Exosomes are endosome-derived nanovesicles actively released into the extracellular environment and biological fluids, both under physiological and pathological conditions, by different cell types. We characterized exosomes constitutively secreted by HER2-overexpressing breast carcinoma cell lines and analyzed in vitro and in vivo their potential role in interfering with the therapeutic activity of the humanized antibody Trastuzumab and the dual tyrosine kinase inhibitor (TKI) Lapatinib anti-HER2 biodrugs. We show that exosomes released by the HER2-overexpressing tumor cell lines SKBR3 and BT474 express a full-length HER2 molecule that is also activated, although to a lesser extent than in the originating cells. Release of these exosomes was significantly modulated by the growth factors EGF and heregulin, two of the known HER2 receptor-activating ligands and naturally present in the surrounding tumor microenvironment. Exosomes secreted either in HER2-positive tumor cell-conditioned supernatants or in breast cancer patients' serum bound to Trastuzumab. Functional assays revealed that both xenogeneic and autologous HER2-positive nanovesicles, but not HER2-negative ones, inhibited Trastuzumab activity on SKBR3 cell proliferation. By contrast, Lapatinib activity on SKBR3 cell proliferation was unaffected by the presence of autologous exosomes. Together, these findings point to the role of HER2-positive exosomes in modulating sensitivity to Trastuzumab, and, consequently, to HER2-driven tumor aggressiveness.

The results are compatible with the hypothesis that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol.

Several studies have shown that hormonal, metabolic and inflammatory mechanisms may affect breast cancer progression. We tested the prognostic value of metabolic syndrome in 110 postmenopausal breast cancer patients, who participated in a 1-year dietary intervention study. The risk of adverse events after 5.5 years of follow-up was examined by Cox' proportional hazard modelling, adjusting for hormone receptor status, stage at diagnosis and serum testosterone level, which were shown to significantly affect prognosis. The adjusted hazard ratio of recurrence for the presence of metabolic syndrome at baseline was 3.0 (95% CI 1.2-7.1). Combining metabolic syndrome and serum testosterone, the adjusted hazard ratio of recurrence among women with metabolic syndrome and testosterone levels higher than 0.40 ng/ml (median value) was 6.7 (95% CI 2.3-19.8) compared with that among women without metabolic syndrome and testosterone levels 0.40 ng/ml. The results suggest that metabolic syndrome may be an important prognostic factor for breast cancer. ' 2006 Wiley-Liss, Inc.Key words: breast cancer; recurrences; metabolic syndromeThe prevalence of metabolic syndrome is increasing in parallel with increasing breast cancer incidence worldwide. 1,2 Several studies have suggested that low HDL-cholesterol, 3 high blood glucose, 4 high triglycerides 5 and other aspects of the metabolic syndrome, such as postmenopausal overweight, 1 abdominal obesity, 6,7 hypertension, 8 high levels of insulin and insulin-like growth factor I (IGF-I), 7,9-11 are associated with breast cancer risk. Metabolic and hormonal parameters related to metabolic syndrome have been suggested to affect breast cancer prognosis too. [12][13][14][15] This is the first report addressing the issue whether breast cancer prognosis is affected by metabolic syndrome, defined by 3 or more of the following indicators: fasting glycaemia 110 mg/dl, HDL-cholesterol <50 mg/dl, triglycerides 150 mg/dl, waist circumference 88 cm, systolic pressure 130 mmHg and diastolic pressure 85 mmHg. 16 If confirmed, these results showing a significantly worse prognosis of patients with metabolic syndrome could have important implications for lifestyle intervention to prevent or decelerate cancer progression. Patients and methodsOne hundred and ten postmenopausal women (mean age: 56.8 6 5.6 years) operated for breast cancer since at least a year (4.6 6 4.4 years on average), not undergoing chemotherapy, and with no clinical evidence of disease recurrence, volunteered to participate in a dietary intervention study in which they were requested to follow kitchen courses and modify their diet for 1 year with the aim of reducing insulin and sex hormone levels (The Diana-2 Study). 12 All patients signed an informed consent and the study was approved by the Institutional Review Board and the Ethical Committee of the Milan National Cancer Institute. Results on hormonal changes and the prognostic values of baseline hormone levels (testosterone, oestradiol and insulin) have been published elsewhere. 12,...

Objectives Evidences from either small series or spontaneous reporting are accumulating that SARS-CoV-2 involves the Nervous Systems. The aim of this study is to provide an extensive overview on the major neurological complications in a large cohort of COVID-19 patients. Methods Retrospective, observational analysis on all COVID-19 patients admitted from February 23rd to April 30th, 2020 to ASST Papa Giovanni XXIII, Bergamo, Italy for whom a neurological consultation/neurophysiological assessment/neuroradiologic investigation was requested. Each identified neurologic complication was then classified into main neurologic categories. Results Of 1760 COVID-19 patients, 137 presented neurologic manifestations that manifested after COVID-19 symptoms in 98 pts and was the presenting symptom in 39. Neurological manifestations were classified as: (a) cerebrovascular disease [53 pts (38.7%)] including 37 ischemic and 11 haemorrhagic strokes, 4 transient ischemic attacks, 1 cerebral venous thrombosis; (b) peripheral nervous system diseases [31 (22.6%)] including 17 Guillain-Barrè syndromes; (c) altered mental status [49 (35.8%)] including one necrotizing encephalitis and 2 cases with RT-PCR detection of SARS-Cov-2 RNA in CSF; (d) miscellaneous disorders, among whom 2 patients with myelopathy associated with Ab anti-SARS-CoV-2 in CSF. Patients with peripheral nervous system involvement had more frequently severe ARDS compared to patients with cerebrovascular disease (87.1% vs 42%; difference = 45.1% 95% CI 42.0-48.2; χ 2 = 14.306; p < 0.0002) and with altered mental status (87.1% vs 55.6%; difference = 31.5% 95% CI 27.5-37.5%; χ 2 = 7.055; p < 0.01). Conclusion This study confirms that involvement of nervous system is common in SARS-CoV-2 infection and offers clinicians useful information for prevention and prompt identification in order to set the adequate therapeutic strategies.

Metabolic syndrome (MS), conventionally defined by the presence of at least three out of five dysmetabolic traits (abdominal obesity, hypertension, low plasma HDL-cholesterol, high plasma glucose and high triglycerides), has been associated with an increased risk of several age-related chronic diseases, including breast cancer (BC). This may have prognostic implications for BC survivors. 2,092 early stage BC survivors aged 35-70, recruited in eleven Italian centres 0-5 years after surgical treatment (1.74 years on average), were followed-up over 2.8 years on average for additional BC-related events, including BC-specific mortality, distant metastasis, local recurrences and contralateral BC. At recruitment, 20 % of the patients had MS. Logistic regression models were carried out to generate OR and 95 % confidence intervals (CI) for new BC events associated with MS, adjusting for baseline pathological prognostic factors. New BC events occurred in 164 patients, including 89 distant metastases. The adjusted ORs for women with MS versus women without any MS traits were 2.17 (CI 1.31-3.60) overall, and 2.45 (CI 1.24-4.82) for distant metastasis. The OR of new BC events for women with only one or two MS traits was 1.40 (CI 0.91-2.16). All MS traits were positively associated with new BC events, and significantly so for low HDL and high triglycerides. MS is an important prognostic factor in BC. As MS is reversible through lifestyle changes, interventions to decrease MS traits in BC patients should be implemented in BC clinics.