middle-aged runners combining for the first time viscoelastometric, biochemical, and functional methodologies with routine clinical examinations. Methods: Eight male runners (Age 49.3 ± 3.9), diagnosed for unilateral AT, were given three ultrasound (US) guided peritendinous HA injections at the baseline (T0) and every fifteenth day with a follow-up on the forty-fifth day (T1, T2, and T3). At all-time points patients were assessed for viscoelastic tone and stiffness, maximal voluntary isometric contraction (MVIC), and pain level (Likert scale 0–5). The peritendinous effusions of the injured tendon were collected at T0 and T2 to quantify the volume variations and the IL-1β and MMP-3 levels. Results: At T0 MVIC and pain score were significantly lower and higher, respectively, in injured tendons. The volume, IL-1β and MMP-3 levels decreased in the course of treatment and the clinical endpoints ameliorated over time. Tone, stiffness, and functional performance also varied significantly at T2 and T3, as compared to T0. Conclusions: The sequential peritendinous injections of HA were effective in the amelioration of the clinical symptoms, as well as of the functional and viscoelastic state associated with AT. The determination of the viscoelastometric state may help to precisely evaluate the healing process in AT patients.

The most common breast cancer (BC) susceptibility genes beyond BRCA1/2 are ATM and CHEK2. For the purpose of exploring the clinicopathologic characteristics of BC developed by ATM or CHEK2 mutation carriers, we reviewed the archive of our Family Cancer Clinic. Since 2018, 1185 multi-gene panel tests have been performed. Nineteen ATM and 17 CHEK2 mutation carriers affected by 46 different BCs were identified. A high rate of bilateral tumors was observed in ATM (26.3%) and CHEK2 mutation carriers (41.2%). While 64.3% of CHEK2 tumors were luminal A-like, 56.2% of ATM tumors were luminal B-like/HER2-negative. Moreover, 21.4% of CHEK2-related invasive tumors showed a lobular histotype. About a quarter of all ATM-related BCs and a third of CHEK2 BCs were in situ carcinomas and more than half of ATM and CHEK2-related BCs were diagnosed at stage I-II. Finally, 63.2% of ATM mutation carriers and 64.7% of CHEK2 mutation carriers presented a positive BC family history. The biological and clinical characteristics of ATM and CHEK2-related tumors may help improve diagnosis, prognostication and targeted therapeutic approaches. Contralateral mastectomy should be considered and discussed with ATM and CHEK2 mutation carriers at the first diagnosis of BC.

Recent evidence highlights that physical activity (PA) is associated with decreased recurrence risk, improved survival and quality of life for breast cancer (BC) patients. Our study aimed to explore patterns of increased/decreased PA, and sedentary behaviors among BC women of the DianaWeb cohort during the first wave of COVID-19 pandemic, and examined the association with residential locations, work changes, different modality used to increase PA, and quality of life. The study analyzed the questionnaires completed by the 781 BC women (age 54.68 ± 8.75 years on both December 2019 and June 2020. Results showed a decrease of 22%, 57%, and 26% for walking activity, vigorous activity, and total PA, respectively. Sitting/lying time increased up to 54.2% of the subjects recruited. High quality of life was associated with lower odds of being sedentary (p = 0.003). Our findings suggest that innovative health management fostering compliance with current guidelines for PA and active behavior should be implemented, especially in unpredictable emergency conditions.

To compare the effect of high-intensity aerobic (AER), resistance (RES), and combined (COMB: RES + AER) exercise, on interstitial glucose (IG) variability and skeletal muscle signalling pathways in type 1 diabetes (T1D). T1D participants (6 M/6F) wore a flash glucose monitoring system in four randomized sessions: one control (CONT), and one AER, RES and COMB (40 min each). Mean amplitude of glycemic excursions (MAGE), standard deviation (SD) and coefficient variation (CV) of IG were used to compare the 24 h post-exercise IG variability. Blood and muscle samples were collected to compare exercise-induced systemic and muscle signalling responses related to metabolic, growth and inflammatory adaptations. Both RES and COMB decreased the 24 h MAGE compared to CONT; additionally, COMB decreased the 24 h SD and CV. In the 6–12 h post-exercise, all exercise modalities reduced the IG CV while SD decreased only after COMB. Both AER and COMB stimulated the PGC-1α mRNA expression and promoted the splicing of IGF-1Ea variant, while Akt and p38MAPK phosphorylation increased only after RES and COMB. Additionally, COMB enhanced eEF2 activation and RES increased myogenin and MRF4 mRNA expression. Blood lactate and glycerol levels and muscle IL-6, TNF-α, and MCP-1 mRNAs increased after all exercise sessions, while serum CK and LDH level did not change. COMB is more effective in reducing IG fluctuations compared to single-mode AER or RES exercise. Moreover, COMB simultaneously activates muscle signalling pathways involved in substrate metabolism and anabolic adaptations, which can help to improve glycaemic control and maintain muscle health in T1D.

Some hereditary ovarian cancer cases can be associated with a mutation of a gene involved in the DNA double-strand break repair system other than BRCA, such as BRIP1. This mutation is an emerging indication for prophylactic risk-reducing salpingo-oophorectomy (RRSO): however, anomalous tubal pathologic lesions have not yet been reported during RRSO performed for this specific indication (BRIP1), as largely reported for BRCA mutation carriers. An asymptomatic 64-year-old woman with a family history of ovarian and breast cancer agreed to undergo RRSO for a pathogenic variant of the BRIP1 gene (heterozygous NM_032043.2: c.124delT, p. Cys42Valfs) with normal BRCA genes. Histological examination showed the presence of high-grade serous carcinoma of the fimbria of the right tube of a maximum diameter of 0.4 cm (final FIGO stage IIB). The pathogenic mechanism that leads to the development of high-grade serous ovarian/fallopian tube cancer in patients with mutations of BRIP1 should be the same as for patients with mutations of BRCA1 and 2. Our case confirms to consider BRIP1 mutation to be sufficient to justify RRSO at 45-50 years old.

There is growing evidence of an association between physical activity and a reduced risk of cancer and cancer recurrence. The aim of this study was to assess the effects of exercise-conditioned human serum (HS) effects on the proliferative and tumorigenic potential of triple-negative breast cancer (TNBC) and prostate cancer (PC) cells. Moreover, modulated mechanisms and several physiological factors that can predict exercise effects were investigated. Thirty healthy sedentary subjects were recruited for the study. The subjects performed two high-intensity endurance cycling (HIEC) sessions before and after a nine-week period of high-intensity interval training (HIIT). Cell tumorigenic capacity affected by HS collected before (t0), immediately after (t1), 4 h (t2), and 24 h (t3) after the HIEC sessions was evaluated by in vitro three-dimensional colony formation. The modulation of molecular pathways was analyzed by western blotting and qPCR in TNBC and PC cells, and in TNBC xenografts in exercised mice. All of the HIEC-conditioned HS (t1, t2, and t3) markedly impacted the proliferative and the microtumor-forming capacity of both TNBC and PC cell lines, while the HS collected from the subjects at rest did not. Modulation of the Hippo and Wnt/β-catenin pathways by HIEC-conditioned HS before and after the period of HIIT was shown. Multiple linear regression analysis showed relationships between the effects of HIEC-conditioned HS in PC cells, lactate threshold and VO2max. These results highlight the potential of HIEC bouts in tumor progression control and the importance of optimizing an approach to identify physiological predictors of the effects of acute exercise in tertiary cancer prevention.

Background Although human epidermal growth factor receptor 2 (HER2) overexpression is associated with poor prognosis, patients (pts) with pT1a N0M0 breast cancers (BCs) have an excellent outcome across all subtypes. Interval cancers (ICs) have poorer survival than screen-detected (SD) tumours, and an association has been reported between ICs and HER2 overexpression. We aimed to determine, in a general population of pT1a N0M0 BCs with known screening status, whether HER2-positive ICs have a poorer outcome than HER2-positive SD cancers. Methods We evaluated all incident pT1a N0M0 BCs (n = 874) collected in the Emilia-Romagna region (Italy) from 2003 to 2009 and diagnosed in women aged 50–69. Pts unexposed to screening, with unknown HER2 status and/or treated with adjuvant trastuzumab were excluded from analysis. Results Sixty-one percent of the BCs were SD, whereas 19% were ICs. BCs with high histologic grade, hormone receptor–negative or HER2-positive status (odds ratio = 1.7; 95% confidence interval [CI]: 1.1–2.7) were more likely ICs. Median follow-up was 115 months. The 10-year invasive disease-free survival (iDFS) for HER2-positive ICs was lower than that for HER2-positive SD cancers: 75.0% (95% CI: 55.5%–94.5%) versus 93.8% (95% CI: 86.5%–100%). An interaction between ICs and HER2-positive status was found for poorer iDFS after adjusting for prognostic variables (HR = 5.3; 95% CI: 1.6–16.7). Conclusions IC detection may identify pts with HER2-positive pT1a N0M0 tumours in whom the rate of recurrence justifies consideration for conventional, anti-HER2, adjuvant treatment.

Simple Summary High body mass index (BMI) is correlated with an increased production of hormones (estrogens, insulin, testosterone, leptin), and pro-inflammatory cytokines, which have been associated with breast cancer (BC) risk and recurrence. Regular physical activity (PA) decreases BMI and blood concentrations of testosterone, estrogens, insulin and pro-inflammatory cytokines. Moreover, the Mediterranean diet (MD) reduces obesity, metabolic syndrome (MS) and insulin resistance, which are all associated with increased risk of BC onset and recurrence. Despite the accumulating evidence of the detrimental effect of physical inactivity and overweight on BC recurrence, weight control and PA counseling are not yet current practice. The principal aim of the lifestyle intervention is to promote weight loss through diet and physical activity in overweight and/or high-risk breast cancer survivors. Moreover, implementing a “lifestyle interventions program” in clinical practice can lead to improvements in psychophysical well-being and favor the correction of cardiovascular risk factors and compliance with endocrine therapy, potentially translating into a prognostic advantage. Abstract A healthy lifestyle plays a strategic role in the prevention of BC. The aim of our prospective study is to evaluate the effects of a lifestyle interventions program based on special exercise and nutrition education on weight, psycho-physical well-being, blood lipid and hormonal profile among BC patients who underwent primary surgery. From January 2014 to March 2017, a multidisciplinary group of oncologists, dieticians, physiatrists and an exercise specialist evaluated 98 adult BC female patients at baseline and at different time points. The patients had at least one of the following risk factors: BMI ≥ 25 kg/m2, high testosterone levels, high serum insulin levels or diagnosis of MS. Statistically significant differences are shown in terms of BMI variation with the lifestyle interventions program, as well as in waist circumference and blood glucose, insulin and testosterone levels. Moreover, a statistically significant difference was reported in variations of total Hospital Anxiety and Depression Scale (HADS) score, in the anxiety HADS score and improvement in joint pain. Our results suggested that promoting a healthy lifestyle in clinical practice reduces risk factors involved in BC recurrence and ensures psycho-physical well-being.

The antimitotic agent eribulin, a synthetic analog of halichondrin B isolated from a marine sponge, resulted particularly effective in improving the overall survival of heavily pretreated metastatic breast cancer (MBC) patients in randomized Phase III clinical trials and real-life studies. However, only scant information is available on the clinical experiences of patients who underwent long-lasting eribulin treatment followed by a rechallenge. Here we presented two cases of MBC women previously treated with several lines of chemotherapy and hormonal therapies, who underwent long-lasting treatment and rechallenge with eribulin, showing a partial response in both periods. These anecdotal experiences suggest that rechallenge with eribulin could represent a treatment strategy for advanced MBC and it should be evaluated in a larger study.

Background: MoviS: ‘Movement and Health Beyond Care’ is a 3-year randomized controlled trial aiming to educate cancer patients after adjuvant therapy on the benefits of personalized physical activity (PA) and a proper nutritional plan Methods: In this project, breast cancer (BC) patients who consent to participate will be randomized to Interventional Arm (A), consisting of 3-months of Movis Training, or Control Arm (B), consisting of standard care with no supervised PA The Movis Training consists of 3-months of aerobic training (2 d/week of supervised training and 1 d/week of unsupervised exercise) with an increase in exercise intensity (40-70% Heart Rate Reserve) and duration (20-60 min) Ad interim analyses every 3-months up to 1-year will be included The first cohort of eligible BC survivors were enrolled in January 2020 and carried out the Movis Training even during the COVID-19 pandemic The primary outcome is improvement of Quality of Life (QoL) assessed by European Organization for Research and Treatment of Cancer QoL (EORTC QLQ-C30) The secondary outcomes are improvement of health-related QoL parameters such as: PA level (International Physical Activity Questionnaire;SenseWear Armband), fitness (VO2max), flexibility, strength, psychological well-being (Psychological distress Inventory;Profile of Mood States and diet habit (DianaWeb, MEDIET modified and recall 24h);Anthropometric measurement, Body mass (kg);BMI (kg/m2);body composition Results: The expected improvement (mean ± SD) of the QoL in Arm A at 3-months is 15 1 ± 17 7, while in Arm B is 6 1 ± 17 1 (Cohen d effect size=0 51, medium effect) Using a t test for independent samples, with 0 05 alpha and 0 80 1-beta will require 60 subjects per group Considering an expected drop-out of 30%, a total of 172 patients will be recruited Conclusions: The targeted exercise oncology through multidisciplinary team would like to provide a coordinated program of cancer care to improve health care quality, improve prognosis, increase survival times and QoL and reduce the risk of BC recurrence Legal entity responsible for the study: Elena Barbieri Funding: Has not received any funding Disclosure: All authors have declared no conflicts of interest

Epidemiological evidence shows that physical activity lowers the risk of developing breast cancer and decreases the risk of disease recurrence [1,2]. The main hypothesis on the positive effects of exercise-oncology has focused on lowering the basal systemic levels of cancer risk factors with exercise training. Recently, the effects of cancer progression control by components released after acute exercise bouts have gained attention [3,4]. However, the evaluation of the antiproliferative potential of a single exercise bout needs technical improvement.Here, we present data of a pilot study showing how to evaluate the anti-cancer potential of single exercise bouts with an in vitro three-dimensional cell growth assay, using a triple-negative breast cancer cell line cultured with exercise-conditioned serum. Keywords: Exercise, Triple negative breast cancer, Three-dimensional in vitro culture, Cell proliferation

In the last decade, several clinical trials have investigated novel endocrine combinations for the first-line treatment of hormone receptor-positive metastatic breast cancer. Nevertheless, the use of combinations for the first-line treatment of bone-only disease is widely discussed as a result of its indolent natural history. We performed a comprehensive search of phase 3 randomized clinical trials published in the literature through September 2018. Our aim was to explore the role of the new endocrine approaches in bone-only metastatic breast cancer, suggesting a possible strategy for their selection. In particular, we evaluated the comparative risk of adverse event occurrence during these treatments. A total of 6 studies were deemed suitable for meta-analysis: the Monaleesa-2, Monaleesa-7, Monarch-3, Paloma-2, SWOG, and Alliance trials. Overall, the novel strategies were shown to improve progression-free survival in bone-only disease (hazard ratio = 0.65; 95% confidence interval, 0.49-0.86; P = .003). Combinations with cyclin-dependent kinase inhibitors improved progression-free survival (hazard ratio = 0.54; 95% confidence interval, 0.39-0.75; P < .001) with an acceptable toxicity profile. Abemaciclib was associated with increased anemia and gastrointestinal toxicity (especially diarrhea), whereas palbociclib was associated with increased leukopenia (but not neutropenia) compared to the other compounds. Increased aspartate aminotransferase levels were reported for both ribociclib and abemaciclib. The combination of cyclin-dependent kinase 4/6 inhibitors and endocrine therapy represents an effective and well-tolerated approach for first-line treatment in bone-only disease settings. Because no direct comparison between the 3 cyclin-dependent kinase 4/6 inhibitors is available, the selection of the most appropriate treatment should be based on toxicity profile as well as patient preference and copathologies.

Background: Sequential intra-articular injections of linear and cross-linked hyaluronic acids in the treatment of gonarthrosis Objectives: This study evaluates clinical and biochemical effects of sequential intra-articular (IA) injections of two different formulations of hyaluronic acid (HA) in gonarthrosic (GA) patients. The first formulation consists in linear HA (LHA, MW 800-1200kDa; Regenflex Starter, Regenyal Labs, Italy) and the second in an intercalated mixture of cross-linked and linear HAs (CL-LHA, MW 1-2 MDa the crosslinked form and 500kDa the linear, intercalated one; Regenflex BioPlus). Methods: 39 knee GA patients, 19 adults (50–65 years) and 20 elderly (>65 years), underwent two IA injections, i.e. LHA only at baseline and CL-LHA after 1 week. The same injections were repeated after 6 months. Clinical assessment - visual analogic scale (VAS) for pain, range of motion (ROM) and WOMAC index for knee functional limitation - was performed at baseline and after 3, 6, 9, 12 months. Blood, collected at baseline, after 1 week and 3 months, was analysed for relevant cytokines and collagen telopeptide II (CTX-II). Synovial fluid (SF) from patients with recurrent knee effusion (GA worse group) was biochemically analysed at baseline and 1 week. SF proteomic analysis was also carried out at specific time points. Results: This HA-regimen improved joint pain and function independently from the age; plasma and synovial biochemical analyses indicate the attenuation of inflammatory cytokines (IL-1β, IL-9 and IL-17) and the stabilization of CTX-II; ultrasonograph data show an improvement of cartilage conditions and thickness at 12 months. Conclusion: Sequential IA injections of LHA and CL-LHA represent a highly effective treatment especially in low degree GA patients and produce a significant and perduring improvement also in the GA worse group. The efficacy is likely dependent on the sequential administration of LHA and CL-LHA: the pharmacokinetic rationale of this combination will be discussed. References: E. Barbieri1,2*, P. Sestili1, F. Mannello1, G. Annibalini1, S. Contarelli1, L. Vallorani1, A. M. Gioacchini1, D. Ligi1, L. Croce1, Tung Tran Dang Xuan3, C. Bartolucci1 V. Stocchi1 and I. Capparucci1 1Department of Biomolecular Sciences, University Urbino Carlo Bo, via A. Saffi 2, 61029 Urbino, Italy 2Interuniversity Institute of Myology 3Stem Cells Center, Van Hanh Hospital, Hochiminh City, Viet Nam Disclosure of Interests: None declared

Growing evidence points to the effectiveness of flywheel (FW) based iso-inertial resistance training in improving physical performance capacities. However, molecular adaptations induced by FW exercises are largely unknown. Eight resistance-trained men performed 5 sets of 10 maximal squats on a FW device. Muscle biopsies (fine needle aspiration technique) and blood samples were collected before (t0), and 2 h (t1) after FW exercise. Blood samples were additionally drawn after 24 h (t2) and 48 h (t3). Paired samples t-tests revealed significant increases, at t1, of mRNA expression of the genes involved in inflammation, in both muscle (MCP-1, TNF-α, IL-6) and peripheral blood mononuclear cells (IkB-α, MCP-1). Circulating extracellular vesicles (EVs) and EV-encapsulated miRNA levels (miR-206, miR-146a) significantly increased at t1 as well. Conversely, muscle mRNA level of genes associated with muscle growth/remodeling (IGF-1Ea, cyclin D1, myogenin) decreased at t1. One-way repeated measure ANOVAs, with Bonferroni corrected post-hoc pairwise comparisons, revealed significant increases in plasma concentrations of IL-6 (t1; t2; t3) and muscle creatine kinase (t1; t2), while IGF-1 significantly increased at t2 only. Our findings show that, even in experienced resistance trained individuals, a single FW training session modifies local and systemic markers involved in late structural remodeling and functional adaptation of skeletal muscle.

The identification of BRCA mutations plays a crucial role in the management of hereditary cancer prevention and treatment. Nonetheless, BRCA-testing in pancreatic cancer (PC) patients is not universally introduced in clinical practice. A retrospective analysis was conducted, firstly, to evaluate the rate of BRCA-positive families among those presenting a family history of PC besides breast and/or ovarian cancer. Secondly, the relationship between BRCA pathogenic variants and PC risk was evaluated. Finally, the characteristics of PC developed in BRCA families were described. Among 5143 family trees reporting breast and/or ovarian cancer cases, 392 showed a family history of PC. A total of 35 families (24.5% selected by the Modena Criteria and 21.3% by the NCCN Criteria) were positive to BRCA testing. Among the BRCA1 mutations, 36.8% were found within a region defined by c.3239&ndash, c.3917, whilst 43.7% of BRCA2 mutations were located within c.7180&ndash, c.8248. This study confirmed that an increase in the rate of positive tests in families with PC when associated to breast and/or ovarian tumors. Moreover, this analysis indicated two possible Pancreatic Cancer Cluster Regions that should be verified in future research. Finally, PC in families with breast and/or ovarian cancer history, particularly in BRCA families, were diagnosed at younger age and showed better one-year overall survival.

Cancer is often accompanied by worsening of the patient’s iron profile, and the resulting anemia could be a factor that negatively impacts antineoplastic treatment efficacy and patient survival. The first line of therapy is usually based on oral or intravenous iron supplementation; however, many patients remain anemic and do not respond. The key might lie in the pathogenesis of the anemia itself. Cancer-related anemia (CRA) is characterized by a decreased circulating serum iron concentration and transferrin saturation despite ample iron stores, pointing to a more complex problem related to iron homeostatic regulation and additional factors such as chronic inflammatory status. This review explores our current understanding of iron homeostasis in cancer, shedding light on the modulatory role of hepcidin in intestinal iron absorption, iron recycling, mobilization from liver deposits, and inducible regulators by infections and inflammation. The underlying relationship between CRA and systemic low-grade inflammation will be discussed, and an integrated multitarget approach based on nutrition and exercise to improve iron utilization by reducing low-grade inflammation, modulating the immune response, and supporting antioxidant mechanisms will also be proposed. Indeed, a Mediterranean-based diet, nutritional supplements and exercise are suggested as potential individualized strategies and as a complementary approach to conventional CRA therapy.

Introduction: Outcomes for women with pT1aN0M0 breast cancers (BC) may vary by biologic subtype. A higher proportion of HER2-positive BCs diagnosed in the interval between scheduled screening rounds has been proposed to account for the more aggressive behaviour of interval cancers (IC) compared with screen-detected (SD) tumors. No data are available on the prognostic role of HER2-positive status in a general population of pT1aN0M0 breast tumors with known screening status. Methods: All incident pT1aN0M0 BCs (n=874), systematically collected by the Cancer Registries of Emilia Romagna Region (northern Italy) and diagnosed in women aged 50-69 from 2003 to 2009 were evaluated. Screening status was ascertained by reference to the Emilia Romagna Breast Cancer Screening Program (ERBSP) database. Patients unexposed to screening, with HER2 unknown primary tumor and/or who received adjuvant chemotherapy or trastuzumab were excluded from analysis. Results: Twenty percent of patients had HER2-positive tumors. Fifty-three percent of the entire study population were SD cancers, while 18% were ICs. Tumors with high histologic grade, high proliferative rate, negative estrogen receptor status, or HER2-positive status were more likely to be diagnosed in the interval between screening. At a median follow-up of 84 months, the 5-year invasive disease-free survival (IDFS) rates were 89% and 95% in patients with HER2-positive and HER2-negative tumors, respectively (P = 0.025). Notably, HER2-positive ICs showed poorer IDFS than HER2-positive SD tumors (84% vs. 95%, respectively; P = 0.04). No difference in IDFS rates were observed between HER2-positive SD cancers and HER2-negative SD cancers. Multivariable analysis of candidate prognostic factors for IDFS will be reported. Conclusions: In a general population of pT1aN0M0 early BCs with known screening status, IC detection may identify patients with HER2-positive pT1aN0M0 tumors in whom the rate of recurrence justifies consideration for systemic, anti-HER2, adjuvant therapy. Citation Format: Musolino A, Michiara M, Boggiani D, Sikokis A, Rimanti A, Pellegrino B, Silini EM, Campanini N, Barbieri E, Sgargi P, Falcini F, Pinto C. Prognostic impact of HER2 overexpression/amplification in women with pT1a N0 M0 breast cancer with known screening status: Results from a multicenter population-based cancer registry study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-07-23.

Background: Current guidelines for BC surveillance in asymptomatic pts recommend annual mammography and periodical physical examination. These recommendations arise from two trials conducted in the 1980's: since then no other randomized controlled trials (RCTs) have been conducted on BC follow-up. However our knowledge on BC biology, diagnosis of metastases and treatment has improved. The aim of this prospective RCT is to verify if the serial measurement of CEA and CA15.3 (followed by 18-FDG PET) can anticipate the diagnosis of breast cancer recurrence compared to control arm. If this intermediate end-point will be met a subsequent extension trial will investigate the impact of the earlier diagnosis of distant metastases on survival. Methods: Pts diagnosed with stage I-III BC, who underwent adequate surgery are eligible. Special histologies and low-risk cases according to St. Gallen criteria are excluded. We will include pts at the beginning of the follow-up after the conclusion of primary treatment (cohort 1), and pts that have concluded without relapse the first 5 years of follow-up (cohort 2). Eligible pts will be randomized in a 1:1 ratio to follow-up according to local practice (control arm) or to three-monthly serial dosing of CEA and CA15.3 and subsequent imaging studies (18-FDG PET) only in case of an increase of CEA and/or CA 15.3 greater than a critical difference (CEA +100% and/or CA15.3 +75%) compared to baseline (experimental arm). The following stratification factors will be used: node negative vs positive, HER2 negative vs positive, ER positive vs negative. Eight-hundred pts will be enrolled over 3 years. For such a calculation, we made the assumption of a 20% 5-year incidence of relapse. The target reduction of 3 months in restricted mean survival time (RMST) between the two arms implies a median time of diagnostic anticipation, conditional on having breast cancer recurrence, of 10 months. The follow-up will continue until 10 years from surgery. The first patient was enrolled on 23rd October 2014, up to now 434 pts have been enrolled. The present trial was approved by the Ethical Commitee of S. Orsola-Malpighi Hospital and is registered on clinicaltrials.gov (NCT02261389). Citation Format: Zamagni C, Gion M, Mariani L, Stieber P, Quercia S, Rubino D, Bernardi A, Cacciari N, Fini A, Lenzi M, Minichillo S, Pizzirani C, Pagliaro M, Tomasini S, Barbieri E. Three-monthly dynamic evaluation of CEA and CA15-3 (followed by 18-FDG PET) vs usual practice in the follow-up of early breast cancer (BC) patients (pts): A prospective randomized trial (KRONOS-patient-oriented new surveillance study, Italy) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-05-01.

Menopause is an age-dependent physiological condition associated with a natural decline in oestrogen levels, which causes a progressive decrease of muscle mass and strength and bone density. Sarcopenia and osteoporosis often coexist in elderly people, with a prevalence of the latter in elderly women. The profound interaction between muscle and bone induces a negative resonance between the two tissues affected by these disorders worsening the quality of life in the postmenopausal period. It has been estimated that at least 1 in 3 women over age 50 will experience osteoporotic fractures, often requiring hospitalisation and long-term care, causing a large financial burden to health insurance systems. Hormonal replacement therapy is effective in osteoporosis prevention, but concerns have been raised with regard to its safety. On the whole, the increase in life expectancy for postmenopausal women along with the need to improve their quality of life makes it necessary to develop specific and safe therapeutic strategies, alternative to hormonal replacement therapy, targeting both sarcopenia and osteoporosis progression. This review will examine the rationale and the effects of dietary protein, vitamin D and calcium supplementation combined with a specifically-designed exercise training prescription as a strategy to counteract these postmenopausal-associated disorders.

Triple-negative breast cancer (TNBC) does not express estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 and is characterized by its aggressive nature, lack of targets for targeted therapies, and early peak of recurrence. Due to these specific characteristics, chemotherapy does not usually yield substantial improvements and new target therapies and alternative strategies are needed. The beneficial responses of TNBC survivors to regular exercise, including a reduction in the rate of tumor growth, are becoming increasingly apparent. Physiological adaptations to exercise occur in skeletal muscle but have an impact on the entire body through systemic control of energy homeostasis and metabolism, which in turn influence the TNBC tumor microenvironment. Gaining insights into the causal mechanisms of the therapeutic cancer control properties of regular exercise is important to improve the prescription and implementation of exercise and training in TNBC survivors. Here, we provide new evidence of the effects of exercise on TNBC prevention, control, and outcomes, based on the inhibition of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (PKB also known as Akt)/mammalian target of rapamycin (mTOR) (PI3K-Akt-mTOR) signaling. These findings have wide-ranging clinical implications for cancer treatment, including recurrence and case management.

Background Combined endocrine/targeted approaches have been investigated as first-line treatment in hormone receptors positive metastatic breast cancer (BC). Randomized trials showed that the addiction of CDK (cyclin-dependent kinase) 4/6 inhibitors to endocrine therapy (ET) increase progression free survival (PFS). Elderly patients (aged >65 years) are under represented in most of the trials. Due to the multi-morbidity and the major toxicity associated with the targeted agents, the combination strategy in that subgroup is widely discussed. The present meta-analysis aimed to understand the role of the new endocrine approaches in elderly women. Methods This meta-analysis included first line phase II/III randomized published trials comparing ET to the experimental strategy. Trials with no data about hazard ratios (HR) for PFS in the subgroup of patients aged > 65 years were excluded. The heterogeneity of the data was evaluated by Chi-square Q test and I2 statistic. Prospero registration number: CRD42019120215. Results 8 studies were included: 4 (Paloma1/TRIO-18, Paloma2, Monaleesa2, Monarch3) investigated the role of CDK 4/6 inhibitors, 2 trials (SWOG and FACT) analysed the combination of Fulvestrant plus Aromatase Inhibitors, while other two trials explored the association of ET with Bevacizumab (LEA) and Temsirolimus (HORIZON), respectively. Overall, the meta-analysis showed a PFS advantage for the experimental arms [HR 0.77, p 0.016] with a significant high/moderate heterogeneity [I2 65.46%, p 0.005]. The 4 studies adding CDK4/6 inhibitors to ET showed a significant improvement in PFS compared to ET alone. No significant advantages for the addition of anti-angiogenic agents or Fulvestrant to ET have been found. Conclusions The novel experimental strategies showed an improvement in PFS in elderly patients. Adding CDK4/6 inhibitors to ET significantly prolongs PFS as compared to ET alone, the magnitude of PFS benefit is age-independent. To define the role of novel agents, future trials should be designed taking in account not only the age, but also adequate geriatric assessment and comorbidity status. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure L. Cortesi: Speaker Bureau / Expert testimony: Astazeneca; Speaker Bureau / Expert testimony: Pierre Fabre Pharma. F. Piacentini: Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Pfizer. S. Cascinu: Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Lilly. L. Moscetti: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche; Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis. All other authors have declared no conflicts of interest.

Type 2 diabetes (T2D) is an age-related chronic disease associated with metabolic dysregulation, chronic inflammation, and activation of peripheral blood mononuclear cells (PBMC). The aim of this study was to assess the effects of a concurrent exercise training program on inflammatory status and metabolic parameters of T2D patients. Sixteen male patients (age range 55–70) were randomly assigned to an intervention group (n=8), which underwent a concurrent aerobic and resistance training program (3 times a week; 16 weeks), or to a control group, which followed physicians’ usual diabetes care advices. Training intervention significantly improved patients’ body composition, blood pressure, total cholesterol, and overall fitness level. After training, plasma levels of adipokines leptin (−33.9%) and RBP4 (−21.3%), and proinflammatory markers IL-6 (−25.3%), TNF-α (−19.8%) and MCP-1 (−15.3%) decreased, whereas anabolic hormone IGF-1 level increased (+16.4%). All improvements were significantly greater than those of control patients. Plasma proteomic profile of exercised patients showed a reduction of immunoglobulin K light chain and fibrinogen as well. Training also induced a modulation of IL-6, IGF-1, and IGFBP-3 mRNAs in the PBMCs. These findings confirm that concurrent aerobic and resistance training improves T2D-related metabolic abnormalities and has the potential to reduce the deleterious health effects of diabetes-related inflammation.

1046 Background: Combined endocrine approaches have been widely investigated as first-line treatment in hormone receptors positive metastatic breast cancer. In particular, multiple randomized trials showed that the addiction of CDK (cyclin-dependent kinase) 4/6 inhibitors to endocrine therapy (ET) increase progression free survival (PFS). Elderly patients (aged ≥65 years) are under represented in most of the clinical studies. Moreover, due to the multi-morbidity and the major toxicity associated with the targeted agents, the combination strategy in that subgroup is widely discussed. The present meta-analysis aimed to understand the role of the new endocrine approaches in women aged ≥65 years. Methods: This meta-analysis included first line phase II/III randomized published trials comparing (ET) to the experimental strategy. Trials with no data about hazard ratios (HR) for PFS in the subgroup of patients aged ≥65 years were excluded. The heterogeneity of the data was evaluated by Chi-square Q test and I2 statistic. Results: 8 studies were included in the analysis. 4 trials (Paloma1/TRIO-18, Paloma2, Monaleesa2, Monarch3) investigated the role of CDK 4/6 inhibitors, 2 trials (SWOG and FACT) analysed the combination of Fulvestrant plus Aromatase Inhibitors, while other two trials explored the association of ET with Bevacizumab (LEA) and Temsirolimus (HORIZON), respectively. Overall, the meta-analysis showed a PFS advantage for the experimental arms [HR 0.77, p 0.016] with a significant high/moderate heterogeneity [I2 65.46%, p 0.005]. The 4 studies adding CDK4/6 inhibitors to ET showed a significant improvement in PFS compared to ET alone. No significant advantages for the addition of anti-angiogenic agents or Fulvestrant to ET have been found in elderly population subgroup. Conclusions: The novel experimental combo-strategies in the first line setting showed an improvement in PFS in the subgroup of elderly patients. Adding CDK4/6 inhibitors to ET significantly prolongs PFS as compared to ET alone. The magnitude of PFS benefit due to addition of CDK4/6 inhibitors to ET is age-independent.

Introduction: Management of triple negative breast cancer (TNBC) is still a major challenge: a significant proportion patients relapse despite adjuvant chemotherapy, and the median survival from relapse rarely exceeds 1 year. Angiogenesis activation as well as impairment in mechanisms of DNA repair are frequently described in sporadic TNBCs, but the role of angiogenesis inhibitors and platinum salts is still controversial. This is a phase II trial of preoperative carboplatin-paclitaxel in combination with bevacizumab in TNBC patients with previously untreated, stage II-III disease. The primary aim of the study is the pathologic complete response (pCR) rate. Among the secondary aims: safety, breast conserving surgery rate, early response assessment with dynamic contrast-enhanced Magnetic Resonance Imaging (DCE-MRI), biomarker analyses. Methods: Patients with hormone receptor negative (ER and PgR Results: the accrual of the 44 planned patients is completed. Patients characteristics were as follows: median age 46 yrs (29-74); clinical stage IIA: 38.2%, IIB: 35.3%, III: 26.5%; ductal histology: 89%; histologic grade 3: 95%. Notably, 59% of the patients had clinically involved axillary nodes. At present, 33 patients are assessable for toxicity. Bevacizumab-associated adverse events (AEs) were mild: grade 1-2 hypertension occurred in 3 patients (9%) and grade 1 bleeding in 9 patients (27%). No grade 4 non-hematologic AEs were recorded; Grade 3 AEs were: liver function tests abnormalities in 3 patients, diarrhea in 3 patients, and neuropathy in 1 patient. Thirty-one patients underwent surgery, 16 patients (51%) received breast conserving surgery. A pCR in breast and axillary lymph-nodes was achieved in 16 patients (51%); 25 patients (81%) had negative axillary nodes (yN0). Conclusions: No unexpected toxicity was observed by combining bevacizumab to neoadjuvant platinum-taxane based CT. This combination is active in TNBCs, and the rate of pCR is in the expected range. Moreover, 80% of the patients have nodal negativity at surgery, and these results are of particular interest taking into account the high proportion of patients with clinically involved nodes at the time of diagnosis. The final results along with biomarkers data and early response assessment with DCE-MRI will be available at the time of the meeting. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-14-03.

Background Emerging literature data are showing that a change in human epidermal growth factor receptor (HER2) status adversely affects breast cancer patient's prognosis. The aim of this study was to evaluate the prognostic impact of HER2 loss in patients with HER2-positive disease treated with neoadjuvant therapy with or without anti-HER2 agents. Methods One hundred and seven consecutive HER2-positive patients were identified from a prospectively maintained database. The first cohort includes 40 patients treated with chemotherapy (CT) alone. The second cohort includes 67 patients treated with neoadjuvant CT plus anti-HER2 agents (trastuzumab and/or lapatinib). HER2 expression was evaluated by immunihistochemistry or fluorescence in situ hybridization on pretreatment core biopsy and on surgical specimen after therapy. Results The rates of pathologic complete response (pCR) and breast-conserving surgery were higher in the CT + anti-HER2 cohort. A loss of HER2 expression was observed in 40% of the patients with residual disease after CT alone versus 14.7% of the patients after CT + anti-HER2 agents (P = 0.019). Patients not achieving a pCR have a significant increase in the risk of relapse when compared with those achieving a pCR (hazard ratio [HR] 9.55, P = 0.028). Patients with HER2 loss tended to have a higher risk of relapse as comparing to patients with maintained HER2 positivity (HR 2.41, P = 0.063). Conclusion The pCR is confirmed as a powerful predictor of long-term outcome. The rate of HER2 loss is higher in patients receiving neoadjuvant CT without anti-HER2 agents. HER2 status on residual disease after preoperative therapy can be helpful in selecting patients at different risk of relapse, to be included in prospective trial exploring further adjuvant therapy.

Previous research has shown that comprehension of complex sentences involving wh-movement (e.g., object-relative clauses) elicits activation in the left inferior frontal gyrus (IFG) and left posterior temporal cortex. However, relatively little is known about the neural correlates of processing passive sentences, which differ from other complex sentences in terms of representation (i.e., noun phrase (NP)-movement) and processing (i.e., the time course of syntactic reanalysis). In the present study, 27 adults (14 younger and 13 older) listened to passive and active sentences and performed a sentence-picture verification task using functional Magnetic Resonance Imaging (fMRI). Passive sentences, relative to active sentences, elicited greater activation in bilateral IFG and left temporo-occipital regions. Participant age did not significantly affect patterns of activation. Consistent with previous research, activation in left temporo-occipital cortex likely reflects thematic reanalysis processes, whereas, activation in the left IFG supports processing of complex syntax (i.e., NP-movement). Right IFG activation may reflect syntactic reanalysis processing demands associated with the sentence-picture verification task.

Background Trastuzumab-related cardiotoxicity has been reported in patients receiving trastuzumab concurrently with other agents, especially with anthracyclines. Cardiac function damage is generally rare, precox and mild with trastuzumab alone. Case presentation We report the case of a 49 year-old woman affected by metastatic breast cancer who developed trastuzumab-related cardiogenic shock due to pump failure (with LVEF of about 15%) after three months of treatment. After a long hospitalization in the cardiac intensive care unit and a proper treatment, LVEF increased to 50% and, due to a severe progression of disease, trastuzumab was resumed and continued for more than one year. Conclusion This is a case of particularly severe cardiotoxicity related to trastuzumab treatment, which was recovered with pharmacological treatment and the temporary discontinuation of the treatment. Trastuzumab was safely resumed after clinical and echocardiographic parameters improvement.

Background: HER3 is thought to play a prominent role in resistance to HER2-directed breast cancer therapies. Recent data suggest that HER3 levels also influence HER2-normal breast tumor biology. HER3 and PI3K signaling are linked in that in HER3 signaling activates PI3K and inhibition of PI3K activity can upregulate HER3 expression. Here, we measured quantitative HER3 protein expression levels and PIK3CA mutation status in matched tissues from the primary tumor and site of metastasis to assess correlations with time to recurrence. Methods: 44 pairs (8 HER2+ by HERmark®) of matched tissues from the primary tumor and the site of metastasis were evaluated for HER3 protein expression using a sensitive, quantitative assay for HER3 protein expression in FFPE tissue sections (VeraTag®). Matched samples were also evaluated for quantitative HER2 expression (HERmark) and for PIK3CA mutations at exon 9 (E542K and E545K) and exon 20 (H1047R). Results: HER3 protein expression at the metastatic site was largely independent of HER3 levels at the primary site (Spearman p = 0.50) in contrast to HER2 expression (Spearman p = 0.0004). HER3 expression in the primary tumor correlated with time to recurrence (TTR) (HR = 2.0 per 2-fold increase in HER3; p < 0.0001). Conversely, HER3 expression measured at the site of metastasis was not correlated with TTR (p = 0.55). Estrogen receptor negative tumors were less likely to have PIK3CA mutations (p = 0.023). In cases of primary tumors with PIK3CA mutations, no reversions to wild-type PIK3CA were observed in the metastatic sites. In metastatic tumors, mutations detected in the primary tumor as well as new mutations were observed. A gain of an exon 9 mutation at the metastatic site correlated with shorter TTR (HR = 2.5; p = 0.043). Excluding the 8 samples that were HER2+ by HERmark, longer TTR was observed for patients with PIK3CA mutations in the primary tumor (HR = 0.47; p = 0.042), which is consistent with previous reports. Interestingly, the longer TTR for those with PIK3CA mutations appeared to be dependent on quantitative HER3 protein level (interaction p = 0.065). Conclusions: HER3 protein expression in matched primary and metastatic breast cancer tissues were unrelated. This may indicate that HER3 protein is influenced by the different tumor microenvironments of the primary and metastatic sites. PIK3CA mutations were either maintained or acquired at metastatic sites. Both low HER3 protein expression and the presence of PIK3CA mutations in the primary tumor but not the metastatic tumor were associated with longer TTR. These observations suggest that HER3 protein expression may be an important prognostic factor for breast cancer progression. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-16.

Introduction: emerging literature data have shown a change of HER2 expression from primary tumors to metastatic deposits. Tumor heterogeneity, genetic drift as well as selective pressure of adjuvant therapy have been suggested to explain this phenomenon. Aim of the present analysis is to evaluate the change in HER2 expression after neoadjuvant chemotherapy with or without anti-HER2 agents. Methods: two consecutive cohorts of HER2+ breast cancer patients treated with neoadjuvant therapy were identified from a prospectively maintained database including 310 patients. The first cohort (A) includes 38 patients enrolled before 2005, treated with chemotherapy alone. The second cohort (B) includes 48 patients treated with neoadjuvant chemotherapy in combination with antiHER2 agents (trastuzumab or lapatinib). HER2 expression was evaluated by IHC on pre-treatment core biopsy (tru-cut with 14 gauge needle) and on surgical specimen after neoadjuvant therapy. FISH analysis was performed on IHC 2+ samples. Results: The two cohorts were balanced in respect of tumor stage, patient age, and HR expression. In particular, a co-expression of HER2 and HR was observed in 60% of the patients in cohort A and in 70% of the patients in cohort B (p=0.2). Patients in cohort B have a significantly higher rate of pathologic complete response (pCR) in comparison to cohort A (45% vs 11%, p=0.001). A change in HER2 expression from biopsy to post-therapy samples was observed in 39% of the patients in cohort A vs 12% of the patients in cohort B (p=0.02). No patients with pCR have recurred so far vs 25% of the patients with less than pCR (p=0.005). The rate of recurrence was significantly higher for patients experiencing a change in HER2 expression (50% vs 19%, p=0.018). Conclusion: contrary to our expectations, patients not receiving anti-HER2 therapy as part of neoadjuvant therapy were more likely to have a change in HER2 status vs patients receiving anti-HER2 neoadjuvant therapy. The change in HER2 status has a negative prognostic impact. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-18.

Purpose: Breast cancer is a heterogeneous disease, and newer technologies have identified different molecular classes with distinct behaviour. In particular, hormone receptor positive tumors can be classified as luminal A or luminal B subtypes. Luminal A is a true endocrine dependent disease, generally characterized by high hormone receptor expression, low proliferation and HER2 negativity. Luminal B tumors show a more aggressive phenotype, expressed as a higher proliferation and/or HER2 positivity. It is known that hormone receptor positive tumors are less likely to achieve a pathologic complete response (pCR) after preoperative chemotherapy. Aim of the present analysis was to discriminate, on the basis of tumor proliferation as measured by Ki67, patients with hormone receptor positive/HER2 negative tumors with different probability of obtaining a pCR, and with different long term outcome. Patients and Methods: 274 consecutive stage II-III breast cancer patients treated with preoperative chemotherapy were evaluated. Patients were classified as having hormone receptor positive tumors in case of ER and/or PgR >/= 10%. On the basis of immunohistochemical characteristic, patients were classified as follows: Luminal A, in case of hormone receptor positivity, HER2 negativity, and Ki67/= 15% (37%); HER2-Luminal B in case of hormone receptor positivity and HER2positivity (19%); HER2, in case of hormone receptor negativity and HER2 positivity (8%); triple negative, in case of hormone receptor negativity and HER2 negativity (20%) Results: Patients characteristics were as follows: median age 50 yrs (range: 27-76); clinical stage: IIA 35.7%, IIB 42.3%, III 22%. After a median of 4 courses of preoperative chemotherapy, 46% of the patients underwent conservative surgery. A pCR, as defined as absence of infiltrating tumor in both breast and axillary lymph-nodes, was observed in 28 patients (10.2%). All hormone receptor positive patients received adjuvant hormonal therapy for 5 years after surgery. The probability of obtaining a pCR was significantly lower in patients with hormone receptor positive tumors: 6.8% vs 17.5% in hormone receptor negative, p=0.010. No pCR was observed in the 40 patients classified as having Luminal A tumor; two pCRs only were observed among the 89 patients classified as having Ki67-Luminal B tumors. Patients in the Ki67-Luminal B group had significantly shorter disease-free survival (DFS) as compared with Luminal A patients (5-yr DFS 63% vs 86%, p= 0.0061). The 5-yr overall survival in Ki67-Luminal B group was 88% versus 93% in the Luminal A group. However, with 14 events only, this difference was not statistically significant. Conclusions: In this analysis, patients with Ki67-Luminal B have a worse DFS as compared to patients with Luminal A disease. Due to the limited number of events, no differences in the probability of obtaining a pCR were observed between Luminal A and Ki67-Luminal B tumors. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-30.

Background: Ulcerous rectocolitis and Crohn’s disease are the best known forms of inflammatory bowel disease (IBD). Skin manifestations are not uncommon in IBD and may be divided into specific cutaneous signs, aspecific cutaneous signs, and cutaneous signs caused by drugs used for IBD therapy. The specific signs (fistulas, rhagades and ulcers) are the result of the diffusion of the intestinal inflammatory process into the skin. Aspecific cutaneous signs (stomatic aphthosis, erythema nodosum, pyoderma gangrenosum, Sweet’s syndrome, vasculitis, bullous diseases) are quite frequently found in those suffering from IBD, but also in apparently healthy subjects, and may sometimes be the first sign of the intestinal disease. Cutaneous manifestations due to drugs vary in clinical aspect and are the direct consequence of the therapies adopted, which in IBD patients can be quite numerous: steroids, immunosuppressants, 5-aminosalicylic acid, biological agents, antibiotics. Objective and Methods:Due to the frequent finding of cutaneous manifestations in patients affected by IBD, a collaboration was set up between the Dermatological Clinic of the University of Bologna and the Center for the Study of IBD of the same university hospital. The aim was to diagnose the cutaneous signs appearing during IBD and to establish their etiopathogenesis in order to assess whether they were the result of epiphenomena of the IBD or side effects of the therapies adopted. Results: The cutaneous manifestations we observed can be divided into three distinct groups: signs that were specific to the basic disease, aspecific signs and finally signs attributable to the drugs used for therapy. Particular attention was given to the aspecific signs and those consequential to therapy. The aspecific cutaneous signs seen in our clinic generally reflect those reported in the literature. The cutaneous manifestations due to drugs were further divided into three groups: rosacea, acneiform dermatitis and psoriasis-like dermatitis. The most notable aspect of our series is the high number of patients presenting psoriasiform-type dermatitides with a generally widespread diffusion. Conclusion: We would like to draw attention to the fact that all patients with psoriasis had been undergoing treatment with drugs inhibiting tumor necrosis factor α (TNF-α) as part of IBD therapy. In all cases, the cutaneous reaction started after the third or fourth infusion of the biological drug. Anti-TNF-α agents have also been successfully used to treat psoriasis in the last few years. The reason for this apparently paradoxical effect of the therapy is still unclear.

The paper discusses and examines the importance of information and communication technologies (ICT) in the contexts of balance sheet categories training. In the contemporary education ICT has an important role. It is the most widely spread technology of the modern age which represents the basis for economy and knowledge society in the 21st century. The society should accept the challenge of new technologies, creating new knowledge as the most important supporting pillars of the knowledge society. The promotion of a knowledge society requires radical changes of the school system in general, and a new concept of school as a ‘learning community’. Implementation of ICT are positively associated with increased productivity in the learning process and better performance of educational tasks. Therefore the educational institutions should be flexible, adapt to new changes, constantly learn and introduce innovations. The introduction of ICT to the accounting courses teaching process allow professors and students to have adequate access to all accounting and balance sheet categories, such as resources, liabilities, equity, income and expenses, and understanding of the inter-correspondent relationships in the preparation of accounting balance system equations and balance sheet categories flow based on the equilibrium state of main groups of balance sheet categories. This will make students become adequately equipped with the competences they will need on the labor market. DOI: 10.5901/mjss.2015.v6n2s5p347

TPS11627 Background: Current recommendations for breast cancer (BC) surveillance in asymptomatic patients (pts) include only mammography and physical examination and arise from two trials conducted in the 80’s. Since then new findings about BC biology, treatment and the introduction of cutting-edge diagnostic technologies such as 18-FDG PET have deeply modified our clinical scenarios. The aim of this prospective randomized trial is to verify if the serial measurement of CEA and CA15-3 followed by 18-FDG PET can anticipate the diagnosis of BC recurrence compared to control arm by estimation of the difference of restricted mean survival time (RMST) between the two arms. If the end-point will be met a subsequent extension trial will investigate the impact of the earlier diagnosis of distant metastases on survival. Methods: Pts diagnosed with stage I-III BC, who underwent adequate surgery are eligible. Special histologies and low-risk cases according to St. Gallen criteria are excluded. The study includes pts at the beginning of the follow-up after the conclusion of primary treatment (cohort 1), and pts that have concluded without relapse the first 5 years of follow-up (cohort 2). Eligible pts will be randomized in a 1:1 ratio to follow-up according to local practice (control arm) or to three-monthly serial dosing of CEA and CA15-3 and subsequent 18 FDG-PET only in case of an increase of CEA and/or CA 15.3 greater than a critical difference compared to baseline (experimental arm). The following stratification factors will be used: node negative vs positive, HER2 negative vs positive, ER positive vs negative. Eight-hundred pts will be enrolled over 3 years. For such a calculation, we made the assumption of a 20% baseline 5-year incidence of relapse. The target reduction of three months in RMST implies a median time of diagnostic anticipation, conditional on having BC recurrence, of 10 months. The follow-up will continue until 10 years from surgery. Since 23rd October 2014 573 pts have been enrolled. The present trial was approved by the Ethical Committee of each participating centre and is registered on Clinical trial information: NCT02261389.

A group of worldwide virtual reality and health-care researchers have decided to combine their efforts in a multidisciplinary project titled VETERAN – virtual environments in the diagnosis, prevention and intervention of age-related diseases. The main goal of the VETERAN project is the tuning and testing of different virtual environments, designed to address the cognitive/functional impairments that may occur due to the aging process and age-related disorders. In particular the developed modules will address the problems commonly found in the following pathologies that have a strong impact on the elderly health care policy: Alzheimer’s disease and other senile dementias; stroke and unilateral spatial neglect; mobility-related accidents within specific environments (e.g., falls, shocks). The project will focus on research into clinical aspects of age-related diseases and disorders of high morbidity and specifically target goals of prevention, treatment, or delay in onset. Another goal of the VETERAN project is to define and develop new protocols and tools to be used for general rehabilitation purposes. These tools will aim to provide systematic restorative training within the context of functionally relevant, ecologically valid simulated environments This approach is hoped to optimize the degree of transfer of training and/or generalization of learning to the person’s real world environment. (Less)

OBJECTIVES—Health related quality of life (HRQOL) inventories are multi-dimensional measures of patient-centred health status developed for clinical research. The MS quality of life 54 (MSQOL-54) is an MS-specific HRQOL inventory originally devised for English speaking patients. It consists of a core measure, the 36-item short form health survey (SF-36) previously adapted into Italian, and 18 additional items exploring domains relevant to patients with MS (MS-18 module). The authors translated and culturally adapted into Italian the MS-18 module of the MSQOL-54 questionnaire, and clinically validated the whole questionnaire. METHODS—The MS-18 module was translated following the methodology of the International Quality of Life Assessment (IQOLA) project. The MSQOL-54 was validated in 204 consecutive patients with MS seen between April and September 1997 at three participating centres. The questionnaire was explained by the physician who also administered the expanded disability status scale (EDSS) and mini mental status scale examination, and the patient filled in the MSQOL-54 and Beck depression inventory questionnaires (BDI), with assistance if required. The contribution of impairments and disabilities to MSQOL-54 scores were assessed, and mean scores were compared with normative data for the general Italian population, and with the original sample of United States MS patients. RESULTS—The mean age of the 204 patients was 42 years; mean EDSS score was 4.5 (range 0-8.5). Patients' participation in the assessment was satisfactory, and all scales satisfied the usual psychometric standards. The characteristics of the United States sample matched those of our patients in all but gender (72% United States patients v 52% Italian patients were women), and education (90% United States patients and 44% Italian patients completed high school); MSQOL-54 profiles were also similar. The EDSS was significantly associated with the physical health composite but not with the mental health composite score. Multiple linear regression modelling showed that age and BDI independently predicted physical health composite (p < 0.001), and mental health composite (p < 0.001). Clinical worsening in the previous year had an independent effect on the physical health composite (p < 0.001). CONCLUSIONS—The Italian version of MSQOL-54 is easy to administer and is well accepted by patients. Neurological impairment has a limited influence on perceived quality of life, while age and depressive symptoms has a major influence.