Adherence to the 2018 WCRF/AICR recommendations and sleep behaviour in people with metabolic syndrome.

OBJECTIVES: to investigate the association between the adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) recommendations and the prevalence of parameters of sleep quality and quantity in people with metabolic syndrome (MS). DESIGN: cross-sectional study. SETTING AND PARTICIPANTS: 126 people with MS included in a randomized controlled trial of Mediterranean diet and metformin for the primary prevention of age-related chronic diseases (Me.Me.Me. study) wore for one week an actigraph called Actiwatch to assess restful sleep parameters (sleep efficiency - SE, actual sleep time - AST, immobile time - IT) and fragmented sleep parameters (moving time - MT, movement and fragmentation index - MFI, sleep latency - SL). At the baseline visit, each participants completed a 24-hour food frequency diary listing what he/she ate the previous day, and the International Physical Activity Questionnaire. These questionnaires were used to build up a score for adherence to seven relevant 2018 WCRF/AICR recommendations. MAIN OUTCOME MEASURES: the prevalence ratios (PRs) and 95% confidence intervals (CIs) of sleep parameters associated with each recommendation and with the number of met recommendations were calculated using a binomial regression model. RESULTS: the PRs for SE>=85% and IT>=84% increased with the number of met recommendations. Meeting 5-7 recommendations compared to 0-2 was associated with a better SE (PR 3.24 for SE>=85%; p=0.03) and IT (PR 1.68 for IT>=84%; p=0.04). The PRs for MFI>=34.5 and SL>=18 minutes decreased with the number of met recommendations. Meeting 5-7 recommendations compared to 0-2 was associated with a 46% lower prevalence of MFI (p=0.02) and 40% lower prevalence of SL (p=0.04). CONCLUSIONS: the findings of this paper suggest that the prevalence of better sleep quality in people with MS might be associated with closer adherence to 2018 WCRF/AICR recommendations.

Imatinib and everolimus in patients with progressing advanced chordoma: A phase 2 clinical study.

BACKGROUND: We present the results of an academic phase 2 study on imatinib plus everolimus in patients who have progressive advanced chordoma. METHODS: In January 2011, 43 adult chordoma patients were enrolled in the study and received imatinib 400 mg/day and everolimus 2.5 mg/day until progression or limiting toxicity. Eligible patients had progressed in the 6 months before study entry. PDGFRB, S6, and 4EBP1 expression and phosphorylation were evaluated by way of immunohistochemistry and/or western blotting. The primary endpoint was the overall response rate (ORR) according to Choi criteria. Secondary endpoints were RECIST 1.1 response, progression-free survival (PFS), overall survival (OS), correlation between S6/4EBP1 phosphorylation and response. RESULTS: Thirteen of 43 patients were pretreated with imatinib. Among 40 of the 43 patients who were evaluable by Choi criteria, the best responses were 9 with partial response (ORR, 20.9%), 24 with stable disease (SD) (ORR, 55.8%), and 7 with progressive disease (ORR, 16.3%). Forty-two patients were evaluable by RECIST criteria, with 1 partial response (ORR, 2.3%), 37 stable disease (ORR, 86%), and 4 progressive disease (ORR, 9.3%). The median PFS according to Choi criteria was 11.5 months (range, 4.6-17.6 months), and 58.8% and 48.1% of patients were progression-free at 9 and 12 months, respectively. The median PFS by RECIST criteria was 14 months; the median OS was 47.1 months. When assessable, S6/4EBP1 was phosphorylated in a high and moderate/low proportion of tumor cells in responsive and nonresponsive patients, respectively. Toxicity caused a temporary and definitive treatment discontinuation in 60.5% and 30.2% of patients, respectively. CONCLUSIONS: Imatinib plus everolimus showed a limited activity in progressing advanced chordoma. Interestingly, the amount of tumor cells activated for mammalian target of rapamycin effectors correlated with the response. Toxicity was not negligible.

Observational study on the prognostic value of testosterone and adiposity in postmenopausal estrogen receptor positive breast cancer patients.

BACKGROUND: Despite the clear endocrine-metabolic relationship between androgenic activity and adiposity, the role of androgens in breast cancer prognosis according to patient's adiposity is scarcely explored. Here, we aimed at investigating the prognostic value of circulating testosterone in association with patient's body mass index (BMI). METHODS: Circulating testosterone and BMI were evaluated at breast cancer diagnosis in 460 estrogen receptor (ER)-positive postmenopausal patients. Local relapse, distant metastasi(e)s and contralateral breast cancer were considered recurrence events. The Kruskal-Wallis test was performed to evaluate if testosterone levels differed within subgroups of categorical tumour characteristics. The Cox proportional hazard regression model was fitted to estimate the impact of standard prognostic factors on relapse-specific hazard ratio (HR). After backward selection, a model including continuous testosterone level, BMI categories (< 25, normal-weight; =25-30, overweight; ≥30 kg/m2, obese), tumour size and lymph nodes number was fitted. Furthermore, Cox models provided the relapse-specific HRs for median, third quartile and 95th percentile compared to the first quartile of testosterone levels, stratified by BMI categories. RESULTS: During a median follow up of 6.3 years, 45 patients relapsed. Testosterone levels significantly increased across BMI categories (p = 0.001). Both circulating testosterone and BMI were positively associated with disease free survival (p = 0.005 and p = 0.021, respectively). A significant interaction was found between testosterone and BMI (p = 0.006). For normal-weight women, testosterone concentration around median (0.403 ng/mL) or third quartile (0.532 ng/mL) showed a high significant HR of relapse (5.52; 95% CI:1.65-18.49 and 4.55; 95% CI:1.09-18.98, respectively). Overweight patients showed increased HR at increasing testosterone levels, reaching a significant high HR (4.68; 95% CI:1.39-15.70) for testosterone values of 0.782 ng/mL (95th percentile). For obese patients HR decreased (not significantly) at increased testosterone concentrations, explaining the interaction between testosterone levels and BMI categories. CONCLUSIONS: In ER-positive postmenopausal breast cancer patients, high testosterone levels are associated with worse prognosis in normal-weight and overweight women, whereas in obese seems to be associated with a better outcome. Although the results require further validation, they suggest that assessment of circulating testosterone and BMI could help to identify postmenopausal ER-positive patients at higher risk of relapse and potentially open new therapeutic strategies.

Correction to: Observational study on the prognostic value of testosterone and adiposity in postmenopausal estrogen receptor positive breast cancer patients.

Following publication of the original article [1], the authors reported that the affiliation of author Annalisa Orenti was omitted.

Serum levels of testosterone and SHBG in association with body mass index improve the predictive capability of consolidate tumor biomarkers in pre- and postmenopausal breast cancer patients.

OBJECTIVE: To investigate the contribution of serum levels of testosterone (TS) and sex hormone binding globulin (SHBG) in association with body mass index (BMI) as a surrogate marker of obesity, to the predictive capability of tumor size (T), lymph node (N) and estrogen receptor (ER) status and proliferative activity (TLI). METHODS: We investigated 120 women with primary breast cancer and median follow-up of 138 months. Serum levels of TS and SHBG and patient's BMI were evaluated before surgery. The contribution of TS, SHBG, their ratio (TS/SHBG) and BMI to the predictive capability of tumor-specific biomarkers was investigated by Harrell's c statistic. RESULTS: TS alone did not affect prognosis, whereas SHBG was protective in postmenopausal patients, in which BMI was associated with a progressive increase in the relapse-specific hazard ratio (HR). When in combination, TS, SHBG and BMI, affected prognosis in different ways depending on menopausal status. The best predictive capability (c = 0.78) was observed in postmenopausal patients when at the basic model (N + TLI) were added TS, BMI, TS * BMI interaction, with or without SHBG. In premenopause subgroup, the best predictive capability (c = 0.67) was provided by the basic model (N + TLI) plus TS and SHBG or their ratio, BMI and TS * BMI or TS/SHBG * BMI interaction. CONCLUSIONS: Patient-associated features such as BMI and serum levels of TS and SHBG can improve the predictive capability of consolidate tumor-specific biomarkers in both pre- and postmenopause, thus providing a relevant contribution to the decision-making process.

Adherence to WCRF/AICR cancer prevention recommendations and metabolic syndrome in breast cancer patients.

Metabolic syndrome (MetS), conventionally defined by the presence of at least three out of five dismetabolic traits (abdominal obesity, hypertension, low plasma HDL-cholesterol and high plasma glucose and triglycerides), has been associated with both breast cancer (BC) incidence and prognosis. We investigated the association between the prevalence of MetS and a score of adherence to the World Cancer Research Fund (WCRF) and American Institute for Cancer Research (AICR) recommendations for the prevention of cancer in a cross-sectional study of BC patients. The DIet and ANdrogen-5 study (DIANA-5) for the prevention of BC recurrences recruited 2092 early stage BC survivors aged 35-70. At recruitment, all women completed a 24-hour food frequency and physical activity diary on their consumption and activity of the previous day. Using these diaries we created a score of adherence to five relevant WCRF/AICR recommendations. The prevalence ratios (PRs) and 95% confidence intervals (CIs) of MetS associated with the number of recommendations met were estimated using a binomial regression model. The adjusted PRs of MetS decreased with increasing number of recommendations met (p < 0.001). Meeting all the five recommendations versus meeting none or only one was significantly associated with a 57% lower MetS prevalence (95% CI 0.35-0.73). Our results suggest that adherence to WCRF/AICR recommendations is a major determinant of MetS and may have a clinical impact.

Management of headache disorders in the Emergency Department setting.

Headache is a common presenting complaint in the Emergency Department. The aim of this study was to delineate the demographic profile of patients presenting a chief complaint of headache and to assess the application of diagnostic algorithms for the management of these patients. We examined patients admitted to the Spedali Civili Hospital ED between January 2005 and December 2009 who complained of headache not related to trauma and all patients hospitalized for headache in Neurological Clinic, from ED, between January 2008 and December 2009. 7495 patients were examined at ED for headaches. 72 % of patients were discharged, 22 % were admitted. From 2005 to 2009, there was a definite decrease in the rate of hospitalization due to headache (15 vs 9.9 % in Department of Neurology and 26 vs 18.9 % in all Departments). Considering the decrease year by year, this reduction was significant from 2007 to 2008, when the algorithms were adopted. The most common diagnosis in the ED was "Non-specific headache" (41 %), followed by "Primary headaches and complications of primary headaches" (20.8 %), "Secondary headaches not associated with risk of serious disease" (20.4 %) and "Secondary headache associated with risk of serious disease" (5 %). Over 2-year period (2008-2009) we found an increase in the diagnosis of "Primary headaches and complications of primary headaches" and "Secondary headaches associated with risk of serious disease" compared with a decrease of "nonspecific headache" and "secondary headaches not associated with risk of serious disease". The use of the diagnostic algorithms and collaborative network between the ED and the Headache Center can improve the management of patients with headache in ED.

Metabolic syndrome and breast cancer prognosis.

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.

Adherence to Diet Quality Indices and Breast Cancer Risk in the Italian ORDET Cohort.

Breast cancer (BC) is the most common cancer in women, with 2.3 million diagnoses in 2020. There is growing evidence that lifestyle factors, including dietary factors, particularly the complex interactions and synergies between different foods and nutrients (and not a single nutrient or food), may be associated with a higher risk of BC. The aim of this work was to evaluate how the Italian Mediterranean Index (IMI), the Greek Mediterranean Index, the DASH score, and the EAT-Lancet score can help lower the risk of BC, and analyze if chronic low-grade inflammation may be one of the possible mechanisms through which dietary patterns influence breast cancer risk. We evaluated the effect of adherence to these four dietary quality indices in the 9144 women of the ORDET cohort who completed a dietary questionnaire. The effect of adherence to dietary patterns on chronic inflammation biomarkers was evaluated on a subsample of 552 participants. Hazard ratios (HRs) with 95% confidence intervals (CIs) for BC risk in relation to the index score categories used were estimated using multivariable Cox models adjusted for potential confounders. Regression coefficients (ß), with 95% CI for C-reactive protein (CRP), TNF-α, IL-6, leptin, and adiponectin levels in relation to adherence to dietary patterns were evaluated with the linear regression model adjusted for potential confounders. IMI was inversely associated with BC in all women (HR: 0.76, 95% CI: 0.60-0.97, P trend = 0.04), particularly among postmenopausal women (HR: 0.64, 95% CI: 0.42-0.98, P trend = 0.11). None of the other dietary patterns was associated with BC risk. Higher IMI and Greek Mediterranean Index scores were inversely associated with circulating CRP (ß: -0.10, 95% CI: -0.18, -0.02, and ß: -0.13, 95% CI: -0.21, -0.04). The higher score of the EAT-Lancet Index was instead associated with a higher concentration of circulating levels of CRP (ß: 0.10, 95% CI: 0.02, 0.18). In conclusion, these results suggest that adherence to a typical Italian Mediterranean diet protects against BC development, especially among postmenopausal women, possibly through modulation of chronic low-grade inflammation.

Hemodialysis and imatinib: Plasma levels, efficacy and tolerability in a patient with metastatic GIST - Case report.

Purpose: To study plasma levels, efficacy and tolerability of imatinib in a patient affected by metastatic GIST treated with oral Imatinib and undergoing hemodialysis. Patients and methods: The patient suffered from metastatic GIST to the liver having a mutation of exon 9 of KIT. He was on hemodialysis and received first-line treatment with imatinib 400 mg/day. Results: The overall mean plasma level of imatinib was 1875,4 ng/ml pre-dialysis, 1553,0 ng/ml post-dialysis and 1998,1 ng/ml post-24h. In red blood cells the overall mean level of imatinib was 619,5 ng/ml pre-dialysis, 484,9 ng/ml post-dialysis and 663,1 ng/ml post-24h. The plasma level of nor-imatinib/imatinib was 16,2% pre-dialysis, 15,6% post-dialysis and 16,4% post-24h. Comparing our findings regarding levels of imatinib in plasma and RBC, we found a statistically significant difference between pre-dialysis and post-dialysis (respectively p < 0,001 and p = 0,002), post-dialysis and post-24h (both p < 0,001), pre-dialysis and post-24h (respectively p = 0.035 and p = 0,042). Ultimately, regarding nor-imatinib/imatinib in plasma, we did not find any statistically significant difference between pre-dialysis and post-dialysis (p = 0,091), post-dialysis and post-24h (p = 0,091), pre-dialysis and post-24h (p = 0.903). Currently the patient is receiving oral imatinib 400 mg/day with radiological evidence of response. Conclusion: In this case, hemodialysis did not affect significantly imatinib plasma levels. The statistically significant difference between pre- and post-dialysis can be explained by the fact that dialysis may likely contribute to a small portion of the normal metabolism of imatinib. The evaluation of imatinib levels in RBC and of its main metabolite in plasma also suggests that hemodialysis did not affect other aspects of the elimination of the drug.

The Effect of Diet on Breast Cancer Recurrence: The DIANA-5 Randomized Trial.

PURPOSE: The DIANA-5 randomized controlled trial assessed the effectiveness of a diet based on Mediterranean and macrobiotic traditions (macro-Mediterranean diet) in reducing breast cancer recurrence. PATIENTS AND METHODS: The DIANA-5 study involved 1,542 patients with breast cancer at high risk of recurrence because of estrogen receptor-negative cancer, or metabolic syndrome, or high plasma levels of insulin or testosterone. Women were randomly assigned to an active dietary intervention (IG) or a control group (CG). Both groups received the 2007 American Institute for Cancer Research/World Cancer Research Fund recommendations for cancer prevention. The intervention consisted of meetings with kitchen classes, community meals, and dietary recommendations. Recommended foods included whole grain cereals, legumes, soy products, vegetables, fruit, nuts, olive oil, and fish. Foods to be avoided were refined products, potatoes, sugar and desserts, red and processed meat, dairy products, and alcoholic drinks. A compliance Dietary Index was defined by the difference between recommended and discouraged foods. RESULTS: Over the 5 years of follow-up, 95 patients of the IG and 98 of the CG developed breast cancer recurrence [HR = 0.99; 95% confidence interval (CI): 0.69-1.40]. The analysis by compliance to the dietary recommendations (IG and CG together) showed that the women in the upper tertile of Dietary Index change had an HR of recurrence of 0.59 (95% CI: 0.36-0.92) compared with women in the lower tertile. CONCLUSIONS: The DIANA-5 dietary intervention trial failed to show a reduction in breast cancer recurrence, although self-reported diet at year 1 in IG and CG combined showed a protective association with the higher Dietary Index change. See related commentary by McTiernan, p. 931.

Where SUNCT contacts TN: a case report.

BACKGROUND: Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) and trigeminal neuralgia (TN) are unilateral painful conditions that can share the same triggering factors, autonomic features and the main location, as well as the cyclically recurrent crises. Both these syndromes are associated with a high percentage of findings of vascular malformation touching the trigeminal nerve, suggesting a pathophysiological relationship. CASE: In this paper, we report a new case with the main purpose to shine a light on the pathophysiology of these conditions. CONCLUSION: Many authors described a SUNCT case deriving from TN or vice versa, suggesting that these conditions are strongly related. Every case of transformed TN or SUNCT should therefore be reported to gather and compare further information.

Reduction in retinal nerve fiber layer thickness in migraine patients.

Migraine is a common disorder and its pathogenesis remains still unclear. Several hypotheses about the mechanisms involved in the pathogenesis of migraine have been proposed, but the issue is still far from being fully clarified. Neurovascular system remains one of the most important mechanisms involved in the pathogenesis of migraine and it could be possible that hypoperfusion might involve other areas besides brain, including the retina. This is, for example, of particular interest in a form of migraine, the retinal migraine, which has been associated with hypoperfusion and vasoconstriction of the retinal vasculature. Although vasoconstriction of cerebral and retinal blood vessels is a transient phenomenon, the chronic nature of the migraine might cause permanent structural abnormalities of the brain and also of the retina. On this basis, a few studies have evaluated whether retina is involved in migraine patients: Tan et al. have not found differences in retinal nerve fiber layer (RNFL) thickness between migraine patients and healthy subjects, while Martinez et al. have shown that RNFL in the temporal retinic quadrant of migraineurs is thinner than in normal people. The aim of our study was to analyze if there are differences in retinal nerve fiber layer thickness between migraine patients and normal subjects by studying 24 consecutive migraine patients who presented at the Headache Center of our Neurological Department. Migraine diagnosis has been made according to the International Classification of Headache disorder (ICHD-II). Patients have been recruited according to strict inclusion criteria; then patients have undergone a complete ophthalmological examination at the Ophthalmological Department. All patients and controls who met the ophthalmological criteria have been examined with ocular coherence tomography spectral domain (OCT-SD) after pupillary dilation. OCT-SD is an optical system designed to acquire the retinal layer images simultaneously with fundus confocal images. The statistical analysis has been performed using the Statistical Package for Social Sciences program. The Student's t test has been used to compare numeric variables between migraine and control groups. p value >0.05 has been considered not significant. We have analyzed 40 female subjects, 24 included in the study group and 16 included in the control group. Two migraine patients have been excluded. No differences have been found in the visual acuity between the two groups. Comparing RNFLs of a single eye per person in the two groups, we have found that migraine patients showed significant reduction in the superior quadrants (p < 0.005). Also evaluating both eyes per person there was a significant difference in the same quadrant between the two groups (p < 0.05). The result of this present study show that migraine patients have RNFL thickness reduction in the superior retinal quadrant compared with normal subjects. It is important to underline that RNFL thickness measurement could be a new interesting technique to evaluate the evolution of migraine and perhaps to study if prophylactic treatment could reduce retinal abnormalities seen in migraine patients. OCT-SD is a simple exam that could be repeated and then used for evaluation of headache progression during the time. Our study shows that RNFLs thickness does not depend on illness duration and frequency.

Circulating choline and phosphocholine measurement by a hydrophilic interaction liquid chromatography-tandem mass spectrometry.

Background: Given the growing interest in studying the role of choline and phosphocholine in the development and progression of tumor pathology, in this study we describe the development and validation of a fast and robust method for the simultaneous analysis of choline and phosphocholine in human plasma. Methods: Choline and phosphocholine quantification in human plasma was obtained using a hydrophilic interaction liquid chromatography-tandem mass spectrometry technique. Assay performance parameters were evaluated using EMA guidelines. Results: Calibration curve ranged from 0.60 to 38.40 µmol/L (R2 = 0.999) and 0.08-5.43 µmol/L (R2 = 0.998) for choline and phosphocholine, respectively. The Limit Of Detection of the method was 0.06 µmol/L for choline and 0.04 µmol/L for phosphocholine. The coefficient of variation range for intra-assay precision is 2.2-4.1 % (choline) and 3.2-15 % (phosphocholine), and the inter-assay precision range is < 1-6.5 % (choline) and 6.2-20 % (phosphocholine). The accuracy of the method was below the ±20 % benchmarks at all the metabolites concentration levels. In-house plasma pool of apparently healthy adults was tested, and a mean concentration of 15.97 µmol/L for Choline and 0.34 µmol/L for Phosphocholine was quantified. Conclusions: The developed method shows good reliability in quantifying Choline and Phosphocholine in human plasma for clinical purposes.

Sleep behavior and daily activity levels in people with metabolic syndrome: effect of 1 year of metformin treatment.

Impaired sleep and low daily activity levels increase the risk of developing metabolic syndrome (MS). Metformin (MET), an insulin sensitizer drug, is effective in regressing MS and has been recently studied as an adjuvant agent for managing sleep disorders. The present study aimed to assess whether 1,700 mg/day of MET treatment modifies sleep and daily activity levels in people with MS evaluated by Rest-Activity circadian Rhythm (RAR), which is the expression of 24 h of spontaneous activity parameters. A total of 133 subjects with MS, randomized into the MET (n = 65) or placebo (PLA, n = 68) group, underwent a clinical/anthropometric examination and carried out a continuous 7-day actigraphic monitoring to investigate sleep and RAR parameters at baseline and after 1 year of intervention. After 1 year of intervention, 105 subjects were analyzed. The MET group showed greater anthropometric and metabolic improvements compared with placebo, with a significant reduction in weight (p = 0.01), body mass index (p = 0.01), waist circumference (p = 0.03), and glucose (p < 0.001). With regard to sleep parameters, the MET group showed a significant increase in actual sleep time (p = 0.01) and sleep efficiency (p = 0.04) compared with placebo. There were no significant changes reported in the RAR parameters. Our study suggests that MET might be used as an adjuvant treatment for sleep disorders in people with MS.

Corrigendum: Sleep behavior and daily activity levels in people with metabolic syndrome: effect of 1 year of metformin treatment.

[This corrects the article DOI: 10.3389/fnut.2023.1240762.].

Association between metabolic syndrome, insulin resistance, and IGF-1 in breast cancer survivors of DIANA-5 study.

PURPOSE: Circulating insulin-like growth factor-1 (IGF-1) is positively associated with the risk of BC recurrence, and is more frequently dysregulated in older people, especially in those with metabolic syndrome (MetS) and obesity. This study aimed to analyze the association between IGF-1 levels and indices of MetS and insulin resistance in BC survivors. METHODS: Baseline data of 563 BC survivors enrolled in the DIet and ANdrogen-5 (DIANA-5; NCT05019989) study were analyzed. RESULTS: Lower circulating IGF-1 levels in subjects with MetS than in those without MetS were found. After stratification of the patients according to the diagnosis of MetS, we highlighted that the insulin was the main predictor of elevated IGF-1 levels only in subjects without MetS. Moreover, we found an interaction between high-density lipoprotein cholesterol (HDL-C), glycemia, and IGF-1 levels, showing a positive correlation between HDL-C and IGF-1, especially in subjects with higher values of glycemia and without a diagnosis of MetS. CONCLUSIONS: While IGF-1 levels appear to be much more impaired in subjects diagnosed with MetS, in non-MetS subjects, IGF-1 levels may respond better to metabolic parameters and lifestyle changes. Further studies are needed to analyze the role of physical activity and/or dietary intervention in modulating IGF-1 concentrations in BC survivors. IMPLICATIONS FOR CANCER SURVIVORS: These results could have important clinical implications for planning customized strategies aimed at modulating IGF-1 levels in BC survivors. In fact, while the IGF-1 system seems to be much more compromised in subjects with a diagnosis of MetS, in noMetS subjects, IGF-1 levels could better respond to lifestyle changes.

Potential role of HER2-overexpressing exosomes in countering trastuzumab-based therapy.

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.

Androgen receptors and serum testosterone levels identify different subsets of postmenopausal breast cancers.

BACKGROUND: Androgen receptors (AR) are frequently expressed in breast cancers, but their implication in cancer growth is still controversial. In the present study, we further investigated the role of the androgen/AR pathway in breast cancer development. METHODS: AR expression was evaluated by immunochemistry in a cohort of 528 postmenopausal breast cancer patients previously examined for the association of serum testosterone levels with patient and tumor characteristics. AR expression was classified according to the percentage of stained cells: AR-absent (0%) and AR-poorly (1%-30%), AR-moderately (>30%-60%), and AR-highly (>60%) positive. RESULTS: Statistical analysis was performed in 451 patients who experienced natural menopause. AR-high expression was significantly related with low histologic grade and estrogen receptor (ER)- and progesterone receptor (PR)-positive status (P trend<0.001). Mean testosterone levels were significantly higher in the AR-high category than in the other categories combined (P=0.022), although a trend across the AR expression categories was not present. When women defined by ER status were analyzed separately, regression analysis in the ER-positive group showed a significant association of high testosterone levels with AR-highly-positive expression (OR 1.86; 95% CI, 1.10-3.16), but the association was essentially due to patients greater than or equal to 65 years (OR 2.42; 95% CI, 1.22-4.82). In ER-positive group, elevated testosterone levels appeared also associated with AR-absent expression, although the small number of patients in this category limited the appearance of significant effects (OR 1.92; 95% CI, 0.73-5.02): the association was present in both age groups (<65 and ≥65 years). In the ER-negative group, elevated testosterone levels were found associated (borderline significance) with AR-absent expression (OR 2.82, 95% CI, 0.98-8.06). In this ER-negative/AR-absent subset of tumors, elevated testosterone levels cannot stimulate cancer growth either directly or after conversion into estrogens, but they probably induce increased synthesis of some other substance that is responsible for cancer growth through binding to its specific receptor. CONCLUSIONS: The findings in the present study confirm that testosterone levels are a marker of hormone-dependent breast cancer and suggest that the contemporary evaluation of ER status, AR expression, and circulating testosterone levels may identify different subsets of cancers whose growth may be influenced by androgens.