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.

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.

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.

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.].

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.

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.

HER2 mRNA Levels, Estrogen Receptor Activity and Susceptibility to Trastuzumab in Primary Breast Cancer.

While the results thus far demonstrate the clinical benefit of trastuzumab in breast cancer (BC), some patients do not respond to this drug. HER2 mRNA, alone or combined with other genes/biomarkers, has been proven to be a powerful predictive marker in several studies. Here, we provide evidence of the association between HER2 mRNA levels and the response to anti-HER2 treatment in HER2-positive BC patients treated with adjuvant trastuzumab and show that this association is independent of estrogen receptor (ER) tumor positivity. While HER2 mRNA expression was significantly correlated with HER2 protein levels in ER-negative tumors, no correlation was found in ER-positive tumors, and HER2 protein expression was not associated with relapse risk. Correlation analyses in the ER-positive subset identified ER activity as the pathway inversely associated with HER2 mRNA. Associations between HER2 levels and oncogene addiction, as well as between HER2 activation and trastuzumab sensitivity, were also observed in vitro in HER2-positive BC cell lines. In ER-positive but not ER-negative BC cells, HER2 transcription was increased by reducing ligand-dependent ER activity or inducing ER degradation. Accordingly, HER2 mRNA levels in patients were found to be inversely correlated with blood levels of estradiol, the natural ligand of ER that induces ER activation. Moreover, low estradiol levels were associated with a lower risk of relapse in HER2-positive BC patients treated with adjuvant trastuzumab. Overall, we found that HER2 mRNA levels, but not protein levels, indicate the HER2 dependency of tumor cells and low estrogen-dependent ER activity in HER2-positive tumors.

A software-assisted untargeted liquid chromatography-mass spectrometry method for lipidomic profiling of human plasma samples.

INTRODUCTION: In this paper, an analytical pipeline designed for untargeted lipidomic profiling in human plasma is proposed. The analytical pipeline was developed for case-control studies nested in prospective cohorts. METHODS: The procedure consisted of isopropanol protein precipitation followed by reverse phase liquid chromatography coupled to high resolution mass spectrometry and software-assisted data processing. The compounds are putatively annotated by matching experimental mass spectrometry data with spectral library data using LipidSearch software. The lipid profile of a pool of plasma samples from 10 healthy volunteers was detected in both positive and negative polarity modes. The impact of the chosen polarity on the number and quality of the lipid identification has been evaluated. RESULTS: More than 1000 lipids from 12 different classes were detected, 1150 in positive mode and 273 in negative mode. Nearly half of them were unambiguously identified by the software in positive mode, and about one-third in negative mode. The method repeatability was assessed on the plasma pool samples by means of variance components analysis. The intra- and inter-assay precision was measured for 10 lipids chosen among the most abundant found within the different lipid classes. The intra-assay coefficients of variation ranged from 2.56% to 4.56% while intra- and inter-day coefficients of variance never exceeded the 15% benchmark adopted. The lipidomic profiles of the 10 healthy volunteers were also investigated. DISCUSSION: This method detects a wide range of lipids and reports their degree of identification. It is particularly fit and well-designed for large case-control epidemiologic studies.

Recruitment in randomized clinical trials: The MeMeMe experience.

INTRODUCTION: Recruitment is essential for the success of clinical trials. We are conducting a randomized clinical trial to test the effect of a Mediterranean dietary intervention with or without 1700 mg/day of metformin for the prevention of age-related chronic diseases, the MeMeMe trial (Trial registration number: EudraCT number: 2012-005427-32 ClinicalTrials.gov ID: NCT02960711). MeMeMe recruiting experience, highlighting strengths, limitations encountered and results is reported. PATIENTS AND METHODS: Statistical analysis focused on the reasons for withdrawal according to the recruitment method ("active" versus "passive" criterion) and the time of withdrawal. Logistic regression models were used to explore the associations between the risk of withdrawal and sex, recruitment method, randomization arm, and with markers of compliance to the intervention, such as one-year change in body weight. RESULTS: Out of 2035 volunteers, 660 (32.4%) were recruited "actively" and 1375 (67.6%) "passively". Among people who dropped out of the trial after randomization, there were 19.5% for the "active" and 22.0% for the "passive" method (p = 0.28). The risk of withdrawal was significantly higher in women (OR:1.91; 95% CI:1.17-3.12; p = 0.01), in volunteers older at recruitment (OR:1.25; 95% CI:1.07-1.45; p = 0.004), and in those with a higher BMI at baseline (OR:1.23; 95% CI:1.07-1.43; p = 0.004). Volunteers who lost at least 2 kg (the median weight change) in the first year of intervention were significantly less (53%) likely to withdraw from the trial (OR:0.48; 95% CI:0.30-0.75; p = 0.001). CONCLUSION: Our findings suggest that the "passive" recruitment method was more effective than the "active" one to advance recruitment. The benefits of "passive" recruitment hardly outweighed the drawbacks. TRIAL REGISTRATION: Trial registration number: EudraCT number: 2012-005427-32. ClinicalTrials.gov ID: NCT02960711.

Prediagnostic Levels of Copper and Zinc and Breast Cancer Risk in the ORDET Cohort.

BACKGROUND: Case-control studies show that copper (Cu) is high and zinc (Zn) low in blood and urine of women with breast cancer compared with controls. METHODS: To assess whether prediagnostic Cu and Zn are associated with breast cancer risk, OR of breast cancer according to Cu, Zn, and Cu/Zn ratio in plasma and urine was estimated in a nested case-control study within the ORDET cohort, using conditional logistic regression adjusted for multiple variables: First 496 breast cancer cases and matched controls, diagnosed ≥2 years after recruitment (to eliminate reverse causation) were analyzed. Then all eligible cases/controls were analyzed with stratification into years from recruitment to diagnosis. RESULTS: For women diagnosed ≥2 years, compared with lowest tertiles, breast cancer risk was higher in the highest tertile of plasma Cu/Zn ratio (OR, 1.75; 95% CI, 1.21-2.54) and the highest tertile of both plasma and urine Cu/Zn ratio (OR, 2.37; 95% CI, 1.32-4.25). Risk did not vary with ER/PR/HER2 status. For women diagnosed <2 years, high Cu/Zn ratio was strongly associated with breast cancer risk. CONCLUSIONS: Our prospective findings suggest that increased Cu/Zn ratio in plasma and urine may be both an early marker of, and a risk factor for, breast cancer development. Further studies are justified to confirm or otherwise our results and to investigate mechanisms. IMPACT: Our finding that prediagnostic Cu/Zn ratio is a strong risk factor for breast cancer development deserves further investigation and, if confirmed, might open the way to interventions to reduce breast cancer risk in women with disrupted Cu/Zn homeostasis.

Adherence to Dietary Recommendations after One Year of Intervention in Breast Cancer Women: The DIANA-5 Trial.

The Diet and Androgen-5 (DIANA-5) trial aimed at testing whether a dietary change based on the Mediterranean diet and on macrobiotic principles can reduce the incidence of breast cancer (BC)-related events. We analyzed the adherence to the DIANA-5 dietary recommendations by randomization group after 1 year of intervention. We evaluated the association between dietary adherence and changes in body weight and metabolic syndrome (MS) parameters. BC women aged 35-70 years were eligible. After the baseline examinations, women were randomized into an intervention group (IG) or a control group (CG). A total of 1344 BC women (689 IG and 655 CG) concluded the first year of dietary intervention. IG showed greater anthropometric and metabolic improvements compared to CG. These changes were significantly associated with increased adherence to the dietary recommendations. Women who increased recommended foods consumption or reduced discouraged foods consumption showed an Odds Ratio (OR) of 1.37 (0.70-2.67) and 2.02 (1.03-3.98) to improve three or more MS parameters. Moreover, women in the higher category of dietary change showed a four times higher OR of reducing body weight compared to the lower category (p < 0.001). The DIANA-5 dietary intervention is effective in reducing body weight and MS parameters.

Erenumab Discontinuation After 12-Month Treatment: A Multicentric, Observational Real-Life Study.

OBJECTIVE: To assess migraine outcome after 12-month treatment with erenumab and compare patients who underwent 3-month erenumab discontinuation following the first treatment cycle with those who continued monthly administrations. METHODS: This is a multicentric observational study in patients with migraine in treatment with erenumab. After a full 12-month treatment cycle (T12), patients could either continue or discontinue erenumab for at least 3 months. Patients who underwent treatment discontinuation were assessed after 3 months (T15) to decide whether to start retreatment. Patients were then assessed following at T16 and T18. RESULTS: Thirty consecutive patients were enrolled. Nineteen patients underwent treatment suspension at T12 up to T15, whereas 11 continued prophylaxis. At T15, patients who discontinued treatment documented significantly more migraine days (17.06 ± 6.5 vs 4.8 ± 2.5; p < 0.0001) and analgesics consumption (14.8 ± 9.2 vs 4.6 ± 2.5; p = 0.002), compared with those who continued treatment. After retreatment, at T16, patients who had previously undergone discontinuation documented a significant improvement in terms of migraine days (9.01 ± 4.4 vs 17.06 ± 6.5; p < 0.0001) and analgesics consumption (9.6 ± 7.3 vs 14.8 ± 9.2; p = 0.004). Such improvement was even greater at T18, comparable with T12. CONCLUSION: After treatment discontinuation, a rapid migraine worsening was found, despite the high clinical response during treatment and at retreatment, which might be secondary to an untimely interruption of a potentially disease-modifying pharmacologic intervention. Although clinical improvement was documented after retreatment, given the high frequency and degree of worsening during discontinuation, it seems plausible-even ethical-to re-evaluate current timing of discontinuation. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that people with migraine discontinuing erenumab migraine prophylaxis after 12 months were more likely to have an increase in nonresponder status and migraine days than those who continued treatment.

Neurologic manifestations in 1760 COVID-19 patients admitted to Papa Giovanni XXIII Hospital, Bergamo, Italy.

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; χ2= 14.306; p < 0.0002) and with altered mental status (87.1% vs 55.6%; difference = 31.5% 95% CI 27.5-37.5%; χ2= 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.

Lifestyle Characteristics in Women Carriers of BRCA Mutations: Results From an Italian Trial Cohort.

BACKGROUND: Women with deleterious mutations in BRCA1/2 have a high lifetime penetrance of developing breast cancer and/or ovarian cancer. Genetic and/or environmental factors may influence BRCA penetrance, and identifying modifiable exposures might be valuable for prevention. PATIENTS AND METHODS: We implemented a multicenter prospective 2-arm (1:1) randomized controlled trial to investigate whether a Mediterranean dietary intervention with moderate protein restriction would reduce potential modulators of BRCA penetrance such as insulin-like growth factor 1 (IGF-1), body weight, and metabolic risk factors. We studied the baseline characteristics of women with BRCA-positive disease who joined the trial cohort, focusing on the relationships between selected lifestyle exposures, metabolic/anthropometric parameters, and BRCA-related cancer. RESULTS: A total of 502 women (304 with a previous diagnosis of breast cancer and/or ovarian cancer and 198 unaffected) with deleterious BRCA mutations, with or without a previous cancer, aged 18 to 70 years and without metastases were included. Late age at menarche and pregnancy were negatively associated with BRCA-related cancer, especially in women with BRCA1-positive disease. Higher fat mass and the presence of 4 or 5 metabolic risk factors were significantly associated with BRCA-related cancer (hazard ratio, 1.87, 95% confidence interval, 1.21-2.88; and hazard ratio, 1.87, 95% confidence interval, 1.11-3.19, respectively), with greater effect in BRCA2-positive women. CONCLUSIONS: Our findings confirm previous observations about reproductive factors in women with BRCA disease and suggest a potential impact of metabolic factors in BRCA-related cancer. The prospective follow-up of the trial cohort will enable us to study the environmental modulators of BRCA penetrance and their impact in relation to the history of BRCA-related cancer. [ClinicalTrials.gov NCT03066856].

A Mediterranean Dietary Intervention in Female Carriers of BRCA Mutations: Results from an Italian Prospective Randomized Controlled Trial.

Background: Women carriers of BRCA1/2 mutations face a high lifetime risk (penetrance) of developing breast and/or ovarian cancer. Insulin-like growth factor I (IGF-I), body weight and markers of insulin resistance affect BRCA penetrance. We conducted a multicenter prospective two-armed (1:1) randomized controlled trial (NCT03066856) to investigate whether a Mediterranean dietary intervention with moderate protein restriction reduces IGF-I and other metabolic modulators of BRCA penetrance. Methods: BRCA carriers, with or without a previous cancer, aged 18-70 years and without metastases were randomly assigned to an active dietary intervention group (IG) or to a control group (CG). The primary endpoint of the intervention was the IGF-I reduction. Results: 416 women (216 in the IG and 200 in the CG) concluded the six-month dietary intervention. The IG showed significantly lowered serum levels of IGF-I (-11.3 ng/mL versus -1.3 ng/mL, p = 0.02), weight (-1.5 Kg versus -0.5 Kg, p < 0.001), waist circumference (-2 cm versus -0.7 cm, p = 0.01), hip circumference (-1.6 cm versus -0.5 cm, p = 0.01), total cholesterol (-10.2 mg/dL versus -3.6 mg/dL, p = 0.04) and triglycerides (-8.7 mg/dL versus + 5.5 mg/dL, p = 0.01) with respect to the CG. Conclusions: A Mediterranean dietary intervention with moderate protein restriction is effective in reducing IGF-I and other potential modulators of BRCA penetrance.

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.

Monitoring Vitamin B12 in Women Treated with Metformin for Primary Prevention of Breast Cancer and Age-Related Chronic Diseases.

Metformin (MET) is currently being used in several trials for cancer prevention or treatment in non-diabetics. However, long-term MET use in diabetics is associated with lower serum levels of total vitamin B12. In a pilot randomized controlled trial of the Mediterranean diet (MedDiet) and MET, whose participants were characterized by different components of metabolic syndrome, we tested the effect of MET on serum levels of B12, holo transcobalamin II (holo-TC-II), and methylmalonic acid (MMA). The study was conducted on 165 women receiving MET or placebo for three years. Results of the study indicate a significant overall reduction in both serum total B12 and holo-TC-II levels according with MET-treatment. In particular, in the MET group 26 of 81 patients and 10 of the 84 placebo-treated subjects had B12 below the normal threshold (<221 pmol/L) at the end of the study. Considering jointly all B12, Holo-TC-II, and MMA, 13 of the 165 subjects (10 MET and 3 placebo-treated) had at least two deficits in the biochemical parameters at the end of the study, without reporting clinical signs. Although our results do not affect whether women remain in the trial, B12 monitoring for MET-treated individuals should be implemented.

A management system for randomized clinical trials: A novel way to supply medication.

BACKGROUND: Randomized controlled clinical trials require management effort, involving huge organizational, economic and informatics investments. Information technology offers opportunities to approach clinical trial methodology in new ways. However, there are only a few reports of computerized data and drug management systems. OBJECTIVE: This paper describes a novel software created specifically for the management of a randomized trial of diet and metformin in people with metabolic syndrome (the Me.Me.Me. trial). METHODS: Me.Me.Me. is an ongoing phase III randomized controlled trial in healthy people with metabolic syndrome to test the hypothesis that comprehensive lifestyle changes and/or metformin can prevent age-related chronic non-communicable diseases. To manage all the phases of the trial, we created a software which is a state pattern machine, user friendly, web-based, able to maintain the correct balance between randomization groups, and structured in various levels of security in order to guarantee the participant's privacy and compliance with the study protocol. The software achieves budget savings: drug management is not based on patients' packs, but on the actual need for drugs according to each participant's "state", with strict guidelines for the handling and supply of medication. RESULTS: The trial is ongoing and recruitment will close on August 31, 2018. To date, 11737 bottles of metformin/placebo have been dispensed to 1054 randomized participants, with drug savings of 29.5%. CONCLUSIONS: A software which takes into account the "state" of participant might be a powerful resource for developing and managing clinical trials, helping avoid poor treatment allocation, and wastage of drugs and money. ME.ME.ME. TRIAL: EUDRACT no. 2012-005427-32. ClinicalTrials.gov Identifier: NCT02960711.