query: Flaxseeds & Breast Cancer Survival: Clinical Evidence

positive: Reduction in Ki-67 in Benign Breast Tissue of High Risk Women with the Lignan Secoisolariciresinol Diglycoside (SDG) Preclinical and correlative studies suggest reduced breast cancer with higher lignan intake or blood levels. We conducted a pilot study of modulation of risk biomarkers for breast cancer in premenopausal women after administration of the plant lignan secoisolariciresinol given as the diglycoside (SDG). Eligibility criteria included regular menstrual cycles, no oral contraceptives, a greater than 3-fold increase in 5 year risk, and baseline Ki-67 ≥2% in areas of hyperplasia in breast tissue sampled by random periareolar fine needle aspiration (RPFNA) during the follicular phase of the menstrual cycle. SDG 50 mg daily was given for 12 months, followed by repeat RPFNA. The primary endpoint was change in Ki-67. Secondary endpoints included change in cytomorphology, mammographic breast density, serum bioavailable estradiol, and testosterone IGF-I and IGFBP-3, and plasma lignan levels. Forty-five of 49 eligible women completed the study with excellent compliance (median = 96%) and few serious side effects (4% grade 3). Median plasma enterolactone increased ~ 9-fold, and total lignans 16 fold. Thirty-six (80%) of the 45 evaluable subjects demonstrated a decrease in Ki-67, from a median of 4% (range 2–16.8 %) to 2% (range 0–15.2%) (p<0.001 by Wilcoxon signed rank test). A decrease from baseline in the proportion of women with atypical cytology (p=0.035) was also observed. Based on favorable risk biomarker modulation and lack of adverse events, we are initiating a randomized trial of SDG vs. placebo in premenopausal women.

positive: Do phytoestrogens reduce the risk of breast cancer and breast cancer recurrence? What clinicians need to know. Oestrogen is an important determinant of breast cancer risk. Oestrogen-mimicking plant compounds called phytoestrogens can bind to oestrogen receptors and exert weak oestrogenic effects. Despite this activity, epidemiological studies suggest that the incidence of breast cancer is lower in countries where the intake of phytoestrogens is high, implying that these compounds may reduce breast cancer risk, and possibly have an impact on survival. Isoflavones and lignans are the most common phytoestrogens in the diet. In this article, we present findings from human observational and intervention studies related to both isoflavone and lignan exposure and breast cancer risk and survival. In addition, the clinical implications of these findings are examined in the light of a growing dietary supplement market. An increasing number of breast cancer patients seek to take supplements together with their standard treatment in the hope that these will either prevent recurrence or treat their menopausal symptoms. Observational studies suggest a protective effect of isoflavones on breast cancer risk and the case may be similar for increasing lignan consumption although evidence so far is inconsistent. In contrast, short-term intervention studies suggest a possible stimulatory effect on breast tissue raising concerns of possible adverse effects in breast cancer patients. However, owing to the dearth of human studies investigating effects on breast cancer recurrence and survival the role of phytoestrogens remains unclear. So far, not enough clear evidence exists on which to base guidelines for clinical use, although raising patient awareness of the uncertain effect of phytoestrogens is recommended.

positive: Antiproliferative activity of lignans against the breast carcinoma cell lines MCF 7 and BT 20. PURPOSE: Phytoestrogens are plant-derived, non-steroidal phytochemicals with anticarcinogenic potential. The major structural classes are the isoflavones and lignans. The aim of this study was to compare the effect of the plant-derived lignans secoisolariciresinol and matairesinol with the human lignans enterodiol and enterolactone as well as with 17β estradiol and tamoxifen on cell proliferation of breast carcinoma cell lines. METHODS: The influence of the lignans, 17β estradiol and tamoxifen on cell proliferation was determined using the BrdU test in MCF 7 and BT 20 cell lines. RESULTS: Enterodiol and enterolactone induced a stronger inhibition of cell growth in MCF 7 and BT 20 cells than secoisolariciresinol and matairesinol. The inhibition effects were less expressed in the BT 20 than in the MCF 7 cells. CONCLUSIONS: The human lignans enterodiol and enterolactone are more biologically active than their precursors secoisolariciresinol and matairesinol, and may be defined as the real drugs in cancer prevention.

positive: Dietary flaxseed alters tumor biological markers in postmenopausal breast cancer. PURPOSE: Flaxseed, the richest source of mammalian lignan precursors, has previously been shown to reduce the growth of tumors in rats. This study examined, in a randomized double-blind placebo-controlled clinical trial, the effects of dietary flaxseed on tumor biological markers and urinary lignan excretion in postmenopausal patients with newly diagnosed breast cancer. EXPERIMENTAL DESIGN: Patients were randomized to daily intake of either a 25 g flaxseed-containing muffin (n = 19) or a control (placebo) muffin (n = 13). At the time of diagnosis and again at definitive surgery, tumor tissue was analyzed for the rate of tumor cell proliferation (Ki-67 labeling index, primary end point), apoptosis, c-erbB2 expression, and estrogen and progesterone receptor levels. Twenty-four-hour urine samples were analyzed for lignans, and 3-day diet records were evaluated for macronutrient and caloric intake. Mean treatment times were 39 and 32 days in the placebo and flaxseed groups, respectively. RESULTS: Reductions in Ki-67 labeling index (34.2%; P = 0.001) and in c-erbB2 expression (71.0%; P = 0.003) and an increase in apoptosis (30.7%; P = 0.007) were observed in the flaxseed, but not in the placebo group. No significant differences in caloric and macronutrient intake were seen between groups and between pre- and posttreatment periods. A significant increase in mean urinary lignan excretion was observed in the flaxseed group (1,300%; P < 0.01) compared with placebo controls. The total intake of flaxseed was correlated with changes in c-erbB2 score (r = -0.373; P = 0.036) and apoptotic index (r = 0.495; P < 0.004). CONCLUSION: Dietary flaxseed has the potential to reduce tumor growth in patients with breast cancer.

positive: Serum enterolactone and prognosis of postmenopausal breast cancer. PURPOSE: Lignans--plant-derived compounds with estrogen-dependent and -independent anticarcinogenic properties--have been associated with postmenopausal breast cancer risk, but data are limited regarding their effect on survival. Dietary lignans are metabolized to enterolignans, which are subsequently absorbed and become bioavailable. PATIENTS AND METHODS: We assessed the prognosis of 1,140 postmenopausal patients with breast cancer age 50 to 74 years who were diagnosed between 2002 and 2005. Vital status through the end of 2009 was ascertained via local population registries, and deaths were verified by death certificates. Information on recurrences and secondary tumors was verified by clinical records and attending physicians. Associations of postdiagnostic serum enterolactone (a biomarker for dietary lignans) with overall survival and distant disease-free survival were assessed by using Cox proportional hazards models stratified by age at diagnosis and adjusted for prognostic factors. RESULTS: Median enterolactone levels for deceased patients and those still alive were 17.0 and 21.4 nmol/L, respectively. During a median of 6.1 years of follow-up after diagnosis, 162 deaths were confirmed. Higher serum enterolactone levels were associated with significantly reduced hazard ratios (HRs) for death (HR per 10 nmol/L increment, 0.94; P = .04; HR for the highest quartile, 0.58; 95% CI, 0.34 to 0.99). For distant disease, HR was 0.94 per 10 nmol/L increment (P = .08) and 0.62 (95% CI, 0.35 to 1.09) for the highest quartile. The highest quartile of serum enterolactone was associated with a significantly reduced risk of death only for estrogen receptor-negative tumors (HR, 0.27; 95% CI, 0.08 to 0.87) but not for estrogen receptor-positive tumors (HR, 0.91; 95% CI, 0.45 to 1.84: P for heterogeneity = .09). CONCLUSION: Postmenopausal patients with breast cancer who have high serum enterolactone levels may have better survival.

positive: Serum enterolactone levels and mortality outcome in women with early breast cancer: a retrospective cohort study. We previously demonstrated that high serum enterolactone levels are associated with a reduced incidence of breast cancer in healthy women. The present study was aimed at investigating whether a similar association might be found between serum enterolactone levels and the mortality of women with early breast cancer. The levels of enterolactone in cryopreserved serum aliquots obtained from 300 patients, operated on for breast cancer, were measured using a time-resolved fluoro-immunoassay. Levels were analyzed in respect to the risk of mortality following surgery. Cox proportional hazard regression models were used to check for prognostic features, to estimate hazard ratios for group comparisons and to test for the interaction on mortality hazards between the variables and enterolactone concentrations. The Fine and Gray competing risk proportional hazard regression model was used to predict the probabilities of breast cancer-related and breast cancer-unrelated mortalities. At a median follow-up time of 23 years (range 0.6-26.1), 180 patients died, 112 of whom died due to breast cancer-related events. An association between a decreased mortality risk and enterolactone levels ≥ 10 nmol/l was found in respect to both all-cause and breast cancer-specific mortality. The difference in mortality hazards was statistically significant, but it appeared to decrease and to lose significance after the first 10 years, though competing risk analysis showed that breast cancer-related mortality risk remained constantly lower in those patients with higher enterolactone levels. Our findings are consistent with those of most recent literature and provide further evidence that mammalian lignans might play an important role in reducing all-cause and cancer-specific mortality of the patients operated on for breast cancer.

positive: Meta-analyses of lignans and enterolignans in relation to breast cancer risk. BACKGROUND: Epidemiologic studies that examined whether lignans, the most important class of phytoestrogens in the Western diet, protect against breast cancer have yielded inconsistent results. OBJECTIVE: In this study, we conducted meta-analyses on the association between lignans and breast cancer risk. DESIGN: We performed a systematic MEDLINE search to identify epidemiologic studies published between 1997 and August 2009. We calculated pooled risk estimates (REs) for total lignan exposure, dietary lignan intake, enterolignan exposure, and blood or urine concentrations of enterolactone and according to menopausal and estrogen receptor (ER) status of tumors. RESULTS: We included 21 studies (11 prospective cohort studies and 10 case-control studies) in the meta-analyses. Lignan exposure was not associated with an overall breast cancer risk (RE: 0.92; 95% CI: 0.81, 1.02; P for heterogeneity = 0.004). However, in postmenopausal women, high lignan intake was associated with a significant reduced risk of breast cancer (13 studies; RE: 0.86; 95% CI: 0.78, 0.94; P for heterogeneity = 0.32). Breast cancer risk was also inversely associated with enterolignan exposure (4 studies; RE: 0.84; 95% CI: 0.71, 0.97) but not with blood or urine enterolactone concentrations. The associations were not significantly different between ER-status subgroups (6 studies). CONCLUSIONS: High lignan exposure may be associated with a reduced breast cancer risk in postmenopausal women. Additional work is warranted to clarify the association between lignan exposure and breast cancer risk.

positive: Dietary lignan intakes in relation to survival among women with breast cancer: the Western New York Exposures and Breast Cancer (WEB) Study Dietary lignan intakes have been associated with reduced breast cancer risks; however, no previous studies have investigated whether lignan intake might be associated with breast cancer survival. We examined the association of dietary lignan intakes with survival in 1122 women with primary, incident, histologically confirmed breast cancer identified between 1996 and 2001, and with vital status determined through December 31, 2006. Diet in the 12–24 months before diagnosis was assessed with an extensive food frequency questionnaire, and potential confounders assessed from an extensive epidemiologic interview and abstracted clinical data. Lignan intake was calculated using published food composition data. Hazard ratios (HR), and 95% confidence intervals (CIs) for dietary lignan intakes with all cause, and breast cancer mortality were estimated using Cox proportional hazards adjusting for age, education, race, total energy intake, tumor stage, and body mass index. Of the 1122 women with complete dietary data, 160 had died by the end of follow-up. Among postmenopausal women only, those in the highest versus lowest quartile of lignan intakes had a statistically significant reduction in the risk of all cause mortality (HR 0.49, 95% CI 0.26–0.91) and a significantly reduced risk of breast cancer mortality (HR 0.29, 95% CI 0.11–0.76). Higher intakes of dried beans (HR 0.61, 95% CI 0.36–1.03), but not fruits, vegetables, or grains, were also weakly associated with overall mortality. In summary, our results suggest that higher lignan intakes may be associated with improved survival among postmenopausal women with breast cancer.

positive: Tamoxifen and Flaxseed Alter Angiogenesis Regulators in Normal Human Breast Tissue In Vivo The incidence of breast cancer is increasing in the Western world and there is an urgent need for studies of the mechanisms of sex steroids in order to develop novel preventive strategies. Diet modifications may be among the means for breast cancer prevention. Angiogenesis, key in tumor progression, is regulated by the balance between pro- and anti-angiogenic factors, which are controlled in the extracellular space. Sampling of these molecules at their bioactive compartment is therefore needed. The aims of this study were to explore if tamoxifen, one of the most used anti-estrogen treatments for breast cancer affected some of the most important endogenous angiogenesis regulators, vascular endothelial growth factor (VEGF), angiogenin, and endostatin in normal breast tissue in vivo and if a diet supplementation with flaxseed had similar effects as tamoxifen in the breast. Microdialysis was used for in situ sampling of extracellular proteins in normal breast tissue of women before and after six weeks of tamoxifen treatment or before and after addition of 25 g/day of ground flaxseed to the diet or in control women. We show significant correlations between estradiol and levels of VEGF, angiogenin, and endostatin in vivo, which was verified in ex vivo breast tissue culture. Moreover, tamoxifen decreased the levels of VEGF and angiogenin in the breast whereas endostatin increased significantly. Flaxseed did not alter VEGF or angiogenin levels but similar to tamoxifen the levels of endostatin increased significantly. We conclude that one of the mechanisms of tamoxifen in normal breast tissue include tipping of the angiogenic balance into an anti-angiogenic state and that flaxseed has limited effects on the pro-angiogenic factors whereas the anti-angiogenic endostatin may be modified by diet. Further studies of diet modifications for breast cancer prevention are warranted.

positive: Supplementation of flaxseed oil diminishes skin sensitivity and improves skin barrier function and condition. BACKGROUND: Skin sensitivity is a common problem in the Western population correlated with changes of skin properties like skin barrier function, hydration and skin physiology. Skin properties can be modulated by dietary fatty acids (FA), especially poly-unsaturated FA. The present study was performed to evaluate the effect of daily supplementation with flaxseed oil and safflowerseed oil on healthy volunteers with sensitive skin. METHODS: The study was designed as a randomized, double-blind 12-week intervention with 2 female treatment groups (n = 13). Plasma FA profile, skin sensitivity, skin hydration, transepidermal water loss (TEWL) and skin surface were evaluated on day 0, week 6 and week 12. RESULTS: Supplementation with flaxseed oil led to significant decreases in sensitivity (after nicotinate irritation), TEWL, skin roughness and scaling, while smoothness and hydration were increased. Concomitantly, the ratio of n-6/n-3 FA in plasma decreased. Upon supplementation with safflowerseed oil, only a significant improvement in skin roughness and hydration was observed; however, the effects were less pronounced and determined at a later point in time than with flaxseed oil. The plasma n-6/n-3 FA ratio increased. CONCLUSION: The data provide evidence that daily intake of flaxseed oil modulates skin condition. Copyright © 2010 S. Karger AG, Basel.

positive: Whole sesame seed is as rich a source of mammalian lignan precursors as whole flaxseed. The mammalian lignans enterolactone and enterodiol, which are produced by the microflora in the colon of humans and animals from precursors in foods, have been suggested to have potential anticancer effects. This study determined the production of mammalian lignans from precursors in food bars containing 25 g unground whole flaxseed (FB), sesame seed (SB), or their combination (FSB; 12.5 g each). In a randomized crossover study, healthy postmenopausal women supplemented their diets with the bars for 4 wk each separated by 4-wk washout periods, and urinary mammalian lignan excretion was measured at baseline and after 4 wk as a marker of mammalian lignan production. Results showed an increase with all treatments (65.1-81.0 mumol/day; P < 0.0001), which did not differ among treatments. Lignan excretion with the whole flaxseed was similar to results of other studies using ground flaxseed. An unidentified lignan metabolite was detected after consumption of SB and FSB but not of FB. Thus, we demonstrated for the first time that 1) precursors from unground whole flaxseed and sesame seed are converted by the bacterial flora in the colon to mammalian lignans and 2) sesame seed, alone and in combination with flaxseed, produces mammalian lignans equivalent to those obtained from flaxseed alone.

positive: Does antibacterial treatment for urinary tract infection contribute to the risk of breast cancer? Low lignan status has been reported to be related to an elevated risk of breast cancer. Since lignan status is reduced by antibacterial medications, it is plausible to hypothesize that repeated use of antibiotics may also be a risk factor for breast cancer. History of treatment for urinary tract infection was studied for its prediction of breast cancer among 9461 Finnish women 19–89 years of age and initially cancer-free. During a follow-up in 1973–1991, a total of 157 breast cancer cases were diagnosed. Women reporting previous or present medication for urinary tract infection at baseline showed an elevated breast cancer risk in comparison with other women. The age-adjusted relative risk was 1.34 (95% confidence interval (CI) = 0.98–1.83). The association was concentrated to women under 50 years of age. The relative risk for these women was 1.74 (95% CI 1.13–2.68), whereas it was 0.97 (95% CI 0.59–1.58) for older women. The relative risk in the younger age-group was 1.47 (95% CI 0.73–2.97) during the first 10 years of follow-up, and 1.93 (95% CI 1.11–3.37) for follow-up times longer than 10 years. These data suggest that premenopausal women using long-term medication for urinary tract infections show a possible elevated risk of future breast cancer. The results are, however, still inconclusive and the hypothesis needs to be tested by other studies. © 2000 Cancer ResearchCampaign

positive: High-performance liquid chromatographic analysis of secoisolariciresinol diglucoside and hydroxycinnamic acid glucosides in flaxseed by alkaline ex... A HPLC method was developed for the analysis of secoisolariciresinol diglucoside (SDG) and hydroxycinnamic acid glucosides in milled defatted flaxseed flour. Direct extraction by 1 M NaOH for 1 h at 20 degrees C resulted in a higher yield than that obtained by hydrolysis of alcoholic extracts. An internal standard, o-coumaric acid, was used and the method was found to be easy, fast, and with good repeatability. On dry matter basis, different samples of flaxseeds varied considerably in their content of (+)-SDG (11.9-25.9 mg/g), (-)-SDG (2.2-5.0 mg/g), p-coumaric acid glucoside (1.2-8.5 mg/g), and ferulic acid glucoside (1.6-5.0 mg/g).

positive: Lignans in man and in animal species. In our laboratories, for several years, two phenolic compounds have been detected during gas chromatographic-mass spectrometric analysis of urinary steroid extracts from human and animal species. Although features of the mass spectra of their trimethylsilyl (TMS) ether derivatives resembled those of oestrogens, they were atypical of steroids. The possibility that they were artefacts of the isolation procedures was discounted after careful studies with blanks, by varying the extraction method and because they were present almost exclusively as conjugates of glucuronic acid. Several of the general characteristics of the unknown compounds were reported after one (referred to as compound 180/442) was found to have a cyclic pattern of excretion during the menstrual cycle of an adult vervet monkey (Fig. 1). An investigation of the nature and distribution of the compounds has shown them to be urinary constituents in humans, baboons, vervet monkeys and rats, and further related compounds have been detected, so far only in vervet monkey urine. We now report spectroscopic and chemical studies that show the two original compounds to be lignans, which have a 2,3-dibenzylbutane skeleton as their basic structure. Unlike all previously known natural lignans, invariably of plant origin, the two mammalian compounds carry phenolic hydroxy groups only in the meta position of the aromatic rings.

positive: Excretion, isolation and structure of a new phenolic constituent of female urine. The regular occurrence of a peak due to an unidentified substance (X) in the gas chromatographic traces obtained from phenolic extracts of urine from human pregnant and non-pregnant females has been reported. The biphasic excretion of X with maxima in the luteal phase of the ovulatory cycle and relatively high levels in the first trimester of pregnancy were noteworthy and suggested that the substance may have a biological significance. Close similarities between the excretory pattern, the chemical and chromatographic properties of X and of those of the known phenolic steroids suggested initially that this compound was steroidal in nature. The same, or a similar, substance seems to be excreted in the vervet monkey (Cercopithecus aethiops pygerythrus). We now report the excretory pattern of X in more detail, the isolation of the pure compound from pooled pregnancy urine and the chemical structure. The structure determined by mass spectrometry, IR spectroscopy and NMR spectrometry is: trans-(+/-)-3,4-bis[(3-hydroxyphenyl)methyl]dihydro-2-(3H)-furanone (HPMF) and was confirmed by synthesis.

positive: Dietary fiber and breast cancer risk: a systematic review and meta-analysis of prospective studies. BACKGROUND: Evidence from case-control studies suggest that dietary fiber may be inversely related to breast cancer risk, but it is unclear if this is supported by prospective data. We conducted a systematic review and meta-analysis of the evidence from prospective studies. METHODS: PubMed was searched for prospective studies of fiber intake and breast cancer risk until 31st August 2011. Random effects models were used to estimate summary relative risks (RRs). RESULTS: Sixteen prospective studies were included. The summary RR for the highest versus the lowest intake was 0.93 [95% confidence interval (CI) 0.89-0.98, I(2) = 0%] for dietary fiber, 0.95 (95% CI 0.86-1.06, I(2) = 4%) for fruit fiber, 0.99 (95% CI 0.92-1.07, I(2) = 1%) for vegetable fiber, 0.96 (95% CI 0.90-1.02, I(2) = 5%) for cereal fiber, 0.91 (95% CI 0.84-0.99, I(2) = 7%) for soluble fiber and 0.95 (95% CI 0.89-1.02, I(2) = 0%) for insoluble fiber. The summary RR per 10 g/day of dietary fiber was 0.95 (95% CI 0.91-0.98, I(2) = 0%, P(heterogeneity) = 0.82). In stratified analyses, the inverse association was only observed among studies with a large range (≥13 g/day) or high level of intake (≥25 g/day). CONCLUSION: In this meta-analysis of prospective studies, there was an inverse association between dietary fiber intake and breast cancer risk.

positive: Determination of urinary lignans and phytoestrogen metabolites, potential antiestrogens and anticarcinogens, in urine of women on various habitual ... Recently two groups of compounds with diphenolic structure, the lignans and the isoflavonic phytoestrogens, were detected and identified in human urine and other biological fluids. These compounds are of great biological interest because they exhibit both in vitro and in vivo weak estrogenic and sometimes also antiestrogenic activities and many plant lignans have been shown to have anticarcinogenic, antiviral, antifungal and other interesting biological effects. The compounds found in relatively large amounts (10-1000 times more than estrogens) in urine are modified by intestinal bacteria from plant lignans and phytoestrogens, which are present in fiber-rich food such as grain and beans. They bind with low affinity to estrogen receptors and preliminary results suggest that they may induce production of sex hormone binding globulin (SHBG) in the liver and in this way may influence sex hormone metabolism and biological effects. Five compounds, the lignans enterolactone (Enl), enterodiol (End) and the isoflavonic phytoestrogen metabolites daidzein (Da), equol (Eq) and O-desmethylangolensin (O-Dma) were measured in urine by gas chromatography-mass spectrometry (selected ion monitoring) using deuterated internal standards in 5 groups of women (total number 53). The members of three dietary groups (omnivores, lactovegetarians and macrobiotics) were living in Boston and of two groups in Helsinki (omnivores and lactovegetarians). Until now measurements have been carried out in 94 72-h samples. The highest mean excretion of the most abundant compound, enterolactone, was found in the macrobiotic group and the lowest in the omnivoric groups. Total mean 24-h excretion of enterolactone was 17,680 nmol in the macrobiotics, 4,170 nmol in the Boston lactovegetarians, 3,650 nmol in the Helsinki lactovegetarians, 2,460 nmol in the Helsinki omnivores and 2,050 nmol in the Boston omnivores. The other diphenols followed approximately the same pattern. In an earlier study the lowest excretion of enterolactone (1,040 nmol/24 h) was found in a group of postmenopausal apparently healthy breast cancer patients living in Boston. It is concluded that further studies are necessary to elucidate the possible role of these compounds in cancer and other diseases. However, the evidence obtained until now seems to justify the conclusion that these compounds may be among the dietary factors affording protection against hormone-dependent cancers in vegetarians and semivegetarians.

positive: Phytoestrogen consumption and association with breast, prostate and colorectal cancer in EPIC Norfolk. Phytoestrogens are polyphenolic secondary plant metabolites that have structural and functional similarities to 17beta-oestradiol and have been associated with a protective effect against hormone-related cancers. Most foods in the UK only contain small amounts of phytoestrogens (median content 21 microg/100 g) and the highest content is found in soya and soya-containing foods. The highest phytoestrogen content in commonly consumed foods is found in breads (average content 450 microg/100 g), the main source of isoflavones in the UK diet. The phytoestrogen consumption in cases and controls was considerably lower than in Asian countries. No significant associations between phytoestrogen intake and breast cancer risk in a nested case-control study in EPIC Norfolk were found. Conversely, colorectal cancer risk was inversely associated with enterolignan intake in women but not in men. Prostate cancer risk was positively associated with enterolignan intake, however this association became non-significant when adjusting for dairy intake, suggesting that enterolignans can act as a surrogate marker for dairy or calcium intake. 2010 Elsevier Inc. All rights reserved.

positive: Estimated enterolignans, lignan-rich foods, and fibre in relation to survival after postmenopausal breast cancer Background: Lignans – oestrogenic substances present in various foods – are associated with postmenopausal breast cancer risk, but not much is known regarding their effects on survival. Methods: In a follow-up study of 2653 postmenopausal breast cancer patients diagnosed between 2001 and 2005, vital status and causes of death were verified through end of 2009. Hazard ratios (HRs) and 95% confidence intervals (CIs) for estimated enterolignans, lignan-rich foods, and dietary fibre in relation to overall survival (OS) and breast cancer-specific survival (BCSS) were assessed using Cox proportional hazards models stratified by age at diagnosis and adjusted for prognostic/confounding factors. Results: Median follow-up time was 6.4 years, and 321 women died, 235 with breast cancer. High estimated enterolactone and enterodiol levels were associated with significantly lower overall mortality (highest quintile, HR=0.60, 95% CI=0.40–0.89, PTrend=0.02 and HR=0.63, 95% CI=0.42–0.95, PTrend=0.02, respectively). Fibre intake was also associated with a significantly lower overall mortality. Differentiated by median fibre intake, associations with estimated enterolignans were still evident at low but not high fibre intake. There was no effect modification by oestrogen receptor status and menopausal hormone therapy. Conclusion: Postmenopausal breast cancer patients with high estimated enterolignans may have a better survival.

positive: Hypothesis: is antibiotic use associated with breast cancer? The hypothesis that antibiotic use may increase cancer risk was first proposed several decades ago and some research suggests an increased risk of breast cancer among women with conditions likely to require long-term antibiotic use (e.g., acne, recurrent urinary-tract infections, UTI). However, this hypothesis has not been verified and the possible biological mechanisms are not entirely clear. A recent cohort study in Finland reported an increased risk of breast-cancer associated with antibiotic use for UTI. The effect of antibiotics on the ability of intestinal microflora to metabolise phytochemicals from edible plants into compounds that may protect against cancer was proposed as a potential mechanism. We extend this hypothesis by proposing that antibiotic use may be associated with breast-cancer risk through effects on immune and inflammatory factors, such as cytokines, T lymphocytes, prostaglandins, and matrix metalloproteinases, as well as disruption of phytochemical and oestrogen metabolism by intestinal microflora. We suggest that some mechanisms may increase breast-cancer risk, while others may decrease risk, depending on the antibiotic classification.

positive: Enterolactone and breast cancer: methodological issues may contribute to conflicting results in observational studies. Lignans found in plant foods are converted by the intestinal microflora to enterolignans. The structure of enterolignans is similar to that of estrogens, which has inspired researchers to examine a potential protective association in relation to health outcomes. Numerous epidemiological studies have measured concentration of enterolignans, mainly enterolactone, in blood or urine as a biomarker of lignan exposure and studied its relation to breast cancer risk. Case-control studies have shown decreased breast cancer risk associated with high circulating enterolactone concentrations, but results demonstrated by prospective cohort studies are less clear. The purpose of this review is to discuss factors that may contribute to these contradictory findings obtained in epidemiological studies, including age distribution, enterolactone measurement error, heterogeneity of breast cancer subtypes, and genetic factors. Different sources of enterolactone precursors may also contribute to inconclusive results. In conclusion, to get robust evidence of the health effects of lignans and enterolactone, more effort has to be put on methodological problems, including reducing measurement errors in enterolactone estimation, and to identify factors that modify the effect. Copyright © 2010 Elsevier Inc. All rights reserved.

positive: Sensitive skin: closing in on a physiological cause. The phenomenon of 'sensitive skin' is a relatively recent complaint in which certain individuals report more intense and frequent adverse sensory effects than the normal population upon use of cosmetic (personal-care) products. Originally defined as a minority complaint, sensitive skin is now claimed by a majority of women in industrialized countries and nearly half of men. Sensitive skin is self-diagnosed and typically unaccompanied by any obvious physical signs of irritation, and the number of individuals who claim sensitivity has risen steadily with the number of consumer products targeted towards this supposedly uncommon group. Believed by many dermatologists, therefore, to be a 'princess and the pea' phenomenon, the problem of sensitive skin has largely avoided focussed research. Over the last few years, however, the evidence of documentable biophysical changes associated with the largely sensory symptoms of this disorder has accumulated, including some gained by improved methods of identifying subclinical signs of skin irritation. Although the understanding of the aetiology of this phenomenon is as yet incomplete, existing research now supports a biophysical origin for this disorder. Effective methods of diagnosis, intrinsic and extrinsic contributors to exaggerated neural sensitivity, and the specific mechanisms of the discomfort associated with the compliant are required, as are appropriate means of prevention and treatment.

positive: Sensitive skin in the American population: prevalence, clinical data, and role of the dermatologist. INTRODUCTION: Sensitive skin is a complex dermatological condition, defined by abnormal sensory symptoms. The aim of this epidemiological survey was to assess the prevalence of sensitive skin and collect data on sensitive skin in the US population. METHODS: A phone survey was conducted in the USA by a poll institute in 2007. A sample was drawn from a representative national cohort of the American population at least 18years of age through the quota method. Data on demographic characteristics, environmental and climatic factors, skin characteristics, dermatological disorders, cosmetics use, and visits to the dermatologist were collected. RESULTS: Of 994 subjects who answered (495 men and 499 women), 44.6% declared having "sensitive" or "very sensitive" skin. Women were more concerned than men (50.9% vs. 38.2%, P<0.0001). There was no significant difference related to geographic localization, age, or ethnic distribution. Subjects with sensitive skin had mainly dry (34.5%) or mixed skin (35.7%), fair phototypes, dermatological disorders, higher skin reactivity to cosmetics and various environmental factors in comparison with subjects who stated having only a "slightly" sensitive or not sensitive skin. The dermatologist had a strong influence on subjects with "sensitive" or "very sensitive" skin through the prescription of skin care products. CONCLUSION: This study, based on a representative sample of the American population, reveals a high prevalence of sensitive skin in the USA. Sensitive skin is mainly associated with dry skin, fair phototype, reactivity to climatic and environmental factors, and cosmetics. American dermatologists seem largely involved in the care of this condition. © 2011 The International Society of Dermatology.

positive: Flaxseed supplementation improved insulin resistance in obese glucose intolerant people: a randomized crossover design Background Obesity leads to an increase in inflammation and insulin resistance. This study determined antioxidant activity of flaxseed and its role in inflammation and insulin resistance in obese glucose intolerant people. Methods Using a randomized crossover design, nine obese glucose intolerant people consumed 40 g ground flaxseed or 40 g wheat bran daily for 12 weeks with a 4-week washout period. Plasma inflammation biomarkers (CRP, TNF-α, and IL-6), glucose, insulin, and thiobaribituric acid reactive substance (TBARS) were measured before and after of each supplementation. Results Flaxseed supplementation decreased TBARS (p = 0.0215) and HOMA-IR (p = 0.0382). Flaxseed or wheat bran supplementation did not change plasma inflammatory biomarkers. A positive relationship was found between TBARS and HOMA-IR (r = 0.62, p = 0.0003). Conclusions The results of the study weakly support that decreased insulin resistance might have been secondary to antioxidant activity of flaxseed. However, the mechanism(s) of decreased insulin resistance by flaxseed should be further determined using flaxseed lignan.

positive: High alpha-linolenic acid flaxseed (Linum usitatissimum): some nutritional properties in humans. Although high alpha-linolenic acid flaxseed (Linum usitatissimum) is one of the richest dietary sources of alpha-linolenic acid and is also a good source of soluble fibre mucilage, it is relatively unstudied in human nutrition. Healthy female volunteers consumed 50 g ground, raw flaxseed/d for 4 weeks which provided 12-13% of energy intake (24-25 g/100 g total fat). Flaxseed raised alpha-linolenic acid and long-chain n-3 fatty acids in both plasma and erythrocyte lipids, as well as raising urinary thiocyanate excretion 2.2-fold. Flaxseed also lowered serum total cholesterol by 9% and low-density-lipoprotein-cholesterol by 18%. Changes in plasma alpha-linolenic acid were equivalent when 12 g alpha-linolenic acid/d was provided as raw flaxseed flour (50 g/d) or flaxseed oil (20 g/d) suggesting high bioavailability of alpha-linolenic acid from ground flaxseed. Test meals containing 50 g carbohydrate from flaxseed or 25 g flaxseed mucilage each significantly decreased postprandial blood glucose responses by 27%. Malondialdehyde levels in muffins containing 15 g flaxseed oil or flour/kg were similar to those in wheat-flour muffins. Cyanogenic glycosides (linamarin, linustatin, neolinustatin) were highest in extracted flaxseed mucilage but were not detected in baked muffins containing 150 g flaxseed/kg. We conclude that up to 50 g high-alpha-linolenic acid flaxseed/d is palatable, safe and may be nutritionally beneficial in humans by raising n-3 fatty acids in plasma and erythrocytes and by decreasing postprandial glucose responses.

positive: Dietary milled flaxseed and flaxseed oil improve N-3 fatty acid status and do not affect glycemic control in individuals with well-controlled type ... OBJECTIVE: To determine the effects of dietary consumption of milled flaxseed or flaxseed oil on glycemic control, n-3 fatty acid status, anthropometrics, and adipokines in individuals with type 2 diabetes. DESIGN: Thirty-four participants were randomized into a parallel, controlled trial. SUBJECTS: The participants were adults with type 2 diabetes (age 52.4 +/- 1.5 years, body mass index 32.4 +/- 1.0 kg/m(2), n = 17 men and 17 women). INTERVENTIONS: Participants consumed a selection of bakery products containing no flax (control group [CTL], n = 9), milled flaxseed (FXS, n = 13; 32 g/d), or flaxseed oil (FXO, n = 12; 13 g/d) daily for 12 weeks. The FXS and FXO groups received equivalent amounts of alpha-linolenic acid (ALA; 7.4 g/day). MEASURES OF OUTCOME: The primary outcome measures were fasting plasma hemoglobin A(1c), glucose, insulin, and phospholipid fatty acid composition. The secondary outcome measures were fasting circulating leptin and adiponectin, as well as body weight, body mass index, and waist circumference. Dietary intake assessment and calculations for homeostasis model assessment for insulin resistance and quantified insulin sensitivity check were also completed. RESULTS: The FXS and FXO groups had increases in plasma phospholipid n-3 fatty acids (ALA, eicosapentaenoic acid [EPA], or decosapentaenoic acid [DPA], but not docosahexaenoic acid), and the FXO group had more EPA and DPA in plasma phospholipids compared to the FXS group. All groups had similar caloric intakes; however, the CTL group experienced a 4% weight gain compared to baseline (p < 0.05), while both flax groups had constant body weights during the study period. All other parameters, including glycemic control, were unchanged by dietary treatment. CONCLUSIONS: Milled FXS and FXO intake does not affect glycemic control in adults with well-controlled type 2 diabetes. Possible prevention of weight gain by flax consumption warrants further investigation.

positive: An open-label study on the effect of flax seed powder (Linum usitatissimum) supplementation in the management of diabetes mellitus. Diabetes mellitus is characterized by hyperglycemia and associated with aberrations in the metabolism of carbohydrate, protein, and lipid that result in development of secondary complications. Extensive studies have indicated that nutritional therapy plays a pivotal role in the controlling or postponing of development of these secondary complications. Several functional foods have been shown to possess hypoglycemic and hypolipidemic properties. Flax seed (FS) is a functional food that is rich in omega 3 fatty acids and antioxidants and is low in carbohydrates. In exploratory studies, FS was incorporated in recipes, which resulted in a reduction in the glycemic index of the food items. These observations prompted us to investigate the efficacy of FS supplementation in type 2 diabetics (n = 29). Subjects were assigned to the experimental (n = 18) or the control group (n = 11) on the basis of their desire to participate in the study. The experimental group's diet was supplemented daily with 10 g of FS powder for a period of 1 month. The control group received no supplementation or placebo. During the study, diet and drug intake of the subjects remained unaltered. The efficacy of supplementation with FS was evaluated through a battery of clinico-biochemical parameters. Supplementation with FS reduced fasting blood glucose by 19.7% and glycated hemoglobin by 15.6%. A favorable reduction in total cholesterol (14.3%), triglycerides (17.5%), low-density lipoprotein cholesterol (21.8%), and apolipoprotein B and an increase in high-density lipoprotein cholesterol (11.9%) were also noticed. These observations suggest the therapeutic potential of FS in the management of diabetes mellitus.

positive: Flaxseed Supplementation (not Dietary Fat Restriction) Reduces Prostate Cancer Proliferation Rates in Men Presurgery Background Prostate cancer affects one-out-of-six men during their lifetime. Dietary factors are postulated to influence the development and progression of prostate cancer. Low-fat diets and flaxseed supplementation may offer potentially protective strategies. Methods We undertook a multi-site, randomized controlled trial to test the effects of low-fat and/or flaxseed-supplemented diets on the biology of the prostate and other biomarkers. Prostate cancer patients (n=161) scheduled at least 21 days before prostatectomy were randomly assigned to one of the following arms: 1) control (usual diet); 2) flaxseed-supplemented diet (30 g/day); 2) low-fat diet (<20% total energy); or 4) flaxseed-supplemented, low-fat diet. Blood was drawn at baseline and prior to surgery and analyzed for prostate specific antigen (PSA), sex hormone binding globulin, testosterone, insulin-like growth factor-1 and binding protein-3, c-reactive protein, and total and low density lipoprotein cholesterol. Tumors were assessed for proliferation (Ki-67, the primary endpoint) and apoptosis. Results Men were on protocol an average of 30 days. Proliferation rates were significantly lower (P < 0.002) among men assigned to the flaxseed arms. Median Ki-67 positive cells/total nuclei ratios (x100) were 1.66 (flaxseed-supplemented diet) and 1.50 (flaxseed-supplemented, low-fat diet) vs. 3.23 (control) and 2.56 (low-fat diet). No differences were observed between arms with regard to side effects, apoptosis, and most serological endpoints; however, men on low-fat diets experienced significant decreases in serum cholesterol (P=0.048). Conclusions Findings suggest that flaxseed is safe, and associated with biologic alterations that may be protective for prostate cancer. Data also further support low-fat diets to manage serum cholesterol.

positive: Effect of mammalian lignans on the growth of prostate cancer cell lines. BACKGROUND: Mammalian lignans, enterolactone (EL) and enterodiol (ED), have been shown to inhibit breast and colon carcinoma. To date, there have been no reports of the effect of lignans on prostatic carcinoma. We investigated the effects of ED and EL on three human prostate cancer cell lines (PC-3, DU-145 and LNCaP). MATERIALS AND METHODS: Cells were treated with either 0.1% (v/v) DMSO (vehicle) or 10-100 microM of EL, ED or genistein (positive control) for 72 hours. Cell viability was measured by the propidium iodide nuclei staining fluorometric assay with each assay performed in triplicate. RESULTS: At 10-100 microM, EL significantly inhibited the growth of all cell lines, whereas ED only inhibited PC-3 and LNCaP cells. While EL was a more potent growth inhibitor than ED, both were less potent than genistein. The dose for 50% growth inhibition of LNCaP cells (IC50) by EL was 57 microM, whereas IC50 was 100 microM for ED, (the observed IC50 for genistein was 25 microM). CONCLUSION: ED and EL suppress the growth of prostate cancer cells, and may do so via hormonally-dependent and independent mechanisms.

positive: Lignans and isoflavonoids in plasma and prostatic fluid in men: samples from Portugal, Hong Kong, and the United Kingdom. BACKGROUND: Chinese men have lower incidences of prostate cancer compared to men from Europe and North America. Asians consume large quantities of soya, a rich source of isoflavanoids phyto-oestrogens and have high plasma and urinary levels of these compounds. The mammalian lignans, enterolactone and enterodiol, are another group of weak plant oestrogens and are derived from seeds, cereals and grains. Vegetarians have high plasma and urinary concentrations of lignans. METHODS: The concentrations lignans and isoflavonic phyto-oestrogens were determined by gas chromatography-mass spectrometry (GC-MS) in plasma and prostatic fluid from Portuguese, Chinese and British men consuming their traditional diets. RESULTS: In prostatic fluid the mean concentrations of enterolactone were 31, 162 and 20.3 ng/ml for Hong Kong, Portugal and Britain respectively. Very high levels of enterolactone (> 600 ng/ml) were observed in the prostatic fluid of some of the men from Portugal. High concentrations of equol (3270 ng/ml) and daidzein (532 ng/ml) were found in a sample of prostatic fluid from Hong Kong. Higher mean levels of daidzein were observed in prostatic fluid from Hong Kong at 70 ng/ml, compared to 4.6 and 11.3 ng/ml in samples from Portugal and Britain respectively. Mean levels of daidzein were higher in the plasma samples from Hong Kong (31.3 ng/ml) compared to those from Portugal (1.3 ng/ml) and Britain (8.2 ng/ml). In general, the mean plasma concentrations of enterolactone from the three centres were similar, at 6.2, 3.9 and 3.9 ng/ml in samples from Hong Kong Portugal and Britain respectively. CONCLUSIONS: Higher concentrations of the isoflavanoid phyto-oestrogens, daidzein and equol, were found in the plasma and prostatic fluid of men from Hong Kong compared to those from Britain and Portugal. However, the levels of the lignan, enterolactone, were very much higher in prostatic fluid of Portuguese men. Isoflavanoids and lignans have many interesting properties and may, in part, be responsible for lower incidences of prostate cancer in men from Asia and also some Mediterranean countries. The isoflavanoids from soya, which are present in high concentrations in the prostatic fluid of Asian men, may be protective against prostate disease.

positive: Pilot study to explore effects of low-fat, flaxseed-supplemented diet on proliferation of benign prostatic epithelium and prostate-specific antigen. OBJECTIVES: Dietary factors may influence the prostate and have an impact on prostatic growth and disease. A small number of studies have suggested that flaxseed-supplemented, fat-restricted diets may thwart prostate cancer growth in both animals and humans. Unknown, however, is the potential effect of such a diet on benign prostatic epithelium. METHODS: We undertook a pilot study to explore whether a flaxseed-supplemented, fat-restricted diet affects the proliferation rates in benign epithelium. We also explored the effects on circulating levels of prostate-specific antigen (PSA), total testosterone, and cholesterol. Fifteen men who were scheduled to undergo repeat prostate biopsy were instructed to follow a low-fat (less than 20% kcal), flaxseed-supplemented (30 g/day) diet and were provided with a supply of flaxseed to last throughout the 6-month intervention period. The PSA, total testosterone, and cholesterol levels were determined at baseline and at 6 months of follow-up. Reports from the original and repeat biopsies were compared, and proliferation (MIB-1) rates were quantified in the benign prostatic epithelium. RESULTS: Statistically significant decreases in PSA (8.47 +/- 3.82 to 5.72 +/- 3.16 ng/mL; P = 0.0002) and cholesterol (241.1 +/- 30.8 to 213.3 +/- 51.2 mg/dL; P = 0.012) were observed. No statistically significant change was seen in total testosterone (434.5 +/- 143.6 to 428.3 +/- 92.5 ng/dL). Although 6-month repeat biopsies were not performed in 2 cases because of PSA normalization, of the 13 men who underwent repeat biopsy, the proliferation rates in the benign epithelium decreased significantly from 0.022 +/- 0.027 at baseline to 0.007 +/- 0.014 at 6 months of follow-up (P = 0.0168). CONCLUSIONS: These pilot data suggest that a flaxseed-supplemented, fat-restricted diet may affect the biology of the prostate and associated biomarkers. A randomized controlled trial is needed to determine whether flaxseed supplementation, a low-fat diet, or a combination of the two regimens may be of use in controlling overall prostatic growth.

positive: Effect of Low-fat Diets on Plasma Levels of NFκB-regulated Inflammatory Cytokines and Angiogenic Factors in Men with Prostate Cancer Diet, nutritional status, and certain dietary supplements are postulated to influence the development and progression of prostate cancer. Angiogenesis and inflammation are central to tumor growth and progression, but the effect of diet on these processes remains uncertain. We explored changes in 50 plasma cytokines and angiogenic factors (CAFs) in 145 men with prostate cancer enrolled in a pre-operative, randomized controlled phase-II trial with four arms: control (usual diet); low-fat (LF) diet; flaxseed-supplemented (FS) diet; and flaxseed-supplemented, low-fat diet. The mean duration of dietary intervention was 30–31 days. Among the individual arms, the largest number of significant changes (baseline vs pre-operative follow-up) was observed in the LF arm, with 19 CAFs decreasing and one increasing (p<.05). Compared to the control arm, 6 CAFs—including pro-angiogenic factors (stromal-cell derived-1α and myeloid factors (granulocyte-colony-stimulating factor, macrophage colony-stimulating factor — all decreased in the LF arm compared to controls; 3 and 4 CAFs changed in the FS and FS+LF arms, respectively. Weight loss occurred in the LF arms and significantly correlated with VEGF decreases (P <0.001). The CAFs that changed in the LF arm are all known to be regulated by nuclear factor-kappa B (NF-κB), and a pathway analysis identified NF-κB as the most likely regulatory network associated with these changes in the LF arm, but not in the FS-containing arms. These results suggest that a low-fat diet without flaxseed may reduce levels of specific inflammatory cytokines and angiogenic factors and suggests that the NF-κB pathway may be a mediator of these changes.

positive: Pilot study of dietary fat restriction and flaxseed supplementation in men with prostate cancer before surgery: exploring the effects on hormonal l... OBJECTIVES: Dietary fat and fiber affect hormonal levels and may influence cancer progression. Flaxseed is a rich source of lignan and omega-3 fatty acids and may thwart prostate cancer. The potential effects of flaxseed may be enhanced with concomitant fat restriction. We undertook a pilot study to explore whether a flaxseed-supplemented, fat-restricted diet could affect the biomarkers of prostatic neoplasia. METHODS: Twenty-five patients with prostate cancer who were awaiting prostatectomy were instructed on a low-fat (20% of kilocalories or less), flaxseed-supplemented (30 g/day) diet. The baseline and follow-up levels of prostate-specific antigen, testosterone, free androgen index, and total serum cholesterol were determined. The tumors of diet-treated patients were compared with those of historic cases (matched by age, race, prostate-specific antigen level at diagnosis, and biopsy Gleason sum) with respect to apoptosis (terminal deoxynucleotidyl transferase [TdT]-mediated dUTP-biotin nick end-labeling [TUNEL]) and proliferation (MIB-1). RESULTS: The average duration on the diet was 34 days (range 21 to 77), during which time significant decreases were observed in total serum cholesterol (201 +/- 39 mg/dL to 174 +/- 42 mg/dL), total testosterone (422 +/- 122 ng/dL to 360 +/- 128 ng/dL), and free androgen index (36.3% +/- 18.9% to 29.3% +/- 16.8%) (all P <0.05). The baseline and follow-up levels of prostate-specific antigen were 8.1 +/- 5.2 ng/mL and 8.5 +/- 7.7 ng/mL, respectively, for the entire sample (P = 0.58); however, among men with Gleason sums of 6 or less (n = 19), the PSA values were 7.1 +/- 3.9 ng/mL and 6.4 +/- 4.1 ng/mL (P = 0.10). The mean proliferation index was 7.4 +/- 7.8 for the historic controls versus 5.0 +/- 4.9 for the diet-treated patients (P = 0.05). The distribution of the apoptotic indexes differed significantly (P = 0.01) between groups, with most historic controls exhibiting TUNEL categorical scores of 0; diet-treated patients largely exhibited scores of 1. Both the proliferation rate and apoptosis were significantly associated with the number of days on the diet (P = 0.049 and P = 0.017, respectively). CONCLUSIONS: These pilot data suggest that a flaxseed-supplemented, fat-restricted diet may affect prostate cancer biology and associated biomarkers. Further study is needed to determine the benefit of this dietary regimen as either a complementary or preventive therapy.

positive: The flip side of immune surveillance: immune dependency. The growths of many and perhaps all tumors may be stimulated rather than inhibited by a quantitatively low level of immunity. The reason tumors have antigens may be that tumors do not develop in vivo in the absence of at least a minimal immune reaction; in this sense, cancer may be considered an autoimmune disease. This review, based largely on the work of our own laboratory, outlines the data showing that the titration of anti-tumor immunity exhibits the phenomenon of hormesis, i.e. the dose-response curve is non-linear such that low levels of immunity are generally stimulatory but larger quantities of the same immune reactants may inhibit tumor growth. Evidence is also reviewed that suggests that the immune response may vary qualitatively and quantitatively during progression, such that there seems to be, during oncogenesis, a very low level of immune reaction that aids initial tumor growth, followed by a larger reaction that may cause remission of early neoplasms, followed, if the neoplasm survives, by a relative immunologic tolerance to the tumor that may be dependent, at least in part, on suppressor cells. This knowledge may help to explain some clinical observations concerning the relationships among tumor types and the organ distribution of metastases.

positive: Immunological enhancement of breast cancer. Breast cancer is a complex disease. Its aetiology is multifactorial, its period of development can span decades, and its clinical course is highly variable. Evaluation of the role of the immune response in either the development or control of breast cancer is also complex. Nevertheless, there is substantial information that in this disease, the immune response is not a host defence reaction and may even serve to facilitate cancer development. This evidence comes from a variety of sources including clinical-pathological investigations in women that show a correlation between the intensity of lymphocytic infiltration into the tumour mass with poor prognosis, studies in breast cancer patients that demonstrate a similar correlation between delayed hypersensitivity reactivity or in vitro assays of immune reactivity to tumour cell membranes or non-specific antigens and poor prognosis, and analyses of cancer incidence in chronically immunosuppressed, kidney transplant recipients who develop an unexpectedly low incidence of breast cancer. The overall conclusions from these human studies are corroborated by observations in mouse mammary tumour models that also demonstrate immune enhancement of breast cell proliferation in vitro and of breast cancer development in vivo. Potential mechanisms for these effects include production, by inflammatory cell infiltrates, of direct or indirect modulators of breast cell growth, e.g. cytokines, peptide or steroid hormones, enzymes involved in steroid metabolism, as well as of antibodies to growth factors or their receptors. These immune facilitatory mechanisms must be overcome if immune-based therapies are to be applied successfully in breast cancer.

positive: Recrudescent Kaposi's sarcoma after initiation of HAART: a manifestation of immune reconstitution syndrome. The objective of this case series and literature review is to characterize the clinical course and prognosis of HIV-infected patients with Kaposi's sarcoma (KS) flare during immune reconstitution inflammatory syndrome (IRIS), a heterogeneous and sometimes fatal disorder of immune perturbation after initiation of highly active antiretroviral therapy (HAART). Medical records of 9 HIV-infected patients with KS flare after virologic and immunologic response to HAART were reviewed from a single institution. An additional 10 cases were abstracted by computerized search of the medical literature. In our single institution series, mean time to onset of KS flare was 5 weeks. Pretreatment mean CD4+ count was 190 cells/mm(3) and mean HIV viral load was 153,934 copies per milliliter. During flare, mean CD4+ count was 256 cells/mm(3) and mean HIV viral load was 1156 copies per milliliter. Similar aggregate results are represented in the literature. Six fatalities are reported, 4 from pulmonary KS and 2 from unrelated causes. Systemic chemotherapy universally led to tumor regression, but was administered in only 10 of 19 cases. In no instance was HAART discontinued. Onset of IRIS-associated KS flare is observed as early as 3 weeks, with most cases diagnosed within 2 months after immunologic and virologic response to HAART. Such a flare does not necessarily portend a poor prognosis. Even for those patients with rapidly symptomatic KS, early systemic chemotherapy is effective in suppressing IRIS-associated flare. Close clinical supervision is warranted for the KS patient initiating, changing, or resuming HAART. Particular vigilance is recommended for pulmonary involvement.

positive: Melanomas in renal transplant recipients. BACKGROUND: It is well documented that renal transplant recipients are at increased risk of developing skin cancers, in particular squamous cell carcinomas. Less extensively reviewed in the literature is the increased incidence of malignant melanoma. We have reviewed 10 patients in the Oxford renal transplant population who developed 12 melanomas following transplantation. OBJECTIVES: To determine the incidence and characteristics of melanoma in renal transplant recipients. METHODS: We reviewed the case notes and pathology of all patients who developed melanoma within the Oxford Renal Transplant Unit. The clinical details were recorded including date of transplant, immunosuppressive therapy, interval between transplant and melanoma, site of occurrence, history of sun exposure, type of clinician diagnosing the melanoma, history of other skin malignancies and outcome. From the histopathology we documented various prognostic factors. RESULTS: Ten patients developed 12 melanomas (one patient had three melanomas) from a population of 1874 transplanted patients. The total number of transplant years was 11 942.2. The incidence of melanoma in our population was 12 per 11 942.2 transplant years, which is approximately 8 times greater than the standardized rate for this region. We found that the mean interval between transplant and melanoma was approximately 11 years (median 8.5). A dermatologist was the diagnosing clinician in at least 67% of cases. Melanomas occurred on the trunk in the majority of cases (58%), followed by the upper limb (25%). All patients apart from one are alive with no recurrence of their melanoma. One patient died as a result of metastatic melanoma. The mean follow-up period following melanoma was 3.7 years. In all patients apart from the patient who died, the melanomas were < 1 mm Breslow thickness. That patient's melanoma was 4.5 mm thick. There was no precursor naevus in eight of the 12 melanomas. In two there was a precursor dysplastic naevus. In the cases in vertical growth phase the tumour-infiltrating lymphocyte response was absent in four cases and nonbrisk in one patient. CONCLUSIONS: In the Oxford transplant population studied melanomas occurred at approximately 8 times the rate in the general population. This is the highest rate reported in the literature. The patients had a better outcome than reported previously. This may be due to detection at a relatively early stage. Renal transplant recipients attend dedicated dermatology clinics in Oxford, which may have contributed to the early diagnosis and good outcome.

positive: Soy food consumption and breast cancer prognosis. BACKGROUND: Contrary to earlier clinical studies suggesting that soy may promote breast tumor growth, two recent studies show that soy-containing foods are not adversely related to breast cancer prognosis. We examined, using data from the Women's Healthy Eating and Living (WHEL) study, the effect of soy intake on breast cancer prognosis. METHODS: Three thousand eighty-eight breast cancer survivors, diagnosed between 1991 and 2000 with early-stage breast cancer and participating in WHEL, were followed for a median of 7.3 years. Isoflavone intakes were measured postdiagnosis by using a food frequency questionnaire. Women self-reported new outcome events semiannually, which were then verified by medical records and/or death certificates. HRs and 95% CIs representing the association between either a second breast cancer event or death and soy intake were computed, adjusting for study group and other covariates, using the delayed entry Cox proportional hazards model. RESULTS: As isoflavone intake increased, risk of death decreased (P for trend = 0.02). Women at the highest levels of isoflavone intake (>16.3 mg isoflavones) had a nonsignificant 54% reduction in risk of death. CONCLUSION: Our study is the third epidemiologic study to report no adverse effects of soy foods on breast cancer prognosis. IMPACT: These studies, taken together, which vary in ethnic composition (two from the United States and one from China) and by level and type of soy consumption, provide the necessary epidemiologic evidence that clinicians no longer need to advise against soy consumption for women with a diagnosis of breast cancer. ©2011 AACR.

positive: Soy Isoflavones and Risk of Cancer Recurrence in a Cohort of Breast Cancer Survivors: Life After Cancer Epidemiology (LACE) Study Purpose Soy isoflavones, structurally similar to endogenous estrogens, may affect breast cancer through both hormonally-mediated and non-hormonally related mechanisms. Although the effects of soy are not well understood, some breast cancer survivors increase their soy intake post-diagnosis in attempt to improve their prognosis. Therefore, we examined the role of soy isoflavone intake and the risk of breast cancer recurrence by hormone receptor status, menopausal status, and tamoxifen therapy. Materials and methods A cohort of 1954 female breast cancer survivors, diagnosed during 1997–2000, was prospective followed for 6.31 years and 282 breast cancer recurrences were ascertained. Isoflavone intake was assessed by mailing modified Block and supplemental soy food frequency questionnaires to participants, on average 23 months post-diagnosis. Risk of breast cancer recurrence, measured by hazard ratios (HR) and 95% confidence intervals (CI), was estimated using multivariable delayed-entry Cox proportional hazards models. Results Suggestive trends for a reduced risk of cancer recurrence were observed with increasing quintiles of daidzein and glycetin intake compared to no intake among postmenopausal women (P for trend: P = .08 for daidzein, P = .06 for glycetin) and among tamoxifen users (P = .10 for daidzein, P = .05 for glycetin). Among postmenopausal women treated with tamoxifen, there was an approximately 60% reduction in breast cancer recurrence comparing the highest to the lowest daidzein intakes (>1453 micrograms (µg)/day versus < 7.7 µg/day) (HR, 0.48; 95% CI, 0.21–0.79, P = .008). Conclusion Soy isoflavones consumed at levels comparable to those in Asian populations may reduce the risk of cancer recurrence in women receiving tamoxifen therapy and moreover, appears not to interfere with tamoxifen efficacy. Further confirmation is required in other large prospective studies before recommendations regarding soy intake can be issued to breast cancer survivors.

negative: Estradiol, tamoxifen, and flaxseed alter IL-1β and IL-1Ra levels in normal human breast tissue in vivo. INTRODUCTION: Sex steroid exposure increases the risk of breast cancer by unclear mechanisms. Diet modifications may be one breast cancer prevention strategy. The proinflammatory cytokine family of IL-1 is implicated in cancer progression. IL-1Ra is an endogenous inhibitor of the proinflammatory IL-1α and IL-1β. OBJECTIVE: The objective of this study was to elucidate whether estrogen, tamoxifen, and/or diet modification altered IL-1 levels in normal human breast tissue. DESIGN AND METHODS: Microdialysis was performed in healthy women under various hormone exposures, tamoxifen therapy, and diet modifications and in breast cancers of women before surgery. Breast tissue biopsies from reduction mammoplasties were cultured. RESULTS: We show a significant positive correlation between estradiol and in vivo levels of IL-1β in breast tissue and abdominal sc fat, whereas IL-1Ra exhibited a significant negative correlation with estradiol in breast tissue. Tamoxifen or a dietary addition of 25 g flaxseed per day resulted in significantly increased levels of IL-1Ra in the breast. These results were confirmed in ex vivo culture of breast biopsies. Immunohistochemistry of the biopsies did not reveal any changes in cellular content of the IL-1s, suggesting that mainly the secreted levels were affected. In breast cancer patients, intratumoral levels of IL-1β were significantly higher compared with normal adjacent breast tissue. CONCLUSION: IL-1 may be under the control of estrogen in vivo and may be attenuated by antiestrogen therapy and diet modifications. The increased IL-1β in breast cancers of women strongly suggests IL-1 as a potential therapeutic target in breast cancer treatment and prevention.

negative: Dietary flavonoid intake and breast cancer survival among women on Long Island. BACKGROUND: Laboratory research and a growing number of epidemiologic studies have provided evidence for a reduced risk of breast cancer associated with dietary intake of certain classes of flavonoids. However, the effects of flavonoids on survival are not known. In a population-based cohort of breast cancer patients, we investigated whether dietary flavonoid intake before diagnosis is associated with subsequent survival. METHODS: Women ages 25 to 98 years who were newly diagnosed with a first primary invasive breast cancer between August 1, 1996, and July 31, 1997, and participated in a population-based, case-control study (n=1,210) were followed for vital status through December 31, 2002. At the case-control interview conducted shortly after diagnosis, respondents completed a FFQ that assessed dietary intake in the previous 12 months. All-cause mortality (n=173 deaths) and breast cancer-specific mortality (n=113 deaths) were determined through the National Death Index. RESULTS: Reduced hazard ratios [age- and energy-adjusted hazard ratio (95% confidence interval)] for all-cause mortality were observed among premenopausal and postmenopausal women for the highest quintile of intake, compared with the lowest, for flavones [0.63 (0.41-0.96)], isoflavones [0.52 (0.33-0.82)], and anthocyanidins [0.64 (0.42-0.98)]. No significant trends in risk were observed. Results were similar for breast cancer-specific mortality only. CONCLUSION: Mortality may be reduced in association with high levels of dietary flavones and isoflavones among postmenopausal U.S. breast cancer patients. Larger studies are needed to confirm our findings.

negative: Diet and breast cancer: understanding risks and benefits. BACKGROUND: Breast cancer is the most commonly diagnosed cancer among women in the United States. Extensive research has been completed to evaluate the relationship between dietary factors and breast cancer risk and survival after breast cancer; however, a summary report with clinical inference is needed. Materials and METHODS: This review summarizes the current epidemiological and clinical trial evidence relating diet to breast cancer incidence, recurrence, survival, and mortality. The review includes emerging epidemiological studies that assess risk within breast cancer subtypes as well as a summary of previous and ongoing dietary intervention trials designed to modify breast cancer risk. RESULTS: The available literature suggests that both low-fat and high-fiber diets may be weakly protective against breast cancer, whereas total energy intake and alcohol appear to be positively associated. Fiber may be weakly protective possibly through modulation of estrogen, whereas fruit and vegetable intake is not clearly associated with risk. Obesity is a risk factor for postmenopausal disease, and adult weight gain should be avoided to reduce risk. In survivors, diet has the greatest potential influence on overall mortality rather than breast cancer-specific events. CONCLUSION: Diet is modestly associated with breast cancer risk; associations appear more pronounced for postmenopausal disease, and healthy choices after diagnosis and treatment likely support longevity more so than reduced risk for recurrent disease.

negative: The DietCompLyf study: a prospective cohort study of breast cancer survival and phytoestrogen consumption. DietCompLyf is a multi-centre prospective study designed to investigate associations between phytoestrogens - naturally occurring plant compounds with oestrogenic properties - and other diet and lifestyle factors with breast cancer recurrence and survival. 3159 women with grades I-III breast cancer were recruited 9-15 months post-diagnosis from 56 UK hospitals. Detailed information on clinico-pathological, diet, lifestyle and quality of life is collected annually up to 5 years. Biological samples have also been collected as a resource for subsequent evaluation. The characteristics of the patients and associations between pre-diagnosis intake of phytoestrogens (isoflavones and lignans; assessed using the EPIC-Norfolk UK 130 question food frequency questionnaire) and breast cancer (i) risk factors and (ii) prognostic factors are described for 1797 women who had complete data for all covariates and phytoestrogens of interest. Isoflavone intakes were higher in the patients who were younger at diagnosis, in the non-smokers, those who had breast-fed and those who took supplements. Lignan intakes were higher in patients with a higher age at diagnosis, in ex-smokers, those who had breast-fed, who took supplements, had a lower BMI at diagnosis, lower age at menarche and were nulliparous. No significant associations between pre-diagnosis phytoestrogen intake and factors associated with improved breast cancer prognosis were observed. The potential for further exploration of the relationship between phytoestrogens and breast cancer recurrence and survival, and for the establishment of evidence to improve dietary and lifestyle advice offered to patients following breast cancer diagnosis using DietCompLyf data is discussed. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

negative: Post-diagnosis dietary factors and survival after invasive breast cancer Little is known about the effects of diet after breast cancer diagnosis on survival. We prospectively examined the relation between post-diagnosis dietary factors and breast cancer and all-cause survival in women with a history of invasive breast cancer diagnosed between 1987 and 1999 (at ages 20–79 years). Diet after breast cancer diagnosis was measured using a 126-item food frequency questionnaire. Among 4,441 women without a history of breast cancer recurrence prior to completing the questionnaire, 137 subsequently died from breast cancer within 7 years of enrollment. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated for intake of macronutrients as well as selected micronutrients and food groups from Cox proportional hazards regression models. After adjustment for factors at diagnosis (age, state of residence, menopausal status, smoking, breast cancer stage, alcohol, history of hormone replacement therapy), interval between diagnosis and diet assessment, and at follow-up (energy intake, breast cancer treatment, body mass index, and physical activity), women in the highest compared to lowest quintile of intake of saturated fat and trans fat had a significantly higher risk of dying from any cause (HR = 1.41, 95% CI = 1.06 to 1.87, P-trend = 0.03) for saturated fat; (HR = 1.78, 95% CI = 1.35 to 2.32, P-trend = 0.01) for trans fat intake. Associations were similar, though did not achieve statistical significance, for breast cancer survival. This study suggests that lower intake of saturated and trans fat in the post-diagnosis diet is associated with improved survival after breast cancer diagnosis.

negative: Study on soy isoflavone consumption and risk of breast cancer and survival. AIM: Isoflavones in soy foods are part of a larger class of flayonoid compounds that have have been demonstrated to be potent dietary anti-cancer agents, and the effect of soy intake on the survival of ovarian cancer is conflicting. Therefore, we aimed to explore the whether soy intake is related to the risk of death of breast cancer. METHODS: A prospective study was conducted. A total of 256 patients included in this study had breast cancer and were recruited between January 2004 and January 2006. All of them were followed up from since January 2011. A univariate Cox's regression analysis was used to assess the association between soy intake and survival. RESULTS: The education level, menopausal status, ER/PR status and TNM stage were significant difference in the survival of breast cancer. The highest soy isoflavone was associated with a decreased death risk of breast cancer (OR=0.25, 95% CI=0.09-0.54). Moreover, the higher consumption of soy protein also presented a trend decreased breast cancer risk, and the highest consumption significantly reduced the cancer risk compared with the lowest consumption (OR=0.38, 95% CI=0.17-0.86). CONCLUSION: The present study suggests soy intake is associated with a significant reduced death risk of breast cancer in Chinese population. Further large sample studies are warranted to confirm the inverse association of soy consumption and breast cancer survival by menopausal status.

negative: Soy food intake after diagnosis of breast cancer and survival: an in-depth analysis of combined evidence from cohort studies of US and Chinese women Background: Soy isoflavones have antiestrogenic and anticancer properties but also possess estrogen-like properties, which has raised concern about soy food consumption among breast cancer survivors. Objective: We prospectively evaluated the association between postdiagnosis soy food consumption and breast cancer outcomes among US and Chinese women by using data from the After Breast Cancer Pooling Project. Design: The analysis included 9514 breast cancer survivors with a diagnosis of invasive breast cancer between 1991 and 2006 from 2 US cohorts and 1 Chinese cohort. Soy isoflavone intake (mg/d) was measured with validated food-frequency questionnaires. HRs and 95% CIs were estimated by using delayed-entry Cox regression models, adjusted for sociodemographic, clinical, and lifestyle factors. Results: After a mean follow-up of 7.4 y, we identified 1171 total deaths (881 from breast cancer) and 1348 recurrences. Despite large differences in soy isoflavone intake by country, isoflavone consumption was inversely associated with recurrence among both US and Chinese women, regardless of whether data were analyzed separately by country or combined. No heterogeneity was observed. In the pooled analysis, consumption of ≥10 mg isoflavones/d was associated with a nonsignificant reduced risk of all-cause (HR: 0.87; 95% CI: 0.70, 1.10) and breast cancer–specific (HR: 0.83; 95% CI: 0.64, 1.07) mortality and a statistically significant reduced risk of recurrence (HR: 0.75; 95% CI: 0.61, 0.92). Conclusion: In this large study of combined data on US and Chinese women, postdiagnosis soy food consumption of ≥10 mg isoflavones/d was associated with a nonsignificant reduced risk of breast cancer–specific mortality and a statistically significant reduced risk of recurrence. One of the studies included in the After Breast Cancer Pooling Project, the Women's Healthy Eating & Living Study, was registered at clinicaltrials.gov as NCT00003787.

negative: Flaxseed - a miraculous defense against some critical maladies. Presence of omega-3, omega-6 rich oil, alpha-linoleic acid, dietary fibers, secoisolariciresinol diglucoside, protein and minerals in flaxseed constitute a very strong basis for the utilization of flaxseed in various food preparations as a curative agent. An extensive body of literature illustrates that flaxseed has gained a significant position in the domain of nutritional sciences owing to its pivotal role as an antioxidant agent. The review discusses at length, numerous health benefits of flaxseed typically focusing its preventive role against cardiovascular diseases, cancer, diabetes and enhancement of spatial memory. Massive increase in the size of population with a special emphasize to the developing countries, there is an urge for exploration of the alternative dietary resources that can meet the dietary and nutritional needs of forthcoming generations. With respect to its remarkable nutritional importance, the review in question enables researchers engaged in nutritional sciences to further investigate the therapeutic value of flaxseed functional components and their dietary application in various food products and availability in processed foods as well as in the human cell line.

negative: Greater Survival After Breast Cancer in Physically Active Women With High Vegetable-Fruit Intake Regardless of Obesity Purpose Single-variable analyses have associated physical activity, diet, and obesity with survival after breast cancer. This report investigates interactions among these variables. Patients and Methods A prospective study was performed of 1,490 women diagnosed and treated for early-stage breast cancer between 1991 and 2000. Enrollment was an average of 2 years postdiagnosis. Only seven women were lost to follow-up through December 2005. Results In univariate analysis, reduced mortality was weakly associated with higher vegetable-fruit consumption, increased physical activity, and a body mass index that was neither low weight nor obese. In a multivariate Cox model, only the combination of consuming five or more daily servings of vegetables-fruits, and accumulating 540+ metabolic equivalent tasks-min/wk (equivalent to walking 30 minutes 6 d/wk), was associated with a significant survival advantage (hazard ratio, 0.56; 95% CI, 0.31 to 0.98). The approximate 50% reduction in risk associated with these healthy lifestyle behaviors was observed in both obese and nonobese women, although fewer obese women were physically active with a healthy dietary pattern (16% v 30%). Among those who adhered to this healthy lifestyle, there was no apparent effect of obesity on survival. The effect was stronger in women who had hormone receptor–positive cancers. Conclusion A minority of breast cancer survivors follow a healthy lifestyle that includes both recommended intakes of vegetables-fruits and moderate levels of physical activity. The strong protective effect observed suggests a need for additional investigation of the effect of the combined influence of diet and physical activity on breast cancer survival.

negative: Positive effects of soy isoflavone food on survival of breast cancer patients in China. AIM: Soy foods are the major source of isoflavones, which are believed to play important roles in genesis of breast cancer and its progression. We here conducted a prospective study to evaluate the association of soy isoflavone food consumption with breast cancer prognosis. METHODS: A prospective study was performed from January 2004 and January 2006 in China. Trained interviewers conducted face-to-face interviews using a structured questionnaire to collect information on dietary habits and potential confounding factors. The relative risk [hazard ratio (HR)] and 95% CI were calculated from the Cox regression model for all significant predictors from cancer diagnosis to the endpoint of the study (event). RESULTS: After a median follow up of 52.1 months (range, 9-60 months), a total of 79 breast cancer related deaths were recorded in our study, risk being inversely associated with a high intake of soy isoflavone. With an average intake of soy isoflavone above 17.3 mg/day, the mortality of breast cancer can be reduced by about 38-36%. We also found the decreased breast cancer death with high soy protein intake, with a HR (95% CI) of 0.71 (0.52-0.98). Stratified analysis with reference to the ER status, further demonstrated a better prognosis of ER positive breast cancer with a high intake of soy isoflavone (HR 0.59, 0.40-0.93). CONCLUSION: Our study shows the soy food intake is associated with longer survival and low recurrence among breast cancer patients. A cohort study with a larger sample size and long term follow-up is now needed.

negative: Dietary fiber intake and risk of breast cancer: a meta-analysis of prospective cohort studies. BACKGROUND: Observational and preclinical studies suggest that dietary fiber intake may reduce the risk of breast cancer, but the results are inconclusive. OBJECTIVE: We aimed to examine the association between dietary fiber intake and risk of breast cancer by conducting a meta-analysis of prospective cohort studies. DESIGN: Relevant studies were identified by a PubMed database search through January 2011. Reference lists from retrieved articles were also reviewed. We included prospective cohort studies that reported RRs with 95% CIs for the association between dietary fiber intake and breast cancer risk. Both fixed- and random-effects models were used to calculate the summary risk estimates. RESULTS: We identified 10 prospective cohort studies of dietary fiber intake and risk of breast cancer involving 16,848 cases and 712,195 participants. The combined RR of breast cancer for the highest compared with the lowest dietary fiber intake was 0.89 (95% CI: 0.83, 0.96), and little evidence of heterogeneity was observed. The association between dietary fiber intake and risk of breast cancer did not significantly differ by geographic region, length of follow-up, or menopausal status of the participants. Omission of any single study had little effect on the combined risk estimate. Dose-response analysis showed that every 10-g/d increment in dietary fiber intake was associated with a significant 7% reduction in breast cancer risk. Little evidence of publication bias was found. CONCLUSION: This meta-analysis provides evidence of a significant inverse dose-response association between dietary fiber intake and breast cancer risk.

negative: Potent antihypertensive action of dietary flaxseed in hypertensive patients. Flaxseed contains ω-3 fatty acids, lignans, and fiber that together may provide benefits to patients with cardiovascular disease. Animal work identified that patients with peripheral artery disease may particularly benefit from dietary supplementation with flaxseed. Hypertension is commonly associated with peripheral artery disease. The purpose of the study was to examine the effects of daily ingestion of flaxseed on systolic (SBP) and diastolic blood pressure (DBP) in peripheral artery disease patients. In this prospective, double-blinded, placebo-controlled, randomized trial, patients (110 in total) ingested a variety of foods that contained 30 g of milled flaxseed or placebo each day over 6 months. Plasma levels of the ω-3 fatty acid α-linolenic acid and enterolignans increased 2- to 50-fold in the flaxseed-fed group but did not increase significantly in the placebo group. Patient body weights were not significantly different between the 2 groups at any time. SBP was ≈ 10 mm Hg lower, and DBP was ≈ 7 mm Hg lower in the flaxseed group compared with placebo after 6 months. Patients who entered the trial with a SBP ≥ 140 mm Hg at baseline obtained a significant reduction of 15 mm Hg in SBP and 7 mm Hg in DBP from flaxseed ingestion. The antihypertensive effect was achieved selectively in hypertensive patients. Circulating α-linolenic acid levels correlated with SBP and DBP, and lignan levels correlated with changes in DBP. In summary, flaxseed induced one of the most potent antihypertensive effects achieved by a dietary intervention.

negative: Statin use after diagnosis of breast cancer and survival: a population-based cohort study. BACKGROUND: Preclinical studies have shown that statins, particularly simvastatin, can prevent growth in breast cancer cell lines and animal models. We investigated whether statins used after breast cancer diagnosis reduced the risk of breast cancer-specific, or all-cause, mortality in a large cohort of breast cancer patients. METHODS: A cohort of 17,880 breast cancer patients, newly diagnosed between 1998 and 2009, was identified from English cancer registries (from the National Cancer Data Repository). This cohort was linked to the UK Clinical Practice Research Datalink, providing prescription records, and to the Office of National Statistics mortality data (up to 2013), identifying 3694 deaths, including 1469 deaths attributable to breast cancer. Unadjusted and adjusted hazard ratios (HRs) for breast cancer-specific, and all-cause, mortality in statin users after breast cancer diagnosis were calculated using time-dependent Cox regression models. Sensitivity analyses were conducted using multiple imputation methods, propensity score methods and a case-control approach. RESULTS: There was some evidence that statin use after a diagnosis of breast cancer had reduced mortality due to breast cancer and all causes (fully adjusted HR = 0.84 [95% confidence interval = 0.68-1.04] and 0.84 [0.72-0.97], respectively). These associations were more marked for simvastatin 0.79 (0.63-1.00) and 0.81 (0.70-0.95), respectively. CONCLUSIONS: In this large population-based breast cancer cohort, there was some evidence of reduced mortality in statin users after breast cancer diagnosis. However, these associations were weak in magnitude and were attenuated in some sensitivity analyses.

negative: Flaxseed: a potential source of food, feed and fiber. Flaxseed is one of the most important oilseed crops for industrial as well as food, feed, and fiber purposes. Almost every part of the flaxseed plant is utilized commercially, either directly or after processing. The stem yields good quality fiber having high strength and durability. The seed provides oil rich in omega-3, digestible proteins, and lignans. In addition to being one of the richest sources of α-linolenic acid oil and lignans, flaxseed is an essential source of high quality protein and soluble fiber and has considerable potential as a source of phenolic compounds. Flaxseed is emerging as an important functional food ingredient because of its rich contents of α-linolenic acid (ALA), lignans, and fiber. Lignans appear to be anti-carcinogenic compounds. The omega-3s and lignan phytoestrogens of flaxseed are in focus for their benefits for a wide range of health conditions and may possess chemo-protective properties in animals and humans. This paper presents a review of literature on the nutritional composition of flaxseed, its health benefits, and disease-prevention qualities, utilization of flaxseed for food, feed, and fiber, and processing of flaxseed.

negative: Chemoprevention of breast cancer by dietary compounds. Breast cancer is the leading cause of cancer-related deaths in women in the United States and many other countries. There is an immediate need for more effective and less toxic therapeutic and preventive strategies for many cancers, especially for breast cancer. Natural products are being tested with a hope of identifying novel potent molecules as anticancer agents. Phytochemicals and dietary compounds have been used for the treatment of various illnesses throughout history due to their safety, low toxicity, and general availability. Currently, many active phytochemicals are in clinical trials. Preclinical and clinical studies have indicated that daily consumption of dietary phytochemicals reduces the risk of several cancers. Phytochemicals can inhibit, delay, or reverse carcinogenesis by inducing detoxifying and antioxidant enzymes, by regulating inflammatory/proliferative signaling pathways, and by inducing apoptosis. This review article describes some of the potential natural cancer preventive compounds, along with a mechanistic discussion of their interactions with key cellular signal transduction pathways as well as their contribution to the suppression of breast cancer cell growth.

negative: Vegetable intake is associated with reduced breast cancer recurrence in tamoxifen users: a secondary analysis from the Women's Healthy Eating and L... The protective effect of vegetables on the risk of breast cancer recurrence is uncertain. We sought to evaluate the association between breast cancer recurrence and vegetable intake including analyses stratified on tamoxifen use. Experimental evidence of anti-carcinogenic activity of phytochemicals in cruciferous vegetables in combination with tamoxifen led to specific evaluation of this class of vegetables as well. To assess the association between vegetable intake and breast cancer recurrence, vegetable intake from repeat 24-h dietary recalls were examined as a secondary analysis of 3,080 breast cancer survivors enrolled in the Women's Healthy Eating and Living (WHEL) Study. At the time of enrollment women were, on average, 23.5 months post-diagnosis. The hazard of recurrence, controlling for relevant and significant clinical and demographic variables, with vegetable intake was assessed overall and separately for women taking tamoxifen. WHEL participants reported mean baseline intakes (⁻x, SE) of 3.1 ± 0.05 and 0.5 ± 0.02 servings/day of total and cruciferous vegetables, respectively. Baseline vegetable intake in the highest as compared to lowest tertiles was associated with an overall lower adjusted hazard ratios (HR) for recurrence of 0.69, 95% CI 0.55-0.87. Among women taking tamoxifen, the HRs were 0.56, 95% CI 0.41-0.77 for total vegetables and 0.65, 95% CI 0.47-0.89 for cruciferous vegetable intake. The hazard in women using tamoxifen who reported cruciferous vegetable intake above the median and who were within the highest tertile of total vegetable intake was HR 0.48; 95% CI 0.32-0.70. This secondary analysis in over 3,000 breast cancer survivors suggests that baseline vegetable intake may be associated with a reduction in the risk of breast cancer recurrent or new events particularly for those using tamoxifen. Such associations should be explored further as the possibility that vegetable intake is simply a surrogate for other health-promoting behaviors cannot be ruled out.

negative: Content of low density lipoprotein receptors in breast cancer tissue related to survival of patients. The content of low density lipoprotein (LDL) receptors in tissue from primary breast cancers was determined and its prognostic information compared with that of variables of established prognostic importance. Frozen tumour specimens were selected, and tissue from 72 patients (32 of whom had died) were studied. The LDL receptor content showed an inverse correlation with the survival time. Analysis by a multivariate statistical method showed that the presence of axillary metastasis, content of receptors for oestrogen and LDL, diameter of the tumour, and DNA pattern were all of prognostic value with regard to patient survival. Improved methods of predicting survival time in patients with breast cancer may be of value in the choice of treatment for individual patients.

negative: Statin Use and Breast Cancer Survival: A Nationwide Cohort Study from Finland Recent studies have suggested that statins, an established drug group in the prevention of cardiovascular mortality, could delay or prevent breast cancer recurrence but the effect on disease-specific mortality remains unclear. We evaluated risk of breast cancer death among statin users in a population-based cohort of breast cancer patients. The study cohort included all newly diagnosed breast cancer patients in Finland during 1995–2003 (31,236 cases), identified from the Finnish Cancer Registry. Information on statin use before and after the diagnosis was obtained from a national prescription database. We used the Cox proportional hazards regression method to estimate mortality among statin users with statin use as time-dependent variable. A total of 4,151 participants had used statins. During the median follow-up of 3.25 years after the diagnosis (range 0.08–9.0 years) 6,011 participants died, of which 3,619 (60.2%) was due to breast cancer. After adjustment for age, tumor characteristics, and treatment selection, both post-diagnostic and pre-diagnostic statin use were associated with lowered risk of breast cancer death (HR 0.46, 95% CI 0.38–0.55 and HR 0.54, 95% CI 0.44–0.67, respectively). The risk decrease by post-diagnostic statin use was likely affected by healthy adherer bias; that is, the greater likelihood of dying cancer patients to discontinue statin use as the association was not clearly dose-dependent and observed already at low-dose/short-term use. The dose- and time-dependence of the survival benefit among pre-diagnostic statin users suggests a possible causal effect that should be evaluated further in a clinical trial testing statins’ effect on survival in breast cancer patients.

negative: The role of diet and physical activity in breast, colorectal, and prostate cancer survivorship: a review of the literature Background: Evidence for the role of diet and physical activity in cancer incidence is well documented, but owing to increased cancer survivorship, an understanding of these lifestyle factors after a cancer diagnosis is of crucial importance. The purpose of this review was to update the literature in a review undertaken for the National Cancer Survivorship Initiative and to include observational studies that were not included in the WCRF survivorship systematic review. Methods: Evidence was initially gathered from pre-defined searches of the Cochrane Library Database and PubMed from March 2006 to February 2010. After a comprehensive review regarding lifestyle and cancer, for the purpose of this article, any studies not related to diet and physical activity, prognostic outcomes, and breast, colorectal or prostate cancers were excluded. Another search of 2011 literature was conducted to update the evidence. Results: A total of 43 records were included in this review. Evidence from observational studies suggests that a low-fat, high-fibre diet might be protective against cancer recurrence and progression. However, there is a paucity of RCTs substantiating this. There is more support for physical activity, with a dose response for better outcomes. When synthesized with findings from the World Cancer Research Fund review of RCTs investigating the effect of diet and physical activity interventions on cancer survival, evidence suggests that the mechanism of benefit from diet and physical activity pertains to body weight, with excess body weight being a risk factor, which is modifiable through lifestyle. Implications: Cancer survivors would like to have a more active role in their health care and to know how to look after themselves after diagnosis, including what diet and lifestyle changes they should make. The challenge is in integrating lifestyle support into standardised models of aftercare.

negative: Pilot evaluation of flaxseed for the management of hot flashes. The objective of this study was to evaluate, in a phase 2 pilot study, tolerability and the effect of 6 weeks of flaxseed therapy on hot flash scores in women not wishing to receive estrogen therapy. Eligibility included 14 hot flashes per week for at least 1 month. In the baseline week, participants took no study medication and documented the characteristics of their hot flashes. Thereafter, crushed flaxseed was administered at 40 g daily. Participants provided weekly toxicity reports and health-related quality of life information. The primary end point was a change in hot flash score prospectively reported in a daily hot flash diary. Thirty women were enrolled between June 17 and November 8, 2005. The mean decrease in hot flash scores after flaxseed therapy was 57% (median decrease 62%). The mean reduction in daily hot flash frequency was 50% (median reduction 50%), from 7.3 hot flashes to 3.6. Fourteen of the 28 participants (50%) experienced mild or moderate abdominal distention. Eight participants (29%) experienced mild diarrhea, one experienced flatulence, and six (21%) withdrew because of toxicities. This study suggests that dietary therapy decreases hot flash activity in women not taking estrogen therapy. This reduction is greater than what would be expected with placebo.

negative: Dietary flaxseed lignan extract lowers plasma cholesterol and glucose concentrations in hypercholesterolaemic subjects. Lignans, derived from flaxseed, are phyto-oestrogens being increasingly studied for their health benefits. An 8-week, randomised, double-blind, placebo-controlled study was conducted in fifty-five hypercholesterolaemic subjects, using treatments of 0 (placebo), 300 or 600 mg/d of dietary secoisolariciresinol diglucoside (SDG) from flaxseed extract to determine the effect on plasma lipids and fasting glucose levels. Significant treatment effects were achieved (P < 0.05 to < 0.001) for the decrease of total cholesterol (TC), LDL-cholesterol (LDL-C) and glucose concentrations, as well as their percentage decrease from baseline. At weeks 6 and 8 in the 600 mg SDG group, the decreases of TC and LDL-C concentrations were in the range from 22.0 to 24.38 % respectively (all P < 0.005 compared with placebo). For the 300 mg SDG group, only significant differences from baseline were observed for decreases of TC and LDL-C. A substantial effect on lowering concentrations of fasting plasma glucose was also noted in the 600 mg SDG group at weeks 6 and 8, especially in the subjects with baseline glucose concentrations > or = 5.83 mmol/l (lowered 25.56 and 24.96 %; P = 0.015 and P = 0.012 compared with placebo, respectively). Plasma concentrations of secoisolariciresinol (SECO), enterodiol (ED) and enterolactone were all significantly raised in the groups supplemented with flaxseed lignan. The observed cholesterol-lowering values were correlated with the concentrations of plasma SECO and ED (r 0.128-0.302; P < 0.05 to < 0.001). In conclusion, dietary flaxseed lignan extract decreased plasma cholesterol and glucose concentrations in a dose-dependent manner.

negative: Can green tea do that? A literature review of the clinical evidence. OBJECTIVE: Habitual green tea consumption has long been associated with health benefits including chemoprevention and cardiovascular protection. This non-systematic literature review presents the clinical evidence to date. METHOD: A literature review of peer-reviewed articles on observational and interventional studies was conducted to include green tea, its extract or its purified polyphenol (-)-epigallocatechin-3-gallate (EGCG). Electronic databases searched included PubMed (1966-2009) and the Cochrane Library (Issue 4, 2008). RESULTS: Observational studies are inconclusive on the benefits of habitual consumption of green tea in the prevention of most cancers. However, there are trends towards prevention in breast and prostate cancers. Interventional studies have demonstrated reduction in relapses following surgical resection in colorectal adenomas and increased survival rates in epithelial ovarian cancer. Observational studies indicate that green tea may provide protection against hypertension and reduce the risk for stroke, and interventional studies are providing biochemical and physiological evidence. CONCLUSION: Although the overall clinical evidence is inconclusive, habitual green tea consumption may be providing some level of chemoprevention in prostate and breast cancer. Green tea may also attenuate the risk factors association with the development of atherosclerosis thus reducing the incidence of cardiovascular events and stoke.

negative: Low-fat dietary pattern and risk of benign proliferative breast disease: a randomized, controlled dietary modification trial Modifiable factors, including diet, might alter breast cancer risk. We used the WHI Dietary Modification (DM) trial to test the effect of the intervention on risk of benign proliferative breast disease, a condition associated with increased risk of and considered to be on the pathway to invasive breast cancer. The WHI DM trial was a randomized, controlled, primary prevention trial conducted in 40 US clinical centers from 1993–2005. 48,835 postmenopausal women, aged 50–79 years, without prior breast cancer, were enrolled. Participants were randomly assigned to the DM intervention group or to the comparison group. The intervention was designed to reduce total dietary fat intake to 20% of total energy intake, and to increase fruit and vegetable intake to ≥5 servings/day and intake of grain products to ≥6 servings/day, but resulted in smaller, albeit significant changes in practice. Participants had biennial mammograms and regular clinical breast exams. We identified women who reported breast biopsies free of cancer, obtained the histologic sections, and subjected them to standardized central review. During follow-up (average, 7.7 years), 570 incident cases of benign proliferative breast disease were ascertained in the intervention group and 793 in the comparison group. The hazard ratio for the association between DM and benign proliferative breast disease was 1.09 (95%CI, 0.98–1.23). Risk varied by levels of baseline total vitamin D intake but it varied little by levels of other baseline variables. These results suggest that a modest reduction in fat intake and increase in fruit, vegetable, and grain intake does not alter the risk of benign proliferative breast disease.

negative: Significant changes in dietary intake and supplement use after breast cancer diagnosis in a UK multicentre study. The diagnosis of cancer can motivate survivors to alter their lifestyle habits. Healthcare providers need to be aware of what changes patients are likely to make in order to derive more pertinent recommendations; however, few studies have reported pre- and post-diagnostic lifestyle behaviours. Semi-quantitative food frequency questionnaires (FFQs) completed approximately 1 year after diagnosis were used to evaluate dietary intake and supplement use before and after diagnosis in a cohort of 1,560 breast cancer patients participating in the UK, prospective DietCompLyf study. Intake of fruit and vegetables, wholegrains and lean sources of protein increased significantly post-diagnosis (P < 0.05, each). Conversely, after diagnosis consumption of high-fat, high-sugar products, red meat, coffee, some alcoholic drinks and refined grains significantly decreased (P < 0.05, each). Post-diagnostic changes in diet were accompanied by changes in the intake of macronutrients and a number of vitamins and minerals. Supplement use was highly prevalent (56.1%) pre-diagnosis, increasing to 62.8% after diagnosis (P = 0.001). Fish oils, multivitamin and minerals, and evening primrose oil were most often used and the proportion of users significantly increased (P < 0.05, each) after diagnosis. The percentage of women using oestrogenic botanical supplements (OBSs) was small but more than doubled to 8.4% after diagnosis (P < 0.05). British women participating in the DietCompLyf study reported significant changes in dietary intake and supplement use after their breast cancer diagnosis. These findings contribute to our understanding of female cancer survivors' dietary behaviours which is crucial for developing and implementing recommendations.

negative: Empirically derived dietary patterns and risk of postmenopausal breast cancer in a large prospective cohort study. BACKGROUND: Inconsistent associations have been reported between diet and breast cancer. OBJECTIVE: We prospectively examined the association between dietary patterns and postmenopausal breast cancer risk in a US-wide cohort study. DESIGN: Data were analyzed from 40 559 women who completed a self-administered 61-item Block food-frequency questionnaire in the Breast Cancer Detection Demonstration Project, 1987-1998; 1868 of those women developed breast cancer. Dietary patterns were defined by using principal components factor analysis. Cox proportional hazard regression was used to assess breast cancer risk. RESULTS: Three major dietary patterns emerged: vegetable-fish/poultry-fruit, beef/pork-starch, and traditional southern. The vegetable-fish/poultry-fruit pattern was associated with higher education than were the other patterns, but was similar in nutrient intake to the traditional southern pattern. After adjustment for confounders, there was no significant association between the vegetable-fish/poultry-fruit and beef/pork-starch patterns and breast cancer. The traditional southern pattern, however, was associated with a nonsignificantly reduced breast cancer risk among all cases (in situ and invasive) that was significant for invasive breast cancer (relative hazard = 0.78; 95% CI = 0.65, 0.95; P for trend = 0.003). This diet was also associated with a reduced risk in women without a family history of breast cancer (P = 0.05), who were underweight or normal weight [body mass index (in kg/m(2)) < 25; P = 0.02], or who had tumors positive for estrogen receptor (P = 0.01) or progesterone receptor (P = 0.003). Foods in the traditional southern pattern associated with reduced breast cancer risk were legumes, low mayonnaise-salad dressing intake, and possibly cabbage. CONCLUSIONS: The traditional southern diet or its components are associated with a reduced risk of invasive breast cancer in postmenopausal women.

negative: Alcohol intake and mortality among women with invasive breast cancer Background: Alcohol intake has consistently been associated with increased breast cancer incidence in epidemiological studies. However, the relation between alcohol and survival after breast cancer diagnosis is less clear. Methods: We investigated whether alcohol intake was associated with survival among 3146 women diagnosed with invasive breast cancer in the Swedish Mammography Cohort. Alcohol consumption was estimated using a food frequency questionnaire. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs). Results: From 1987 to 2008 there were 385 breast cancer-specific deaths and 860 total deaths. No significant association was observed between alcohol intake and breast cancer-specific survival. Women who consumed 10 g per day (corresponding to approximately 0.75 to 1 drinks) or more of alcohol had an adjusted HR (95% CI) of breast cancer-specific death of 1.36 (0.82–2.26;ptrend=0.47) compared with non-drinkers. A significant inverse association was observed between alcohol and non-breast cancer deaths. Those who consumed 3.4–9.9 g per day of alcohol had a 33% lower risk of death compared with non-drinkers (95% CI 0.50–0.90;ptrend=0.04). Conclusion: Our findings suggest that alcohol intake up to approximately one small drink per day does not negatively impact breast cancer-specific survival and a half drink per day is associated with a decreased risk of mortality from other causes.

negative: Prospective study of grapefruit intake and risk of breast cancer in postmenopausal women: the Multiethnic Cohort Study In vitro and in vivo studies have shown that cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of oestrogens. There is evidence that grapefruit, an inhibitor of CYP3A4, increases plasma oestrogen concentrations. Since it is well established that oestrogen is associated with breast cancer risk, it is plausible that regular intake of grapefruit would increase a woman's risk of breast cancer. We investigated the association of grapefruit intake with breast cancer risk in the Hawaii–Los Angeles Multiethnic Cohort Study, a prospective cohort that includes over 50 000 postmenopausal women from five racial/ethnic groups. A total of 1657 incident breast cancer cases were available for analysis. Grapefruit intake was significantly associated with an increased risk of breast cancer (relative risk=1.30, 95% confidence interval 1.06–1.58) for subjects in the highest category of intake, that is, one-quarter grapefruit or more per day, compared to non-consumers (Ptrend=0.015). An increased risk of similar magnitude was seen in users of oestrogen therapy, users of oestrogen+progestin therapy, and among never users of hormone therapy. Grapefruit intake may increase the risk of breast cancer among postmenopausal women.

negative: The association between dietary lignans, phytoestrogen-rich foods, and fiber intake and postmenopausal breast cancer risk: a German case-control st... Phytoestrogens are structurally similar to estrogens and may affect breast cancer risk by mimicking estrogenic/antiestrogenic properties. In Western societies, whole grains and possibly soy foods are rich sources of phytoestrogens. A population-based case-control study in German postmenopausal women was used to evaluate the association of phytoestrogen-rich foods and dietary lignans with breast cancer risk. Dietary data were collected from 2,884 cases and 5,509 controls using a validated food-frequency questionnaire, which included additional questions phytoestrogen-rich foods. Associations were assessed using conditional logistic regression. All analyses were adjusted for relevant risk and confounding factors. Polytomous logistic regression analysis was performed to evaluate the associations by estrogen receptor (ER) status. High and low consumption of soybeans as well as of sunflower and pumpkin seeds were associated with significantly reduced breast cancer risk compared to no consumption (OR = 0.83, 95% CI = 0.70-0.97; and OR = 0.66, 95% CI = 0.77-0.97, respectively). The observed associations were not differential by ER status. No statistically significant associations were found for dietary intake of plant lignans, fiber, or the calculated enterolignans. Our results provide evidence for a reduced postmenopausal breast cancer risk associated with increased consumption of sunflower and pumpkin seeds and soybeans.

negative: Mastalgia. OBJECTIVE: To review the current management of women with breast pain. OPTIONS: The effect of various treatment modes and health practices, including medications, was considered for the management of both cyclical and noncyclical breast pain. OUTCOMES: Effective and timely management of the woman with breast pain and improved quality of life. EVIDENCE: A literature search was performed to identify reports published in English between 1975 and July 2003 using MEDLINE and Cochrane Database of Systematic Reviews. VALUES: Levels of evidence, as outlined, have been determined using the criteria outlined by the Canadian Task Force on the Periodic Health Examination. Participants were the principal authors: a clinical dietitian, a surgeon oncologist, and a nurse. BENEFITS, HARMS, AND COSTS: Utilizing the information will increase knowledge, enabling a consistent approach, which will reduce the number of ineffective interventions and ensure appropriate use medications. VALIDATION: Comparison has been made with management protocols in the literature, but no clinical guidelines have been located. No formal clinical testing has taken place. SPONSOR: The Society of Obstetricians and Gynaecologists of Canada (SOGC). Work on these guidelines was initiated by team members to fill a need for practice guidelines at Winnipeg Regional Health Authority Breast Health Centre, Winnipeg, MB. RECOMMENDATIONS: 1. Education and reassurance is an integral part of the management of mastalgia and should be the first-line treatment. (II-1 A) 2. The use of a well-fitting bra that provides good support should be considered for the relief of cyclical and noncyclical mastalgia. (II-3 B) 3. A change in dose, formulation, or scheduling should be considered for women on HRT. HRT may be discontinued if appropriate. (III C) 4. Women with breast pain should not be advised to reduce caffeine intake. (1 E) 5. Vitamin E should not be considered for the treatment of mastalgia. (1 E) 6. There is presently insufficient evidence to recommend the use of evening primrose oil (EPO) in the treatment of breast pain. (II-2 C) 7. Flaxseed should be considered as a first-line treatment for cyclical mastalgia. (I A) 8. Topical non-steroidal anti-inflammatory gel, such as diclofenac 2% in pluronic lethicin organogel, should be considered for pain control for localized treatment of mastalgia. (I A) 9. Tamoxifen 10 mg daily or danazol 200 mg daily should be considered when first-line treatments are ineffective. (I A) 10. Mastectomy or partial mastectomy should not be considered an effective treatment for mastalgia. (III E).

negative: Effect of flax seed ingestion on the menstrual cycle. Lignans are a group of phytochemicals shown to have weakly estrogenic and antiestrogenic properties. Two specific lignans, enterodiol and enterolactone, are absorbed after formation in the intestinal tract from plant precursors particularly abundant in fiber-rich food and are excreted in the urine. We evaluated the effect of the ingestion of flax seed powder, known to produce high concentrations of urinary lignans, on the menstrual cycle in 18 normally cycling women, using a balanced randomized cross-over design. Each subject consumed her usual omnivorous, low fiber (control) diet for 3 cycles and her usual diet supplemented with flax seed for another 3 cycles. The second and third flax cycles were compared to the second and third control cycles. Three anovulatory cycles occurred during the 36 control cycles, compared to none during the 36 flax seed cycles. Compared to the ovulatory control cycles, the ovulatory flax cycles were consistently associated with longer luteal phase (LP) lengths (mean +/- SEM, 12.6 +/- 0.4 vs. 11.4 +/- 0.4 days; P = 0.002). There were no significant differences between flax and control cycles for concentrations of either estradiol or estrone during the early follicular phase, midfollicular phase, or LP. Although flax seed ingestion had no significant effect on LP progesterone concentrations, the LP progesterone/estradiol ratios were significantly higher during the flax cycles. Midfollicular phase testosterone concentrations were slightly higher during flax cycles. Flax seed ingestion had no effect on early follicular phase concentrations of DHEA-S, PRL, or sex hormone-binding globulin. Our data suggest a significant specific role for lignans in the relationship between diet and sex steroid action, and possibly between diet and the risk of breast and other hormonally dependent cancers.

negative: Prospective study of the association between grapefruit intake and risk of breast cancer in the European Prospective Investigation into Cancer and ... Grapefruit inhibits cytochrome P450 3A4 and may affect estrogen metabolism. In the European Prospective Investigation into Cancer and Nutrition (EPIC), we examined the relationships of grapefruit intake with risk of breast cancer and with serum sex hormone levels. 114,504 women with information on dietary intake of grapefruit and on reproductive and lifestyle risk factors were followed for a median 9.5 years and 3,747 incident breast cancers were identified. Fifty-nine percent of women reported eating grapefruit, 4% ate > or = 60 g/day. Cox proportional hazard models were used to estimate the hazard ratio (HR) for breast cancer according to grapefruit intake, adjusting for study centre, reproductive factors, body mass index, energy intake, and alcohol intake. Grapefruit intake was not related to the risk of breast cancer: compared with women who ate no grapefruit, women with the highest intake of > or =60 g/day had a HR of 0.93 (95% CI 0.77-1.13), p for linear trend = 0.5. There was no relationship between grapefruit intake and breast cancer risk among premenopausal women, all postmenopausal women, or postmenopausal women categorized by hormone replacement therapy use (all p>0.05). There was no association between grapefruit intake and estradiol or estrone among postmenopausal women. In this study, we found no evidence of an association between grapefruit intake and risk of breast cancer.

negative: Recommendations for the prevention of chronic disease: the application for breast disease. Experimental and epidemiological evidence suggest that a diet with dietary fat as low as 20% of kcal may be necessary to reduce the risk of breast cancer. Two groups of women, postmenopausal women treated for breast cancer and premenopausal women with cystic breast disease accompanied by cyclical mastaligia, participated in an intervention program to determine the feasibility of such a low-fat diet. After 3 mo of intervention both groups were consuming a low-fat diet; in the premenopausal groups serum estrogen levels decreased in response to the fat reduction. Other nutrition-education programs in research institutions, restaurants, and schools are attempting to influence the public's knowledge and behavior regarding the importance of dietary fat reduction.