Cancer-associated foam cells hamper protective T cell immunity and favor tumor progression in human colon carcinogenesis.

BACKGROUND: Colorectal cancer (CRC) remains a significant healthcare burden worldwide, characterized by a complex interplay between obesity and chronic inflammation. While the relationship between CRC, obesity and altered lipid metabolism is not fully understood, there are evidences suggesting a link between them. In this study, we hypothesized that dysregulated lipid metabolism contributes to local accumulation of foam cells (FC) in CRC, which in turn disrupts antitumor immunosurveillance. METHODS: Tumor infiltrating FC and CD8+ were quantified by digital pathology in patients affected by T2-T4 CRC with any N stage undergoing radical upfront surgery (n=65) and correlated with patients' clinical outcomes. Multiparametric high-resolution flow cytometry analysis and bulk RNAseq of CRC tissue were conducted to evaluate the phenotype and transcriptomic program of immune cell infiltrate in relation to FC accumulation. The immunosuppressive effects of FC and mechanistic studies on FC-associated transforming growth factor-beta (TGF-ß) and anti-PD-L1 inhibition were explored using an in-vitro human model of lipid-engulfed macrophages. RESULTS: FC (large CD68+ Bodipy+ macrophages) accumulated at the tumor margin in CRC samples. FChigh tumors exhibited reduced CD8+ T cells and increased regulatory T cells (Tregs). Functional transcriptional profiling depicted an immunosuppressed milieu characterized by reduced interferon gamma, memory CD8+ T cells, and activated macrophages mirrored by increased T-cell exhaustion and Treg enrichment. Furthermore, FChigh tumor phenotype was independent of standard clinical factors but correlated with high body mass index (BMI) and plasma saturated fatty acid levels. In CD8low tumors, the FChigh phenotype was associated with a 3-year disease-free survival rate of 8.6% compared with 28.7% of FClow (p=0.001). In-vitro studies demonstrated that FC significantly impact on CD8 proliferation in TFG-ß dependent manner, while inhibition of TGF-ß FC-related factors restored antitumor immunity. CONCLUSIONS: FC exert immunosuppressive activity through a TGF-ß-related pathway, resulting in a CD8-excluded microenvironment and identifying immunosuppressed tumors with worse prognosis in patients with primary CRC. FC association with patient BMI and dyslipidemia might explain the link of CRC with obesity, and offers novel therapeutic and preventive perspectives in this specific clinical setting.

Effect of anti-inflammatory molecules from food on organoids derived from adenomatous polyps of FAP subjects.

INTRODUCTION: Individuals with Familial Adenomatous Polyposis (FAP) or APC-associated polyposis, an autosomal dominant inherited condition, develop multiple adenomatous polyps and have an increased colorectal cancer (CRC) risk. A change in diet can help reduce cancer risk, and several dietary components have an antitumor effect. We aimed to evaluate the potential of the anti-inflammatory and anticancer substances quercetin (QER), epigallocatechin gallate (EGG) and fisetin (FIS) in decreasing the risk of CRC by reducing the growth of polyps in an organoid model. METHODS: Patient-derived organoid (PDO) lines were generated from polyps obtained from patients with FAP undergoing prophylactic colectomy. PDOs were treated with QER, EGG, or FIS to determine their effect on cell growth. Changes in caspase 3/7 activity and expression of inflammation and apoptosis mediators were assessed by luminescent and colorimetric assays. RESULTS: Three PDO lines with different inactivating pathogenic variants in the APC gene were developed using a combinatorial approach. FIS was the most active of the three substances tested, presenting the lowest IC50 in all PDO lines (range: 42.6-9.2 uM). The IC50 was defined as the concentration required to halve the number of cells after 72 hours. All molecules tested induced apoptosis through activation of caspases 3/7. CONCLUSIONS: QER, EGG, and FIS can be easily taken from foods or dietary supplements, show toxicity on PDOs derived from adenomatous polyps, while they are known to be harmless on normal cells. Diets enriched with these substances could be potential supplemental treatments to reduce the risk of CRC in individuals with FAP.

Current management of familial adenomatous polyposis.

INTRODUCTION: APC-associated polyposis is a rare hereditary disorder characterized by the development of multiple adenomas in the digestive tract. Individuals with APC-associated polyposis need to be managed by specialized multidisciplinary teams in dedicated centers. AREAS COVERED: The study aimed to review the literature on Familial adenomatous polyposis (FAP) to provide an update on diagnostic and surgical management while focusing on strategies to minimize the risk of desmoid-type fibromatosis, cancer in anorectal remnant, and postoperative complications. FAP individuals require a comprehensive approach that includes diagnosis, surveillance, preventive surgery, and addressing specific extracolonic concerns such as duodenal and desmoid tumors. Management should be personalized considering all factors: genotype, phenotype, and personal needs. Total colectomy and ileo-rectal anastomosis have been shown to yield superior QoL results when compared to Restorative Procto colectomy and ileopouch-anal anastomosis with acceptable oncological risk of developing cancer in the rectal stump if patients rigorously adhere to lifelong endoscopic surveillance. Additionally, a low-inflammatory diet may prevent adenomas and cancer by modulating systemic and tissue inflammatory indices. EXPERT OPINION: FAP management requires a multidisciplinary and personalized approach. Integrating genetic advances, innovative surveillance techniques, and emerging therapeutic modalities will contribute to improving outcomes and quality of life for FAP individuals.

Modulation of faecal miRNAs highlights the preventive effects of a Mediterranean low-inflammatory dietary intervention.

BACKGROUND: Dietary interventions have been proposed as therapeutic approaches for several diseases, including cancer. A low-inflammatory Mediterranean dietary intervention, conducted as a pilot study in subjects with Familial Adenomatous Polyposis (FAP), reduced markers of local and systemic inflammation. We aim to determine whether this diet may modulate faecal microRNA (miRNA) and gene expression in the gut. METHODS: Changes in the faecal miRNome were evaluated by small RNA sequencing at baseline (T0), after the three-month intervention (T1), and after an additional three months (T2). Changes in the transcriptome of healthy rectal mucosa and adenomas were evaluated by RNA sequencing at T0 and T2. The identification of validated miRNA-gene interactions and functional analysis of miRNA targets were performed using in silico approaches. RESULTS: Twenty-seven subjects were included in this study. It was observed that the diet modulated 29 faecal miRNAs (p < 0.01; |log2 Fold Change|>1), and this modulation persisted for three months after the intervention. Levels of miR-3612-3p and miR-941 correlated with the adherence to the diet, miR-3670 and miR-4252-5p with faecal calprotectin, and miR-3670 and miR-6867 with serum calprotectin. Seventy genes were differentially expressed between adenoma and normal tissue, and most were different before the dietary intervention but reached similar levels after the diet. Functional enrichment analysis identified the proinflammatory ERK1/2, cell cycle regulation, and nutrient response pathways as commonly regulated by the modulated miRNAs and genes. CONCLUSIONS: Faecal miRNAs modulated by the dietary intervention target genes that participate in inflammation. Changes in levels of miRNAs and genes with oncogenic and tumour suppressor functions further support the potential cancer-preventive effect of the low-inflammatory Mediterranean diet. CLINICAL TRIAL NUMBER REGISTRATION: NCT04552405, Registered in ClinicalTrials.gov.

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.

miRNA deregulation and relationship with metabolic parameters after Mediterranean dietary intervention in BRCA-mutated women.

Background: Breast cancer onset is determined by a genetics-environment interaction. BRCA1/2 gene alterations are often genetically shared in familial context, but also food intake and hormonal assessment seem to influence the lifetime risk of developing this neoplasia. We previously showed the relationship between a six-months Mediterranean dietary intervention and insulin, glucose and estradiol levels in BRCA1/2 carrier subjects. The aim of the present study was to evidence the eventual influence of this dietary intervention on the relationship between circulating miRNA expression and metabolic parameters in presence of BRCA1/2 loss of function variants. Methods: Plasma samples of BRCA-women have been collected at the baseline and at the end of the dietary intervention. Moreover, subjects have been randomized in two groups: dietary intervention and placebo. miRNA profiling and subsequent ddPCR validation have been performed in all the subjects at both time points. Results: ddPCR analysis confirmed that five (miR-185-5p, miR-498, miR-3910, miR-4423 and miR-4445) of seven miRNAs, deregulated in the training cohort, were significantly up-regulated in subjects after dietary intervention compared with the baseline measurement. Interestingly, when we focused on variation of miRNA levels in the two timepoints, it could be observed that miR-4423, miR-4445 and miR-3910 expressions are positively correlated with variation in vitaminD level; whilst miR-185-5p difference in expression is related to HDL cholesterol variation. Conclusions: We highlighted the synergistic effect of a healthy lifestyle and epigenetic regulation in BC through the modulation of specific miRNAs. Different miRNAs have been reported involved in the tumor onset acting as tumor suppressors by targeting tumor-associated genes that are often downregulated.

Dietary intervention for tertiary prevention in head and neck squamous cell carcinoma survivors: clinical and translational results of a randomized phase II trial.

Background: There is a strong need for preventive approaches to reduce the incidence of recurrence, second cancers, and late toxicities in head and neck squamous cell carcinoma (HNSCC) survivors. We conducted a randomized controlled trial (RCT) to assess a dietary intervention as a non-expensive and non-toxic method of tertiary prevention in HNSCC survivors. Methods: Eligible participants were disease-free patients with HNSCC in follow-up after curative treatments. Subjects were randomized 1:1 to receive a highly monitored dietary intervention plus the Word Cancer Research Fund/American Institute for Cancer Research recommendations for cancer prevention (intervention arm) or standard-of-care recommendations (control arm). The planned sample size for the event-free survival evaluation (primary endpoint) was not reached, and the protocol was amended in order to investigate the clinical (nutritional and quality-of-life questionnaires) and translational study [plasma-circulating food-related microRNAs (miRNAs)] as main endpoints, the results of which are reported herein. Results: One hundred patients were screened, 94 were randomized, and 89 were eligible for intention-to-treat analysis. Median event-free survival was not reached in both arms. After 18 months, nutritional questionnaires showed a significant increase in Recommended Food Score (p = 0.04) in the intervention arm vs. control arm. The frequency of patients with and without a clinically meaningful deterioration or improvement of the C30 global health status in the two study arms was similar. Food-derived circulating miRNAs were identified in plasma samples at baseline, with a significant difference among countries. Conclusion: This RCT represented the first proof-of-principle study, indicating the feasibility of a clinical study based on nutritional and lifestyle interventions in HNSCC survivors. Subjects receiving specific counseling increased the consumption of the recommended foods, but no relevant changes in quality of life were recorded between the two study arms. Food-derived plasma miRNA might be considered promising circulating dietary biomarkers.

Physical activity and sleep behaviour in women carrying BRCA1/2 mutations.

The aim of the present study is to explore the potential association between sleep quality and physical activity (PA) in women carriers of BRCA1/2 mutations. 63 women completed the Pittsburgh Sleep Quality Index (PSQI) and Godin Shepard Leisure-Time Physical Activity Questionnaire (GSL-TPAQ) and were included in the present cross-sectional analysis. Globally, women showed a PSQI score of 7.0 ± 3.6 and a GSL-TPAQ score of 22.8 ± 18.3. Good sleepers (PSQI score ≤ 5) showed significantly higher PA levels compared to bad sleepers (PSQI score > 5). Women in the higher tertile of GSL-TPAQ total score (≥ 27 METs/week) have a prevalence ratio (PR) of being a good sleeper of 2.85 (1.25-6.52, 95% confidence intervals) compared to women in the lower tertile (≤ 11 METs/week). These results were consistent in BRCA1 and BRCA2 women. Considering each single question of PA intensity, the PR of being a good sleeper by unit of increase of MET/week was higher and significant in women engaged in strenuous and moderate intensity PA. These results suggests a direct association between PA and sleep quality in women carriers of BRCA mutations.

MALAT1-dependent hsa_circ_0076611 regulates translation rate in triple-negative breast cancer.

Vascular Endothelial Growth Factor A (VEGFA) is the most commonly expressed angiogenic growth factor in solid tumors and is generated as multiple isoforms through alternative mRNA splicing. Here, we show that lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) and ID4 (inhibitor of DNA-binding 4) protein, previously referred to as regulators of linear isoforms of VEGFA, induce back-splicing of VEGFA exon 7, producing circular RNA circ_0076611. Circ_0076611 is detectable in triple-negative breast cancer (TNBC) cells and tissues, in exosomes released from TNBC cells and in the serum of breast cancer patients. Circ_0076611 interacts with a variety of proliferation-related transcripts, included MYC and VEGFA mRNAs, and increases cell proliferation and migration of TNBC cells. Mechanistically, circ_0076611 favors the expression of its target mRNAs by facilitating their interaction with components of the translation initiation machinery. These results add further complexity to the multiple VEGFA isoforms expressed in cancer cells and highlight the relevance of post-transcriptional regulation of VEGFA expression in TNBC cells.

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.

The Impact of Mediterranean Dietary Intervention on Metabolic and Hormonal Parameters According to BRCA1/2 Variant Type.

The female carriers of BRCA1/2 pathogenic variants (mutations) face a high lifetime risk of developing breast and/or ovarian cancer. However, the risk may differ depending on various genetic and non-genetic elements, including metabolic and hormonal factors. We previously showed that a 6-month Mediterranean dietary intervention trial reduced body weight and the levels of insulin-like growth factor I and other metabolic factors in BRCA mutation carriers. We also found that higher baseline levels of glucose and insulin were significantly associated with BRCA loss-of-function (LOF) variants. In this study, we evaluated whether the BRCA mutation type influences in a different way the metabolic and hormonal response to the dietary intervention in 366 female carriers. The LOF variant carriers randomized in the intervention group (IG) showed significantly higher changes in most considered parameters compared to the control group (CG). The nonsynonymous variant carriers in the IG showed similar changes, but none of them were statistically significant. Performing the "delta" analysis of differences (intention-to-treat analysis), we observed that in LOF variant carriers, the reduction of insulin levels was significantly more pronounced that in nonsynonymous variant carriers. These findings suggest that the changes in insulin levels might be modulated by a different response to the dietary intervention mediated by BRCA LOF variants.

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.

Preventive Anti-inflammatory Diet to Reduce Gastrointestinal Inflammation in Familial Adenomatous Polyposis Patients: A Prospective Pilot Study.

Familial adenomatous polyposis (FAP) is an autosomal-dominant hereditary condition associated with germline mutations in the adenomatous polyposis coli gene. Patient management involves prophylactic surgery and intensive life-long endoscopic surveillance. Diet is a major concern for patients with FAP, who are generally free of symptoms before surgery but tend to have issues related to bowel function postoperatively. We hypothesized that a low-inflammatory diet based on the principles and recipes of the Mediterranean diet would reduce markers of local and systemic inflammation. Twenty-eight patients with FAP over 18 years of age who underwent rectum-sparing prophylactic colectomy and were included in our surveillance program participated in a pilot dietary intervention study. Blood and stool samples at baseline (T0), at the end of the dietary intervention (T1, three months), and at the end of the study (T2, six months after T0) were collected. Gastrointestinal inflammation markers including fecal calprotectin, cyclooxygenase-2, and 15-hydroxyprostaglandin dehydrogenase were evaluated. Serum calprotectin, insulin, insulin-like growth factor-1, C-reactive protein, and glycated hemoglobin were also assessed. Significant changes in serum calprotectin, insulin, and insulin-like growth factor-1 levels occurred over time. Borderline significant changes were observed in the neutrophil-lymphocyte ratio. These changes were noticeable immediately at the end of the 3-month active dietary intervention (T1). A significant increase in 15-hydroxyprostaglandin dehydrogenase expression in the normal crypts of matched samples was also observed between T0 and T2. This pilot study supports the hypothesis that a low-inflammatory diet can modulate gastrointestinal markers of inflammation in individuals with FAP. PREVENTION RELEVANCE: Cancer is known to be related to inflammatory conditions. This study suggests that anti-inflammatory dietary intervention may potentially prevent adenomas and cancer in FAP patients by reducing systemic and tissue inflammatory indices.

Sex Differences in Rest-Activity Circadian Rhythm in Patients With Metabolic Syndrome.

Rest-Activity circadian Rhythm (RAR) can be used as a marker of the circadian timing system. Recent studies investigated the relationship between irregular circadian rhythms and cardiovascular risk factors such as hypertension, obesity, and dyslipidemia. These factors are related to the Metabolic Syndrome (MS), a clustering of metabolic risk factors that increases the risk of several cardiovascular and metabolic diseases. This cross-sectional analysis aimed to explore the RAR characteristics by actigraphy in subjects with MS, particularly in relation to sex and MS parameters, using parametric and non-parametric analyses. Distinguishing the characteristics of RAR based on sex could prove useful as a tool to improve the daily level of activity and set up customized activity programs based on each person's circadian activity profile. This study showed that female participants exhibited higher values than male participants in the Midline Estimating Statistic of Rhythm (MESOR) (243.3 ± 20.0 vs 197.6 ± 17.9 activity count), Amplitude (184.5 ± 18.5 vs 144.2 ± 17.2 activity count), which measures half of the extent of the rhythmic variation in a cycle, and the most active 10-h period (M10) (379.08 ± 16.43 vs 295.13 ± 12.88 activity count). All these parameters are indicative of a higher daily activity level in women. Female participants also had lower Intradaily Variability (IV) than male participants (0.75 ± 0.03 vs 0.85 ± 0.03 activity count), which indicates a more stable and less fragmented RAR. These preliminary data provide the first experimental evidence of a difference in RAR parameters between male and female people with MS.

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].