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Randomized trial of weight loss in primary breast cancer: Impact on body composition, circulating biomarkers and tumor characteristics.
Demark-Wahnefried, W, Rogers, LQ, Gibson, JT, Harada, S, Frugé, AD, Oster, RA, Grizzle, WE, Norian, LA, Yang, ES, Della Manna, D, et al
International journal of cancer. 2020;146(10):2784-2796
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Obesity directly impacts survival in individuals with breast cancer. Previous studies in animals and at the cellular level have shown that calorie restriction and increased physical activity to achieve a negative energy balance may inhibit cancer progression, however effects in patients are unknown. This randomised control trial aimed to determine the impact of a pre surgery weight loss programme in 32 women with breast cancer on tumour biology and other markers of disease. The results were mixed and showed that proteins which bind to hormones involved in breast cancer were increased, which could decrease severity of disease. However, tumour biology was negatively affected; specific genes involved in breast cancer progression were increased and those involved in tumour suppression were decreased. Although this did result in no net effect on the rate at which new tumours were formed. It was concluded that although the study showed mixed results, ultimately the rate at which new tumours were formed remained unaffected. This trial could be used by healthcare professionals to understand that the role of negative energy intake in breast cancer development is complicated and warrants further research.
Abstract
Obesity adversely impacts overall and cancer-specific survival among breast cancer patients. Preclinical studies demonstrate negative energy balance inhibits cancer progression; however, feasibility and effects in patients are unknown. A two-arm, single-blinded, randomized controlled weight-loss trial was undertaken presurgery among 32 overweight/obese, Stage 0-II breast cancer patients. The attention control arm (AC) received basic nutritional counseling and upper-body progressive resistance training whereas the weight loss intervention (WLI) arm received identical guidance, plus counseling on caloric restriction and aerobic exercise to promote 0.68-0.92 kg/week weight loss. Anthropometrics, body composition, blood and survey data were collected at baseline and presurgery ∼30 days later. Tumor markers (e.g., Ki67) and gene expression were assessed on biopsy and surgical specimens; sera were analyzed for cytokines, growth and metabolic factors. Significant WLI vs. AC differences were seen in baseline-to-follow-up changes in weight (-3.62 vs. -0.52 kg), %body fat (-1.3 vs. 0%), moderate-to-vigorous physical activity (+224 vs. +115 min/week), caloric density (-0.3 vs. 0 kcal/g), serum leptin (-12.3 vs. -4.0 ng/dl) and upregulation of tumor PI3Kinase signaling and cell cycle-apoptosis related genes (CC-ARG; all p-values <0.05). Cytolytic CD56dim NK cell expression was positively associated with weight loss; CC-ARG increased with physical activity. Increased tumor (nuclear) TNFα and IL-1β, CX3CL1 and CXCL1 gene expression was observed in the WLI. Tumor Ki67 did not differ between arms. Feasibility benchmarks included 80% accrual, 100% retention, no adverse effects and excellent adherence. Short-term weight loss interventions are feasible; however, mixed effects on tumor biology suggest unclear benefit to presurgical caloric restriction, but possible benefits of physical activity.
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Influenza virus and atherosclerosis.
Peretz, A, Azrad, M, Blum, A
QJM : monthly journal of the Association of Physicians. 2019;(10):749-755
Abstract
Influenza viruses infect the upper respiratory system, causing usually a self-limited disease with mild respiratory symptoms. Acute lung injury, pulmonary microvascular leakage and cardiovascular collapse may occur in severe cases, usually in the elderly or in immunocompromised patients. Acute lung injury is a syndrome associated with pulmonary oedema, hypoxaemia and respiratory failure. Influenza virus primarily binds to the epithelium, interfering with the epithelial sodium channel function. However, the main clinical devastating effects are caused by endothelial dysfunction, thought to be the main mechanism leading to pulmonary oedema, respiratory failure and cardiovascular collapse. A significant association was found between influenza infection and acute myocardial infarction (AMI). The incidence of admission due to AMI during an acute viral infection was six times as high during the 7 days after laboratory confirmation of influenza infection as during the control interval (10-fold in influenza B, 5-fold in influenza A, 3.5-fold in respiratory syncytial virus and 2.7-fold for all other viruses). Our review will focus on the mechanisms responsible for endothelial dysfunction during influenza infection leading to cardiovascular collapse and death.
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Dietary Changes Impact the Gut Microbe Composition in Overweight and Obese Men with Prostate Cancer Undergoing Radical Prostatectomy.
Frugé, AD, Ptacek, T, Tsuruta, Y, Morrow, CD, Azrad, M, Desmond, RA, Hunter, GR, Rais-Bahrami, S, Demark-Wahnefried, W
Journal of the Academy of Nutrition and Dietetics. 2018;(4):714-723.e1
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BACKGROUND Diet and obesity influence prostate cancer risk and progression-effects that may be mediated through the gut microbiome. OBJECTIVE Our aim was to explore relationships among diet, gut microbes, and Gleason sum in overweight and obese prostate cancer patients enrolled in a presurgical weight-loss trial. DESIGN Randomized controlled trial (NCT01886677) secondary analysis. PARTICIPANTS/SETTING In 2013-2014, 40 prostate cancer patients in the southeastern United States were randomized and allocated equally to weight-loss and wait-list control arms while they awaited prostatectomy; stool samples were collected on a subset of 22 patients. INTERVENTION Registered dietitian nutritionists and exercise physiologists provided semi-weekly in-person and telephone-based guidance on calorie-restricted diets and exercise to promote an approximate weight loss of 0.91 kg/wk. MAIN OUTCOME MEASURES Baseline and follow-up 24-hour dietary recalls were conducted and analyzed (using the Automated Self-Administered 24-hour dietary recall system; National Cancer Institute, Bethesda, MD) for macronutrients, micronutrients, and food groups. Microbiome analysis targeting the V4 region of the 16S ribosomal RNA gene was performed on fecal samples. Biopsy Gleason sum data were accessed from diagnostic pathology reports. STATISTICAL ANALYSES PERFORMED Associations between dietary factors and operational taxonomic units were determined by β-diversity analysis. Wilcoxon signed rank, and Mann-Whitney U testing assessed within- and between-arm differences. Associations between Gleason sum and operational taxonomic units, and diet and operational taxonomic units, were analyzed using Spearman correlations. RESULTS At baseline, Proteobacteria (median 0.06, interquartile range 0.01 to 0.16) were abundant, with four orders positively associated with Gleason sum. Gleason sum was associated with Clostridium (ρ=.579; P=0.005) and Blautia (ρ=-0.425, P=0.049). Increased red meat consumption from baseline was associated with Prevotella (ρ=-.497; P=0.018) and Blautia (ρ=.422; P=0.039). Men who increased poultry intake had decreased Clostridiales abundance (P=0.009). CONCLUSIONS This hypothesis-generating study provides a starting point for investigating the relationships between the fecal microbiome, diet, and prostate cancer. Adequately powered studies are required to further explore and validate these findings.
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Presurgical weight loss affects tumour traits and circulating biomarkers in men with prostate cancer.
Demark-Wahnefried, W, Rais-Bahrami, S, Desmond, RA, Gordetsky, JB, Hunter, GR, Yang, ES, Azrad, M, Frugé, AD, Tsuruta, Y, Norian, LA, et al
British journal of cancer. 2017;117(9):1303-1313
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Obesity is a risk factor for 13 different cancers and a recent meta-analysis has shown increased weight to be associated with biochemical recurrence in men with prostate cancer. However, few studies have explored whether presurgical intentional weight loss results in improved prostate cancer outcomes. The aim of this trial was to explore the efficacy of weight loss among overweight and obese men with prostate cancer. Forty participants were randomised to either the presurgical weight loss intervention group or control arm, and changes in weight, body composition, quality of life, tumour biology and biomarkers were recorded. This study found that intentional weight loss caused mixed effects on tumour proliferation and gene expression. Based on these results, the authors recommend that more research is needed before effectively recommending presurgical weight loss among overweight men with prostate cancer.
Abstract
BACKGROUND Obesity is associated with aggressive prostate cancer. To explore whether weight loss favourably affects tumour biology and other outcomes, we undertook a presurgical trial among overweight and obese men with prostate cancer. METHODS This single-blinded, two-arm randomised controlled trial explored outcomes of a presurgical weight loss intervention (WLI) that promoted ∼1 kg per week loss via caloric restriction and increased physical activity (PA). Forty overweight/obese men with clinically confirmed prostate cancer were randomised to the WLI presurgery or to a control arm; changes in weight, body composition, quality-of-life, circulating biomarkers, gene expression, and immunohistochemical markers in tumour and benign prostatic tissue were evaluated. RESULTS The study period averaged 50 days. Mean (s.d.) change scores for the WLI vs control arms were as follows: weight: -4.7 (3.1) kg vs -2.2 (4.4) kg (P=0.0508); caloric intake: -500 (636) vs -159 (600) kcal per day (P=0.0034); PA: +0.9 (3.1) vs +1.7 (4.6) MET-hours per day (NS); vitality: +5.3 (7.l4) vs -1.8 (8.1) (P=0.0491); testosterone: +55.1 (86.0) vs -48.3 (203.7) ng dl-1 (P=0.0418); sex hormone-binding globulin: +14.0 (14.6) vs +1.8 (7.6) nmol l-1 (P=0.0023); and leptin: -2.16 (2.6) vs -0.03 (3.75) (P=0.0355). Follow-up Ki67 was significantly higher in WLI vs control arms; median (interquartile range): 5.0 (2.5,10.0) vs 0.0 (0.0,2.5) (P=0.0061) and several genes were upregulated, for example, CTSL, GSK3B, MED12, and LAMC2. CONCLUSIONS Intentional weight loss shows mixed effects on circulating biomarkers, tumour gene expression, and proliferative markers. More study is needed before recommending weight loss, in particular rapid weight loss, among men with prostate cancer.
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Feasibility outcomes of a presurgical randomized controlled trial exploring the impact of caloric restriction and increased physical activity versus a wait-list control on tumor characteristics and circulating biomarkers in men electing prostatectomy for prostate cancer.
Demark-Wahnefried, W, Nix, JW, Hunter, GR, Rais-Bahrami, S, Desmond, RA, Chacko, B, Morrow, CD, Azrad, M, Frugé, AD, Tsuruta, Y, et al
BMC cancer. 2016;16:61
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There is a strong body of evidence associating obesity and increased risk for more aggressive and progressive cancer. This paper aims to assess the feasibility of a presurgical diet and exercise weight loss intervention in men with newly-diagnosed prostate cancer who elected for prostatectomy. It also aims to explore the intervention’s effects on tumour proliferation rates and other biomarkers. The 3-weeks randomised controlled study included 40 overweight or obese men newly-diagnosed with prostate cancer. Participants in experimental arm were assigned to a healthy energy-restricted diet versus wait-list control arm. All feasibility endpoints were achieved with accrual completed within 2 years, retention of 85%, adherence of 95% and no adverse events. Biologic outcomes were not included in this paper, as biological testing was still ongoing. Authors concluded that this study’s methods and data on feasibility could provide useful framework for the design of future trials. They also highlighted the importance of presurgical trials as a feasible and safe means to assess the impacts of diet and exercise on tumour tissue.
Abstract
BACKGROUND Obesity is associated with tumor aggressiveness and disease-specific mortality for more than 15 defined malignancies, including prostate cancer. Preclinical studies suggest that weight loss from caloric restriction and increased physical activity may suppress hormonal, energy-sensing, and inflammatory factors that drive neoplastic progression; however, exact mechanisms are yet to be determined, and experiments in humans are limited. METHODS We conducted a randomized controlled trial among 40 overweight or obese, newly-diagnosed prostate cancer patients who elected prostatectomy to explore feasibility of a presurgical weight loss intervention that promoted a weight loss of roughly one kg. week(-1) via caloric restriction and physical activity, as well as to assess effects on tumor biology and circulating biomarkers. Measures of feasibility (accrual, retention, adherence, and safety) were primary endpoints. Exploratory aims were directed at the intervention's effect on tumor proliferation (Ki-67) and other tumor markers (activated caspase-3, insulin and androgen receptors, VEGF, TNFβ, NFκB, and 4E-BP1), circulating biomarkers (PSA, insulin, glucose, VEGF, TNFβ, leptin, SHBG, and testosterone), lymphocytic gene expression of corresponding factors and cellular bioenergetics in neutrophils, and effects on the gut microbiome. Consenting patients were randomized in a 1:1 ratio to either: 1) weight loss via a healthful, guidelines-based diet and exercise regimen; or 2) a wait-list control. While biological testing is currently ongoing, this paper details our methods and feasibility outcomes. RESULTS The accrual target was met after screening 101 cases (enrollment rate: 39.6%). Other outcomes included a retention rate of 85%, excellent adherence (95%), and no serious reported adverse events. No significant differences by age, race, or weight status were noted between enrollees vs. non-enrollees. The most common reasons for non-participation were "too busy" (30%), medical exclusions (21%), and "distance" (16%). CONCLUSIONS Presurgical trials offer a means to study the impact of diet and exercise interventions directly on tumor tissue, and other host factors that are feasible and safe, though modifications are needed to conduct trials within an abbreviated period of time and via distance medicine-based approaches. Pre-surgical trials are critical to elucidate the impact of lifestyle interventions on specific mechanisms that mediate carcinogenesis and which can be used subsequently as therapeutic targets. TRIAL REGISTRATION NCT01886677.
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Exploring effects of presurgical weight loss among women with stage 0-II breast cancer: protocol for a randomised controlled feasibility trial.
Tsuruta, Y, Rogers, LQ, Krontiras, H, Grizzle, WE, Frugé, AD, Oster, RA, Umphrey, HR, Jones, LW, Azrad, M, Demark-Wahnefried, W
BMJ open. 2016;(9):e012320
Abstract
INTRODUCTION Obesity is a known risk factor for postmenopausal breast cancer and is associated with poorer prognosis for premenopausal and postmenopausal patients; however, the aetiological mechanisms are unknown. Preclinical studies support weight loss via caloric restriction and increased physical activity as a possible cancer control strategy, though few clinical studies have been conducted. We undertook a feasibility trial among women recently diagnosed with stage 0-II breast cancer hypothesising that presurgical weight loss would be feasible, safe and result in favourable changes in tumour markers and circulating biomarkers. METHODS AND ANALYSIS A two-arm randomised controlled trial among 40 overweight or obese women, newly diagnosed with stage 0-II breast cancer and scheduled for surgery was planned. The attention control arm received upper body progressive resistance training and diet counselling to correct deficiencies in nutrient intake; the experimental arm received the same plus counselling on caloric restriction and aerobic exercise to achieve a weight loss of 0.68-0.919 kg/week. In addition to achieving feasibility benchmarks (accruing and retaining at least 80% of participants, and observing no serious adverse effects attributable to the intervention), we will explore the potential impact of an acute state of negative energy balance on tumour proliferation rates (Ki-67), as well as other tumour markers, serum biomarkers, gene expression, microbiome profiles and other clinical outcomes (eg, quality of life). Outcomes for the 2 study arms are compared using mixed models repeated-measures analyses. ETHICS AND DISSEMINATION Ethics approval was received from the University of Alabama at Birmingham Institutional Review Board (Protocol number F130325009). Study findings will be disseminated through peer-reviewed publications. Given that this is one of the first studies to investigate the impact of negative energy balance directly on tumour biology in humans, larger trials will be pursued if results are favourable. TRIAL REGISTRATION NUMBER NCT02224807; Pre-results.
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Disparate results between proliferation rates of surgically excised prostate tumors and an in vitro bioassay using sera from a positive randomized controlled trial.
Azrad, M, Vollmer, RT, Madden, J, Polascik, TJ, Snyder, DC, Ruffin, MT, Moul, JW, Brenner, D, He, X, Demark-Wahnefried, W
Biotechnic & histochemistry : official publication of the Biological Stain Commission. 2015;(3):184-9
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Abstract
In vitro bioassay has been used extensively to test the effects of culturing cancer cells in sera from humans participating in dietary interventions, i.e, studies of modified intake of nutrients for the purpose of reducing cancer risk or progression. It has been hypothesized that cell proliferation rates determined by the in vitro bioassay indicate whether modification of dietary intake could decrease cancer cell growth in vivo. It has been suggested, however, that the in vitro bioassay may not correlate with tumor cell proliferation rates in prostate cancer. We investigated the concordance of cell proliferation rates from surgically excised prostate tumor tissue with the in vitro bioassay using sera from matched patients. We used samples from an earlier randomized clinical trial that showed that supplementation with flaxseed significantly inhibited prostate cancer cell proliferation rates in vivo as indicated by Ki67 staining in tumor specimens. Proliferation rates of LNCaP, DU145 and PC3 cell lines cultured in 10% human sera from participants in the flaxseed trial were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Spearman's Rho correlation coefficients (ρ) indicated no association between Ki67 staining in prostate tumors and the in vitro bioassay for the three cell lines. These disparate findings suggest that the in vitro bioassay may not provide an accurate assessment of the environment in vivo.
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Current evidence linking polyunsaturated Fatty acids with cancer risk and progression.
Azrad, M, Turgeon, C, Demark-Wahnefried, W
Frontiers in oncology. 2013;:224
Abstract
There is increasing evidence that polyunsaturated fatty acids (PUFAs) play a role in cancer risk and progression. The n-3 family of PUFAs includes alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) while the n-6 family includes linolenic acid (LA) and arachidonic acid (AA). EPA and DHA are precursors for anti-inflammatory lipid mediators while AA is a precursor for pro-inflammatory lipid mediators. Collectively, PUFAs play crucial roles in maintaining cellular homeostasis, and perturbations in dietary intake or PUFA metabolism could result in cellular dysfunction and contribute to cancer risk and progression. Epidemiologic studies provide an inconsistent picture of the associations between dietary PUFAs and cancer. This discrepancy may reflect the difficulties in collecting accurate dietary data; however, it also may reflect genetic variation in PUFA metabolism which has been shown to modify physiological levels of PUFAs and cancer risk. Also, host-specific mutations as a result of cellular transformation could modify metabolism of PUFAs in the target-tissue. Clinical trials have shown that supplementation with PUFAs or foods high in PUFAs can affect markers of inflammation, immune function, tumor biology, and prognosis. Pre-clinical investigations have begun to elucidate how PUFAs may mediate cell proliferation, apoptosis and angiogenesis, and the signaling pathways involved in these processes. The purpose of this review is to summarize the current evidence linking PUFAs and their metabolites with cancer and the molecular mechanisms that underlie this association. Identifying the molecular mechanism(s) through which PUFAs affect cancer risk and progression will provide an opportunity to pursue focused dietary interventions that could translate into the development of personalized diets for cancer control.
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Racial differences in adiponectin and leptin in healthy premenopausal women.
Azrad, M, Gower, BA, Hunter, GR, Nagy, TR
Endocrine. 2013;(3):586-92
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The aim of this article is to longitudinally investigate racial differences in serum adiponectin and leptin in European-American (EA) and African-American (AA) women in the overweight and weight-reduced states. Sixty-two EA and 58 AA premenopausal women were weight reduced from body mass index (BMI) 27-30 kg/m(2) to BMI ≤ 24. Fasting serum adiponectin and leptin were determined; body composition and intra-abdominal adipose tissue (IAAT) were measured with dual-energy X-ray absorptiometry and computed tomography, respectively. In repeated-measure MANOVA, there was a significant race effect for IAAT and total fat mass; compared to AA women, EA women had higher IAAT and total fat mass (p < 0.0001 and p = 0.027, respectively). In the mixed-model for adiponectin that adjusted for IAAT, limb fat, and total fat, race was significantly associated with adiponectin (p = 0.046). AA women had significantly lower adjusted adiponectin compared to EA women at baseline [7.67 (6.85, 8.60) vs. 9.32 (8.34, 10.4) μg/ml, p < 0.05] and following weight loss [9.75 (8.70, 10.9) vs. 11.8 (10.6, 13.2) μg/ml, p < 0.05]. In a mixed-model for leptin that adjusted for insulin, estradiol, and fat mass, race was significantly associated with leptin (p < 0.0001). AA women had significantly higher adjusted leptin compared to EA women at baseline [24.7 (22.3, 27.4) vs. 19.9 (18.1, 21.8) ng/dl, p < 0.05] and following weight loss [11.7 (10.2, 13.3) vs. 8.48 (7.50, 9.57) ng/dl, p < 0.05]. Despite having a more favorable body fat distribution, AA women had lower adjusted adiponectin and higher leptin. Differences in body composition and fat distribution do not appear to be significant factors in explaining lower adiponectin and higher leptin in AA women.
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Flaxseed-derived enterolactone is inversely associated with tumor cell proliferation in men with localized prostate cancer.
Azrad, M, Vollmer, RT, Madden, J, Dewhirst, M, Polascik, TJ, Snyder, DC, Ruffin, MT, Moul, JW, Brenner, DE, Demark-Wahnefried, W
Journal of medicinal food. 2013;(4):357-60
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Enterolactone and enterodiol, mammalian lignans derived from dietary sources such as flaxseed, sesame seeds, kale, broccoli, and apricots, may impede tumor proliferation by inhibiting activation of nuclear factor kappa B (NFκB) and vascular endothelial growth factor (VEGF). We examined the associations between urinary enterolactone and enterodiol with prostatic tumor expression of NFκB, VEGF, and Ki67 among 147 patients with prostate cancer who participated in a presurgical trial of flaxseed supplementation (30 g/day) for ~30 days. Urinary enterolignans and tissue biomarkers were determined by high-performance liquid chromatography and immunohistochemistry, respectively. After supplementation, we observed significant correlations between intakes of plant lignan and urinary concentrations of total enterolignans (ρ=0.677, P<.0001), enterolactone (ρ=0.676, P<.0001), and enterodiol (ρ=0.628, P<.0001). Importantly, we observed that total urinary enterolignans and enterolactone were significantly and inversely correlated with Ki67 in the tumor tissue (ρ=-0.217, P=.011, and ρ=-0.230, P=.007, respectively), and a near-significant inverse association was observed for enterodiol (ρ=-0.159, P=.064). An inverse association was observed between enterolactone and VEGF (ρ=-0.143, P=.141), although this did not reach statistical significance. We did not observe an association between enterolignans and NFκB. In conclusion, flaxseed-derived enterolignans may hinder cancer cell proliferation via VEGF-associated pathways.