There is a substantial rise in the incidence of cancer in Saudi Arabia. Life style models and lack of awareness are the prime suspect in this substantial increase. Therefore, the objective of the present study was to assess the relationship between lifestyle and cancer in a population-based Survey in Northern Saudi Arabia.This cross-sectional study was conducted in North Saudi Arabia (Hail Region). Data was collected as a part of a community based cancer's awareness movement that covered an area inhibited with approximately 500,000 individuals.In this study, about 2558/3227 (79.3%) and 641/794 (80.7%) believed that tobacco smoking and smokeless are not a risk of cancer development. In this study large section (87.2%) of the study population believe that exposure to diverse occupational or non-occupational chemicals has no role in cancer development. Furthermore, around 59% of the study subjects in the current study believed that repeated exposure to insecticidal chemicals doesn't influence the risk of cancer.The present study point to the urgent need for awareness educational programs and preventive measures towards may lifestyle factors that can increase or decrease the overall risk of cancer among Saudi population. Regardless of resource limitations a country experiencing, when well-perceived and well-managed, a NCCP supports decrease the cancer burden and improve facilities for cancer patients and their families 2). Regular physical activity, decreases the risk of colorectal cancer and breast cancer. Alcoholic beverage consumption was found to increase the risk of some cancers including; liver, esophagus, pharynx, oral cavity and breast cancer. Foods frequently contaminated with Aflatoxin increases the risk of hepatocellular carcinoma. Salt preserved foods and high salt consumption perhaps upsurge the risk of carcinoma of the stomach. Certain salted fish was found to increase the risk of nasopharyngeal carcinoma. Preserved food particularly red meat possibly increase the risk for colorectal cancer.Increased weight or obesity elevates the risk of several cancers in many organs including; esophagus, colorectum, breast endometrium and kidney. It is necessary to maintain the body mass index within the normal range . Data was collected as a part of a community based cancer's awareness movement that covered an area inhibited with approximately 500,000 individuals. The sample size was calculated using online sample size calculator available at: Applying confidence interval of 60 ± 1.66 and confidence level of 95%, the sample size was 3326.Participants were targeted in different public settings including University of Hail. Each participant was asked to fill a questionnaire about tobacco and alcohol habits and other information regarding their attitudes towards these factors in relation to cancer etiology. Beside the demographical characteristics, the questionnaire also included; Living with smoker, Smokeless tobacco; Chemical usage, Insecticidal exposure, Vegetable and fruit wash before eating, Radiation exposure, Soft or refined food can increase the risk of cancer, Preserved food can increase the risk of cancer, Some food can increase the risk of cancer, Some food can decrease the risk of cancer, Natural food can decrease the risk of cancer, Vegetable and fruit intake decrease cancer risk, Green Tea and other antioxidant decrease cancer risk, Physical activity decrease cancer risk, Increased body weight increases cancer risk, Obesity can increase the risk of cancer.2.1.Statistical analysis was performed by proportion. The Microsoft Excel Office 2007 and the SPSS software (version 16) were used for statistical analysis. The software was used for calculation and production of frequencies and percentages.2.2.Written informed consent was obtained from each respondent, ensuring strict anonymity. The Ethical Committee of the Department of Pathology, College of Medicine at the University of Hail has approved the study.3.This study included 3326 participants, their ages ranging from 15 to 77 years old with a mean age of 25 years. Out of 3253 respondents for gender classification, 1701 (52.3%) were males and 1552 (47.7%) were females.The knowledge about the relationship between cancer risk and factors such as tobacco usage and alcoholic beverages consumption was summarized in With regard to exposure to passive smoking (living with smoker), 1430/3103 (46%) participants were found to believe that exposure to passive smoke is a risk for cancer and the remaining 1673/3103 (54%), were not. Out of 1430 respondents “Yes”, 761/1597 (47.7%) were males and 669/1506 (44.4%) were females. Out of 1673 respondent “No”, 836/1597 (52.3%) were males and 837/1506 (55.6%) were females, as shown in With regard to smokeless tobacco, 1139/1322 (86.2%) participants has pointed out that, smokeless tobacco is a major risk for cancer and only 183/1322 (13.8%) have answered “No”. Out of the 1139 “Yes” respondents, 641/794 (80.7%) were males and 498/528 (94.3%) were females. Out of 183 answered “No”, 153/794 (19.3%) were males and 30/528 (5.7%) were females, as shown in For alcoholic beverages consumption, only 57/3207 (1.8%) have agreed that alcohol consumption may be a risk factor for cancer and the remaining 3150/3207 (98.2%) believed that alcohol beverage consumption is not considered as a cancer risk factor, as indicated in The knowledge on the relationship between cancer, chemical usage, insecticidal, and radiation exposure was summarized in Out of the 3153 respondents, about 1292/3153 (41%) participants believed that comprehensive repeated exposure to insecticidal chemicals is a major cancer risk factor and the remaining 1861/3153 (59%) have reverse believe. Out of the 1861 participants answered “No”, 1210/1663 (72.9%) were males and the remaining 651/1490 (43.7%) were females.Out of the 3207 respondents, about 469/3207 (14.6%) participants believed that comprehensive repeated eating of vegetables and fruits without wash is a major cancer risk factor and the remaining 2738/3207 (85.4%) have reverse believe. Out of the 2738 participants answered “No”, 1341/2738 (49%) were males and the remaining 1397/2738 (51%) were females.Out of the 1750 respondents, about 1514/1750 (86.5%) participants believed that exposure to radiation is a major cancer risk factor and the remaining 236/1750 (13.5%) have reverse believe. Out of the 236 participants answered “No”, 195/1055 (18.5%) were males and the remaining 41/695 (6%) were females, as indicated in The relationship between cancer, and food habits was summarized in When asking the participants whether preserved food can increase the risk of cancer, about 1372 participants have responded. Out 1372 respondents, 1082 (79%)  answered “Yes” and 290 (21%)  answered “No”.When asking the participants whether some food can increase the risk of cancer, about 465 participants have responded. Out 465 respondents, 89 (19%)  answered “Yes” and 376 (81%)  answered “No”.When asking the participants whether some food can decrease the risk of cancer, about 2858 participants have responded. Out 2858 respondents, 1767 (19%)  answered “Yes” and 1091 (81%)  answered “No”.When asking the participants whether natural food can decrease the risk of cancer, about 2581 participants have responded. Out 2581 respondents, 2072 (80%)  answered “Yes” and 509 (20%)  answered “No”.When asking the participants whether vegetable/fruit intake can decrease the risk of cancer, about 2039 participants have responded. Out 2039 respondents, 1738 (80%)  answered “Yes” and 301 (20%)  answered “No”.When asking the participants whether anti-oxidants such as green tea intake can decrease the risk of cancer, about 1834 participants have responded. Out 1834 respondents, 1169 (64%)  answered “Yes” and 301 (36%)  answered “No”, as shown in The relationship between cancer, and body weight and physical activity was summarized in With regard to increased body weight as a factor that can increase the risk of cancer, out of 3172 respondents, 1631 (51%) participants greed “Yes”  that increased body weight can increase the risk of cancer, hence, about 1541 (49%) participants  disagreed “No”.With regard to obesity as a factor that can increase the risk of cancer, out of 1124 respondents, 745 (66%) participants greed “Yes”  that obesity can increase the risk of cancer, hence, about 379 (34%) participants  disagreed “No”.4.Cancer represent a major health problem worldwide. Although the prevalence of cancer is high in developed countries, but there is a tremendous increase of cancer in developing countries. In light of increasing of new cancer cases, there is an uprising need for implementing cancer awareness programs.In the present study we tried to highlight some important cancer issues in order to find out the gaps in this context to make available more information to take effective cancer prevention strategies.2 and a population of 547226 (2010 census) In the current study we screened a large population in a cross sectional survey in Hail region (Northern Saudi Arabia) in order to evaluate the level community awareness and knowledge toward some cancer related life style habits. Hail is a province of Saudi Arabia, located in the north of the country. It has an area of 103,887 kmIn this study, about 79.3% and 80.7% believed that tobacco smoking and smokeless are not a risk of cancer development. These findings have great discrepancies from other studies that reported much lower percentages. In study to evaluate the awareness of oral cancer and perception of tobacco use cessation counseling 97.6% Indian, 96.5% Saudi, 96.5% Yemeni and 98.4% United Arab Emirates respondents recognized the association between oral cancer and cigarette smoking In the present study about 98.2% of the participants disagreed that alcohol consumption is a risk factor for cancer development. Although it was well established that alcohol beverages consumption is a risk for the development of several precancerous and cancerous lesions In this study large section (87.2%) of the study population believe that exposure to diverse occupational or non-occupational chemicals has no role in cancer development. The exposure to diverse types of chemical substances has been linked to a number of cancers. Early-life arsenic exposure, has been linked to lung and bladder cancer Furthermore, around 59% of the study subject in the current study believed that repeated exposure to insecticidal chemicals doesn't influence the risk of cancer. Exposure to insecticidal chemicals such as Organochlorine insecticides has been linked to some cancers, particularly leukemia In the present study about 85.4% of the participants believed that comprehensive repeated eating of vegetables and fruits without wash doesn't increase the risk of cancer. The majority of these vegetables and fruits are contaminated with various chemicals including pesticides insecticides, and herbicides, the risk of which is well established With regard to the exposure to radiation, approximately 86.5% of the participants believed that exposure to radiation is a major cancer risk factor. This is high percentage of awareness toward radiation hazard.When asked the participants whether soft or refined food can increase the risk of cancer, around 74.8% answered yes. Many studies have suggested the relationship between intake of refined and fast food and the risk of cancer When asked the participants whether preserved food can increase the risk of cancer, about 79% of the participants agreed. However, the intake of preserved foods was positively associated with the incidence of epithelial ovarian cancer On we asked the participants whether some food can increase the risk of cancer, only 19% have answered yes. It was suggested that vegetable fiber and total fiber play very important roles in protecting against colorectal cancer On asking the participants whether natural food can decrease the risk of cancer, 80% answered yes. Because of their role as antioxidants, the intake of carotenoids has been found to reduce the risk of head and neck cancer (HNC) On asking the participants whether vegetable/fruit intake can decrease the risk of cancer, about 80% agreed. A higher consumption of vegetable and fruit was found to be associated with a decreased risk of several cancers, such as breast cancer, hepatocellular carcinoma, gastric carcinoma etc When asking the participants whether anti-oxidants such as green tea intake can decrease the risk of cancer, about 64% agreed. An inverse association between green tea intake and lung cancer risk has been observed among never smokers but not among smokers With regard to the physical activity as a factor that can decrease the risk of cancer, about 46% of the study population disagreed. Physical activity is consistently associated with a reduced risk of colorectal cancer in epidemiologic studies. Overall, a stronger relative risk of physical activity on colorectal cancer risk was observed in the higher body mass index group, although the difference was not statistically significant, suggesting an added benefit of physical activity as a cancer prevention strategy in population groups with strong risk factors for colorectal cancer With regard to increased body weight as a factor that can increase the risk of cancer, about 49% of the study population in the present study disagreed. he joint association between energy balance and cancer risk are hypothesized to share the same underlying mechanisms, the amplification of chemical mediators that modulate cancer risk depending on the responsiveness to those hormones to the target tissue of interest. Disentangling the connection between obesity, the insulin-IGF axis, endogenous hormones, inflammatory markers, and their molecular interaction is vital The limitations in the current study include its cross-sectional design. Longitudinal studies in the future might give up insight into developments in the outcomes of existing and future lifestyle related cancer control measures. Another limitation of the present study is that data were obtained via self-report.5.The present study point to the urgent need for awareness educational programs and preventive measures towards may lifestyle factors that can increase or decrease the overall risk of cancer among Saudi population. There is a necessity for in depth cancer prevention related studies and further specific measurements to prove that life style risk factors have influence on cancer burden in Saudi Arabia and in Northern Saudi Arabia in particular.


New York Times (NYT) that she had undergone risk-reducing bilateral mastectomy (RRBM) after learning that she was a BRCA1 mutation carrier. We examined the rates of BRCA testing and RRBM from 1997 to 2016, and quantified trends before and after the Jolie op-ed.In 2013, Angelina Jolie disclosed in the BRCA testing and RRBM rates among females ≥ 18 years. Censoring events were breast cancer or ovarian cancer diagnosis, last follow-up date (September 2016), or death. Interrupted time series analyses were used to quantify trends before and after the op-ed.This observational study of insurance claims data representative of the commercially-insured US population (Truven MarketScan® database) measured NYT op-ed led to a statistically significant increase in the uptake of genetic testing and in RRBM among women without previous diagnosis of breast or ovarian cancer in the US population, and in women who did not undergo testing for BRCA (P < 0.0001 for both). The rate (slope) of RRBM among women who were previously tested for BRCA (P = 0.70) was unchanged. After excluding women with in-situ tumors, the editorial’s effect became less pronounced, suggesting that high-risk women with in-situ breast cancers were most influenced by Jolie’s announcement.Angelina Jolie’s Angelina Effect—a term coined by Time magazine to describe the rise in internet searches related to breast cancer genetics and counseling—represents a long-lasting impact of celebrity on public health awareness as significant increases in genetic testing and mastectomy rates were observed and sustained in subsequent years.The The online version of this article (10.1007/s10549-018-4824-9) contains supplementary material, which is available to authorized users. New York Times entitled “My Medical Choice” that she had learned she was a BRCA1 mutation carrier and had undergone a risk-reducing bilateral mastectomy procedure with reconstruction  for Study Population Identified in MarketScan Database (1997–2016) (online only) (EPS 809 KB)


Women carrying a BRCA mutation have an increased risk of developing breast and ovarian cancer. The most effective strategy to reduce this risk is the bilateral salpingo-oophorectomy, with or without additional risk-reducing mastectomy. Risk-reducing bilateral salpingo-oophorectomy (RRBSO) is recommended between age 35 and 40 and between age 40 and 45 years for women carriers of BRCA1 and BRCA2 mutations, respectively. Consequently, most BRCA mutation carriers undergo this procedure prior to a natural menopause and develop an anticipated lack of hormones. This condition has a detrimental impact on various systems, affecting both the quality of life and longevity; in particular, women carrying BRCA1 mutation, who are likely to have surgery earlier as compared to BRCA2. Hormonal replacement therapy (HRT) is the only effective strategy able to significantly compensate the hormonal deprivation and counteract menopausal symptoms, both in spontaneous and surgical menopause. Although recent evidence suggests that HRT does not diminish the protective effect of RRBSO in BRCA mutation carriers, concerns regarding the safety of estrogen and progesterone intake reduce the use in this setting. Furthermore, there is strong data demonstrating that the use of estrogen alone after RRBSO does not increase the risk of breast cancer among women with a BRCA1 mutation. The additional progesterone intake, mandatory for the protection of the endometrium during HRT, warrants further studies. However, when hysterectomy is performed at the time of RRBSO, the indication of progesterone addition decays and consequently its potential effect on breast cancer risk. Similarly, in patients conserving the uterus but undergoing risk-reducing mastectomy, the addition of progesterone should not raise significant concerns for breast cancer risk anymore. Therefore, BRCA mutation carriers require careful counselling about the scenarios following their RRBSO, menopausal symptoms or the fear associated with HRT use. Historically, menopause was considered to be a form of neurosis resulting from the loss of femininity and until 1980, menopause was included among the criteria defining psychosis in the Diagnostic and Statistical Manual of Mental Disorders (DSM). The psychoanalytic theory which underpins this diagnosis relates to that of female sexual development and according to Freud’s theory, women may face depression at this time which can be explained by the female castration complex.Nowadays, according to the National Comprehensive Cancer Network (NCCN) guidelines, risk-reducing bilateral salpingo-oophorectomy (RRBSO) is recommended after completion of childbearing between age 35 and 40 years for women carriers of BRCA1 mutations and between age 40 and 45 years for women carriers of BRCA2 mutations in order to reduce their risk of developing breast and ovarian cancer. It is estimated that 65% of women carrying BRCA1 mutation will have risk-reducing salpingo-oophorectomy prior to their natural menopause [p < 0.0001) as compared to BRCA2 mutated women for whom the reduction in breast cancer-specific mortality loses significance  [The beneficial effects of an RRBSO include a reduction in ovarian cancer incidence of up to 96% and in breast cancer incidence up to 50% ,3. This  = 0.75) .The drawback of such a strikingly effective strategy in reducing the risk to develop a potentially deadly cancer, such as ovarian cancer is an earlier onset of menopause with subsequent associated long-term health consequences .In the general population, menopause occurs at a median age of 52 and the onset of menopause at an age younger or equal to 40 years, in gynecology, is defined as premature ovarian failure.The lack of hormones that characterizes this status involves various systems and may affect both quality of life and longevity. Consequently, in women incurring premature ovarian failure, according to the European Society of Human Reproduction and Embryology (ESHRE) guidelines, hormonal replacement therapy should be started at the time of diagnosis. This should be continued until the average age at which the menopause occurs in the general population as a prevention measure against menopausal symptoms, cardiovascular diseases, osteoporosis, and to reduce the long-term morbidity associated with the hormone depletion .The most characteristic menopausal symptoms, which result from estrogen deprivation and affecting more than 80% of women, are the hot flushes, which can significantly impair the quality of life .Following premature ovarian failure, 43–50% of the women report low sexual desire, over 50% of the women report vaginal dryness, 17–42% report sexual discomfort and/or pain, and 60% report difficulties in reaching an orgasm . To reliIn addition to these symptoms, neurological dysfunction, cognitive impairment, and dementia are reported in several cases ,12. DespGiven the crucial role played by the estrogens in the metabolism of the bones, it is clear that the early onset of menopause has detrimental effects on the bone density and bone structure leading to an increased risk of bone fracture ,14. The Finally, the lack of estrogens in women with premature ovarian failure leads to a modification of the lipid profile that leads to endothelial dysfunction with an increased risk of early cardiovascular-related mortality ,18. WhenAlthough hormone replacement in women with premature ovarian failure may occur via combined oral contraceptives or via conventional hormonal replacement therapy, the latter method more closely mimics the physiological concentrations of both estrogen and progesterone .Estrogens can be administered orally, transdermally, or topically. The preferred route of administration is the transdermal as it guarantees a systematic distribution of the hormone and is not associated with an increased risk of cardiovascular morbidity linked to the oral administration of the estrogens. The risk of endometrial cancer is 4.5 times greater among women exposed to estrogen therapy without combined progesterone therapy . The sysProgestins can be administered orally, vaginally, or via a medicated intrauterine device. At present, it is unclear whether the administration of progestins via subcutaneous implants and intramuscular injections imparts sufficient endometrial protection during hormonal replacement therapy. Among the various progestins, it seems that micronized progesterone has a greater cardiovascular protective effect and may reduce the risk of breast cancer risk as compared with other progestins . AlthougDespite ESHRE recommendations and the apparent benefits of hormone replacement therapy, approximately 40% of women with premature ovarian failure discontinue treatment within one year ,24.Two of the largest studies of HRT raised concerns regarding the safety of HRT in general population, in terms of risk of breast cancer and heart disease ,26. The Based on the available evidence, which constitutes mostly on retrospective studies, the short-term use of HRT does not have any influence on the protective effect of the RRBSO on breast cancer incidence ,27,28. Wp  =  0.04) and was particularly striking for women undergoing RRBSO prior to 45 years of age . In this subgroup of women who underwent RRBSO prior to age 45, the protective effect on breast cancer risk conferred by an estrogen-only hormonal replacement therapy reached statistical significance with an 18% risk reduction  per year of treatment. In the same subgroup of women, a non-significant increase in breast cancer risk of 14%  was calculated for every year of combined estrogen-progestin replacement therapy. These findings are consistent with those reported in large prospective studies and randomized clinical trials performed in women who do not carry mutations of the BRCA genes [For BRCA1 mutation carriers, the use of HRT after RRBSO did not increase the incidence of breast cancer in a large prospective study [CA genes ,30,31,32The potential negative effect of the progestins on breast cancer risk may be explained by the role of the progesterone/receptor activator of nuclear factor-kB (RANK)-signaling pathway in BRCA 1 breast cancer development ,34. AlthFor BRCA 2 mutation carriers, available data on the use of HRT are less available. In these patients, the adoption of an HRT is probably less important given the later age at which they typically undergo an RRBSO and given their propensity to develop hormone receptor-positive breast cancers. Hence, HRT in this subset of patients should be adopted with caution.In conclusion, the adoption of an estrogen-only hormonal replacement therapy after RRBSO does not increase the risk of breast cancer among women with a BRCA 1 mutation and should reassure BRCA1 mutation carriers considering risk-reducing surgery that HRT is safe. The potential adverse effect of progestin containing HRT warrants further studies. Similarly, studies should investigate whether route, regimen or dose of HRT differentially impacts breast cancer risk as well as the impact of intrauterine devices as HRT. The risk associated with progestins may be of little clinical impact in women undergoing both RRBSO and risk-reducing mastectomy. For women who select not to undergo a mastectomy, the use of progestins may be avoided in cases of previous hysterectomy or when a hysterectomy is performed in conjunction with the RRBSO.Although the morbidity of a hysterectomy and bilateral salpingo-oophorectomy is somewhat higher than that of a bilateral salpingo-oophorectomy, women undergoing RRBSO, especially if aged under 45 years, should be counseled that the removal of the uterus will eradicate the need for progestins.


We aimed to explore left atrial (LA) remodeling in the patients with solid cancer before initiation of chemo- or radiotherapy. This retrospective investigation included 92 chemo- and radiotherapy-naive cancer patients and 40 age- and gender-matched controls with a similar cardiovascular risk profile as the cancer group. All participants underwent comprehensive echocardiographic examination before the start of chemo- or radiotherapy. LA phasic function was evaluated in volumetric and strain method. Indexed minimal and pre-A LA volumes were significantly higher in the cancer patients. Total and passive LA emptying fraction (EF) were significantly lower, whereas active LAEF was significantly higher in the cancer patients. LA total longitudinal strain was significantly lower in the cancer patients. Strain rate analysis of LA phasic function showed that LA function during systole and early diastole was reduced in the cancer group, while it was increased during late diastole. These findings indicated that LA reservoir and conduit functions, assessed with LA volumetric and strain analysis, were deteriorated in the cancer group. On the other hand, LA booster pump function was elevated in the cancer group in comparison with the controls. In the whole population, cancer was associated with reduced LA total longitudinal strain independently of age, gender, BMI, LV hypertrophy, E/e’ ratio, diabetes, and hypertension. LA phasic function was impaired in the chemo- and radiotherapy-naive cancer patients in comparison with the control group. Cancer, LV hypertrophy, and hypertension were associated with reduced LA longitudinal strain independently of other important clinical parameters.  Left ventricular (LV) remodeling in the treated cancer patients has been confirmed in the large number of studies ,2,3, andRecently published studies showed significant dilatation and reduction in LA contractile function in patients after chemotherapy ,7,8. TheThe primary aim of this investigation was to evaluate LA phasic function in the chemo- and radiotherapy-naive cancer patients meaning before starting any anti-cancer treatment. The secondary aim was to explore the association between cancer and LA total longitudinal strain.This is a retrospective study that involved 92 consecutive patients with solid cancer who were referred to echocardiographic assessment before initiation of chemotherapy or radiotherapy in the period between January 2016 and July 2017. The inclusion criteria were normal LV ejection fraction (EF > 50%) and absence of any chemotherapy or radiotherapy. Additionally, 40 subjects of similar age and sex distribution with the same profile of cardiovascular risk factors  as the cancer patients and who were referred to our echocardiography laboratory in the same period as the cancer patients were retrospectively included as the control group. The subjects in the control group were referred to the echocardiographic department due to regular check-up, an innocent heart murmur, or as a part of investigation in hypertensive patients. Patients with cancer metastasis, symptoms or signs of coronary artery disease, more than mild valvular heart disease, heart failure, atrial fibrillation, congenital heart disease, or liver or kidney failure were excluded from this study. Patients with inadequate echocardiographic images of the LA were not included (n = 18). All the patients underwent anthropometric measurement . Body mass index (BMI) and body surface area (BSA) were calculated for each patient. Data regarding blood pressure values, hypertension, diabetes, smoking, and other comorbidities were obtained from the electronic medical records. According to the rules of the Ethics Committee of our clinic, a retrograde study does not require approval if the investigators only use the existing data, without follow-up or any further contact with the study participants.2 for women and > 115 g/m2 for men) [An EPIQ 7  ultrasound machine was used for echocardiographic examinations of all the participants. The frame rate ranged between 60 and 100 Hz. Reported values of all 2DE parameters were obtained as the average value of three consecutive cardiac cycles. LV diameters and septum and relative wall thickness were measured according to the current recommendations . LV ejecThe apical four-chamber view was used for the assessment of transmitral LV flow and deceleration time by the pulsed-wave Doppler . Tissue LA phasic function was determined by volumetric and strain analysis. LA volumes were obtained in three various parts of the cardiac cycle: maximal LA volume was calculated just before the mitral valve opening, pre-A  LA volume was evaluated at the beginning of atrial systole (peak of P wave in ECG), and minimal LA volume was assessed at the mitral valve closure. All LA volumes were determined according to the biplane method in four- and two-chamber views and all the values were indexed for BSA. The total emptying volume (LA reservoir function parameter) was calculated as the difference between maximum and minimum LA volume; passive emptying volume (LA conduit function parameter) was computed as the difference between maximum and pre-A LA volume; and active emptying volume (LA booster function parameter) was calculated as the difference between pre-A and minimum LA volume . Figure The 2DE strain analysis was performed in the apical four- and two-chamber views  by commet-test was used to detect differences between the two groups. LAVs and LA longitudinal strain was also presented with median values and interquartile ranges. The interquartile range was the range between the first and third quartile. The differences in proportions were compared by using the χ². The cut-off values for LA total longitudinal strain (< |–27%|) were used from the literature [p-value < 0.05 was considered statistically significant.The data were analyzed by using SPSS version 21 . Continuous variables were presented as mean ± standard deviation (SD). Normal distribution of included variables was confirmed by the Kolmogorov–Smirnov test. The Student’s terature . The assAge, gender distribution, BMI, blood pressure, prevalence of hypertension, diabetes, and smoking was similar between the controls and the cancer patients . The stuThere was no difference in LV diameters, wall thickness, and ejection fraction between the controls and the cancer group . LV massMinimal and pre-A LAVs indexed for BSA were significantly higher in the cancer patients with the borderline significance only for maximal LAVI . ConsequLA total longitudinal strain was significantly lower in the cancer patients than in the controls, which confirms the impairment of LA reservoir function in these patients . FurtherLV hypertrophy, hypertension, diabetes, and cancer were each associated with reduced LA strain in the univariate analysis, but in the multivariate analysis diabetes only LV hypertrophy, cancer, and hypertension were independently associated with decreased LA longitudinal strain .There are several findings of this study that deserve our attention and further discussion. First, minimal and pre-A LA indexed volumes were significantly higher in the cancer patients even before initiation of chemo- or radiotherapy. Second, reservoir and conduit LA functions were reduced in the cancer patients, whereas LA booster pump function was elevated in this group. This was showed by both volumetric and strain analysis of LA phasic function. Third, the presence of cancer by itself was associated with reduced LA longitudinal strain independently of other important demographic and clinical characteristics. Our study showed that minimal and pre-A LAVIs were significantly higher in the cancer patients with borderline statistical significance for maximal LAVI. Yaylali et al. showed that maximal and pre-contraction LAVs were significantly higher in the patients after anthracycline therapy in comparison with the healthy controls . Shi et The results regarding LA phasic function are not concomitant among different authors, but it seems that a kind of pattern does exist. Our findings showed that LA reservoir and conduit functions were reduced in the cancer patients, whereas LA pump function was elevated in the same group. This elevation of LA pump function is probably a compensatory mechanism that serves to maintain LV filling volume during late diastole, which we described earlier ,16,17. HShi and Yaylali reported significantly reduced passive LAEF and increased active LAEF, which demonstrated impaired conduit LA function and elevated booster pump LA function in breast cancer and non-Hodgkin lymphoma patients treated with anthracyclines ,7. Both An important finding of the present study is the relationship between cancer and LA dysfunction independent of common risk factors for LA remodeling such as age, obesity, hypertension, diabetes, LV hypertrophy, and LV diastolic function. The clinical importance of this finding lies in the fact that current knowledge of this topic indicates chemo- or radiotherapy as the main responsible factor for cardiac remodeling in the cancer patients. Our results show that cancer itself could be responsible for cardiac remodeling even before starting anti-cancer therapy, which underlines the necessity for more detailed evaluation of LA and overall cardiac function before initiation of anti-cancer therapy. Furthermore, LA dysfunction is associated with atrial fibrillation occurrence which is more frequent arrhythmia in the cancer patients . TherefoThere are several potential mechanisms that could explain the independent association between cancer and impaired LA phasic function. Numerous circulating biomarkers, cytokines, vasoactive peptides, pro-BNP, and pro-ANP that are significantly increased in cancer patients could explain cancer-induced cardiotoxicity and eventually LA remodeling . Our stuThe main strength of this study is the unique group of untreated cancer patients and findings that indicate impaired LA phasic function in oncology patients comparing with controls. These data might imply that chemo- and radiotherapy are not the only factors responsible for cardiac remodeling and cardiotoxicity, as it was believed previously. Additionally, this could help in determination of patients who are at higher risk of cardiotoxicity during anti-cancer therapy.The present investigation has several limitations. The cancer group is not pathologically homogenous. However, our aim was not to investigate the effect of only one type of cancer. Additionally, as cardiologists in the clinical practice, we are not treating only one type of cancer, but all cancer patients. Important selection bias came from the fact that patients who are not receiving potentially cardiotoxic therapy (for example brain tumors) were not referred to echocardiohgraphic treatment and not included in this investigation. Furthermore, this was a retrospective study conducted at a tertiary center and the oncologists were only referring patients who potentially might receive cardiotoxic agents to the echocardiography department, which is why there could be a degree of selection bias present. The weight loss, which possibly occurred in the patients with cancer, was not considered as a confounding variable on LA remodeling and it should be included in future investigations. Asymptomatic atrial fibrillation could not be excluded as one of the potential reasons for deteriorated of LA function. LA evaluation was mostly performed on conventional echocardiographic views and not in views dedicated to LA assessment. We had to accept this limitation considering that the study was retrospective and there was no possibility to repeat the examination. This is a retrospective study and the causal relationship between cancer and LA phasic function could not be definitely established. On the other hand, it would be difficult to conduct a follow-up study with untreated cancer patients.Our study showed that LA phasic function is significantly deteriorated in the cancer patients even before initiation of chemo- or radiotherapy. The volumetric and strain analysis provided concurrent results that showed significantly reduced LA reservoir and conduit functions, but compensatory increased LA booster pump function. The presence of cancer was independent of other demographic and clinical parameters associated with reduced LA total longitudinal strain. The question that arises is whether or not chemo- and radiotherapy actually do have such a negative impact on cardiac remodeling or if a large part of this remodeling could be ascribed to the cancer itself. Future studies with larger number of cancer patients are necessary to confirm the relationship between cancer and LA remodeling and its predictive value during chemo- and radiotherapy.


This cohort study reports the long-term accuracy of the Tyler-Cuzick model combined with breast density in assessment of risk for breast cancer among women in a state registry. How accurate is breast cancer risk assessment during more than 10 years of follow-up?In a cohort study of 132 139 women attending screening from 1996 to 2014, the Tyrer-Cuzick model with mammographic density was well calibrated , with no significant loss in calibration to 19 years after assessment. A high-risk group suitable for preventive therapy included 4645 women (3.5%) and 273 cancers (10.1%).Accurate risk assessment for breast cancer is needed for risk-adapted screening and prevention strategies; risk assessment combining classic risk factors and mammographic density may be valid for many years after evaluation. Accurate long-term breast cancer risk assessment for women attending routine screening could help reduce the disease burden and intervention-associated harms by personalizing screening recommendations and preventive interventions.To report the accuracy of risk assessment for breast cancer during a period of 19 years.This cohort study of the Kaiser Permanente Washington breast imaging registry included women without previous breast cancer, aged 40 to 73 years, who attended screening from January 1, 1996, through December 31, 2013. Follow-up was completed on December 31, 2014, and data were analyzed from March 2, 2016, through November 13, 2017.Risk factors from a questionnaire and breast density from the Breast Imaging and Reporting Data System at entry; primary risk was assessed using the Tyrer-Cuzick model.Incidence of invasive breast cancer was estimated with and without breast density. Follow-up began 6 months after the entry mammogram and extended to the earliest diagnosis of invasive breast cancer, censoring at 75 years of age, 2014, diagnosis of ductal carcinoma in situ, death, or health plan disenrollment. Observed divided by expected (O/E) numbers of cancer cases were compared using exact Poisson 95% CIs. Hazard ratios for the top decile of 10-year risk relative to the middle 80% of the study population were estimated. Constancy of relative risk calibration during follow-up was tested using a time-dependent proportional hazards effect.In this cohort study of 132 139 women , 2699 invasive breast cancers were subsequently diagnosed after a median 5.2 years of follow-up . Observed number of cancer diagnoses was close to the expected number . The Tyrer-Cuzick model estimated 2554 women (1.9%) to be at high risk (10-year risk of ≥8%), of whom 147 subsequently developed invasive breast cancer . The Tyrer-Cuzick model with density estimated more women to be at high risk . The hazard ratio for the highest risk decile compared with the middle 80% was 2.22  for the Tyrer-Cuzick model and 2.55  for the Tyrer-Cuzick model with density. Little evidence was found for a decrease in relative risk calibration throughout follow-up for the Tyrer-Cuzick model  or the Tyrer-Cuzick model with density .Breast cancer risk assessment combining classic risk factors with mammographic density may provide useful data for 10 years or more and could be used to guide long-term, systematic, risk-adapted screening and prevention strategies. A prerequisite for the implementation of risk-adapted screening intervals and use of preventive therapies in precision medicine is accurate risk assessment.Breast cancer is the most common cancer in women, with at least 1.7 million cases diagnosed and 0.5 million deaths per annum worldwide.9 The Tyrer-Cuzick model incorporates classic breast cancer risk factors, including information on affected second- and third-degree relatives, body mass index, menopause, and hormone therapy. However, the model identifies few women in the general population to be at high risk (taken to be an absolute 10-year risk of ≥8%).11 Accumulating evidence suggests that risk assessment may identify more high- and low-risk women when mammographic density is also taken into account,15 but the performance of the Tyrer-Cuzick model has not been directly assessed in any cohort study from a screening population in the United States.17Breast cancer risk models have been used to guide entry criteria in prevention trials and to determine the eligibility of women for preventive therapy and supplemental screening by magnetic resonance imaging.18An important question for risk assessment is the follow-up time over which a model is accurate. Short-term predictions are useful for decisions such as additional screening modalities at the time of mammography, whereas longer-term risk predictions are important for deciding a risk-adapted screening regimen and eligibility for preventive therapy. Although several risk models provide the residual lifetime risk for a woman by year, studies to validate their performance have mostly considered cases within 5 years of risk assessment.19The main aim of this study was to evaluate the Tyrer-Cuzick model to 19 years after risk assessment or 75 years of age in a screening cohort. We assessed the performance at different follow-up times and determined how much the accuracy of the model improves by adding a Breast Imaging and Reporting Data System (BI-RADS) measure of breast density.22 This registry was used because of the more detailed family history of breast and ovarian cancer collected than for other BCSC registries.23 All procedures are compliant with the Health Insurance Portability and Accountability Act, and the registry has received a Federal Certificate of Confidentiality and other protection for the identities of women, physicians, and facilities who are the subjects of this research. The Kaiser Permanente Washington breast imaging registry has received approval from the institutional review board for active or passive consenting processes or a waiver of consent to enroll participants, link data, and perform analytic studies.The study included women in the Kaiser Permanente Washington Breast Cancer Surveillance Consortium (BCSC) registry who attended mammography screening from January 1, 1996, through December 31, 2013, with follow-up to December 31, 2014.14Women entered the cohort 6 months after completing their first risk factor questionnaire in the registry. To restrict to a cohort with negative screening findings, we excluded women diagnosed with in situ or invasive breast cancer within 6 months of their initial screening mammogram. All women aged 40 to 73 years at entry who attended at least 1 screening visit (baseline) with BI-RADS density recorded and did not have a prior diagnosis of invasive breast cancer or ductal carcinoma in situ were included; women with a lobular carcinoma in situ diagnosis before or at baseline were excluded. Some data from this cohort contributed to the BCSC model.24 and pathology databases. All benign and malignant breast pathologic findings at Kaiser Permanente Washington were collected from electronic medical records, given manual, standardized codes,26 and used to supplement tumor registry data.The primary outcome was the time from 6 months after the entry questionnaire to diagnosis of invasive breast cancer or censoring. Women were censored at the earliest of death, health plan disenrollment, diagnosis of ductal carcinoma in situ, 75 years of age (the recommended end of screening), or the end of calendar time follow-up. Outcomes were obtained through linkage with the regional population-based Surveillance, Epidemiology, and End Results tumor registry25 Demographic factors included urban environment  and a geocoded measure of median income determined by linking a woman’s address at the time of each questionnaire to income and urban environmental data from her 2010 US census tract.27Risk factors used in the Tyrer-Cuzick model (version 7.02) were investigated, and mammographic density risk was integrated using risk estimates from a different case-control study   statistics between a proportional hazards model that included only age and one that additionally incorporated the yearly predicted hazard. All analysis was undertaken using statistical software R (version 3.4.1) and the survival, survminer, amd mgcv packages.32Data were analyzed from March 2, 2016, through November 13, 2017. Categories for demographic and risk factor categories were chosen based on questionnaire fields or established cut points, and their hazard ratios (HRs) were estimated with 95% Wald CIs. Breast cancer incidence was predicted to the end of each woman’s follow-up, converted to a cumulative hazard using a natural logarithm, and summated to provide the expected number of breast cancer diagnoses. Exact 95% CIs for the observed divided by the expected (O/E) numbers of cancer diagnoses assumed that the observed number was generated by a Poisson distribution, with a rate equal to the expected number if well calibrated. Population risks were shown using annual incidence rates (IRs) per 1000 women for the complete cohort and across 10-year risk subgroups using categories defined at baseline to be below average (<2%), average (2% to <3%), above average (3% to <5%), moderately increased (5% to <8%) and high (≥8%), following clinical guidelines in the United Kingdom.We included 132 139 women with a median follow-up of 5.2 years . Follow-up was greater for younger women who entered the cohort earlier . Most of the women were white (80.4%) and lived in a metropolitan area (95.4%) . Median 21 in which high-risk women were recommended to start annual breast imaging at 40 years of age and low-risk women were recommended to start at 50 years of age . Two peaks in the entry distribution occurred at 40 and 50 years of age. These peaks reflect the cohort’s risk-based screening programIn total, 2699 invasive breast cancers were diagnosed. Women were censored owing to disenrollment (62 331 [47.2%]), end of follow-up (48 317 [36.6%]), being 75 years of age (15 827 [12.0%]), death (2328 [1.8%]), or a diagnosis of ductal carcinoma in situ (637 [0.5%]). Of the 2699 invasive cancers, 412 were larger than 2 cm and had lymph node involvement . Invasive cancer rates increased from approximately 1.3 per 1000 women/y at 42 years of age to 5.1 per 1000 women/y at 70 years of age and were similar to recent rates in Washington State but departed from the marginal rate assumption in the Tyrer-Cuzick model , affected first-degree relatives , and previous atypical hyperplasia diagnosis   . AbsolutOverestimation of the highest decile relative to the middle 80% was also apparent . The haz2 = 290.5; Tyrer-Cuzick model with density, ΔLR-χ2 = 541.4); density added approximately 86% to all factors in the Tyrer-Cuzick model other than age. A reclassification matrix demonstrated that this information translated into improved risk stratification for individual women (eTable 5 in the Other analyses showed more predictive information than age in the models (Tyrer-Cuzick model, ΔLR-χIn this article, we evaluated the accuracy of long-term breast cancer risk assessment in a US screening cohort and found that breast cancer risk models based on classic risk factors and mammographic density remain accurate during a longer period than considered to date. We found continued differences in observed risk during a 19-year period between predicted risk strata formed at baseline .BRCA1/2 mutations or other inherited genetic factors. Combining mammographic density with classic risk factors appears to be particularly important for this aim because the strategy almost doubled the number identified in a high-risk group. Genetic or high-risk clinics may only have a moderate effect on breast cancer in the general population because most breast cancers are attributable to nongenetic factors. Most of these reproductive, hormonal, lifestyle, or other factors are common but relatively weak factors for individual women (The long-term calibration of breast cancer risk models has important clinical implications. Arguably the main role of breast cancer risk assessment to date has been to triage women for genetic counseling and thereby guide their eligibility for genetic testing, preventive therapy, and screening modalities in addition to mammography. Our results lend support to extending such triage to more general high-risk clinics based on risk to 19 years using a combined risk assessment, not just familial risk associated with al women , and few33Implementing risk assessment and prevention strategies that are effective during a longer period could be easier than more frequent risk assessment, but updated risk assessments are likely to also play a role because they will be more precise for individual women. For example, risk would increase after a first diagnosis of proliferative benign disease, and taking into account a sequence of mammographic density measurements will be more precise than only using the most recent measurement.The overall rates predicted by the models were broadly consistent with the observed rates, but some evidence suggested overestimation for the women at highest risk, and the models also predicted relatively more cancers than observed in younger women and fewer in older women. Although changing risk thresholds or applying a recalibration of the absolute risks may be considered, this is unnecessary because the aim is to use the risk model to form broad risk strata. For example, the observed risks in the chosen groups were consistent with the predicted 10-year risk . Another36 but models for subtypes could also play a role in decision making. For instance, it has long been considered likely that mammographic screening in women younger than 50 years should be more frequent than in older women despite their lower risk because on average tumor progression is more rapid in the younger group and the breast tissue is denser; one might seek to use models that assess risk of aggressive or lethal types of cancer and a false-negative mammography screening result.Validated and freely available models for invasive breast cancer have merit for guiding personalized breast cancer screening and prevention strategies,37 and an active risk-based screening program, which will provide information on younger women who are at higher risk. All women had health insurance, the median census family income was relatively high, and the cohort mainly consisted of women who regularly attend screening, which might represent more healthy individuals. The relative homogeneity of the sample has the potential to limit the factors that influence the model and mask the influence of socioeconomic or other risk factors. Some data were missing (This study has several limitations. Results are derived from a single registry in 1 area of the United States with one of the highest IRs for breast cancer in the nation missing , for whi missing . FinallyRisk models combining classic risk factors with mammographic density were informative to 19 years after risk assessment. Mammographic density helped to identify a greater number of women at the extremes of the risk distribution where preventive measures or different screening intervals might be considered to minimize intervention-associated harms and the public health burden of breast cancer.


BRCA1 and BRCA2 (BRCA1/2) over two decades ago, much has been accomplished in the field of breast cancer genetic predisposition. On one hand, novel genes harboring rare pathogenic variants, most of which act in the same BRCA1/2 pathway, causing increasing disease risk have been identified. In addition, several single nucleotide polymorphisms (SNPs) that modify the breast cancer risk in individuals with BRCA1/2 mutations are now known. These moderate-to-high penetrant genetic variants now represent key elements for improving risk prediction in familial cases. On the other hand, hundreds of common low-risk SNPs have been discovered and can be incorporated into prediction models to improve the identification of women at risk of breast cancer in the general population. Moreover, multifactorial analyses, family studies and high throughput functional assays have been developed to validate candidate genes, classify the variants of uncertain significance (VUS) detected by gene-panel next generation sequencing in clinical and research settings, and to measure the risk magnitude conferred by known pathogenetic variants. Articles in the present Frontiers in Oncology e-book explore these aspects of breast cancer predisposition further.Since the discovery of breast cancer genes BRCA1/2 pathogenic variants have an average cumulative risk of developing breast cancer, by age 80 years, of ~70% , PALB2 is now considered the third high-risk gene with pathogenic variants associated with 44% lifetime risk of developing breast cancer  are due to pathogenic variants in BRCA2 while CHEK2 and PALB2 account for a smaller proportion of cases. In their study these authors suggest that monoallelic mutation of MUTYH gene, which cause the recessive MUTYH-associated polyposis (MAP) syndrome may also cause MBC.Individuals who carry ime risk , 4. Morefor TNBC –8. All tfor TNBC . In thisBRCA1/2 pathogenic variants is the most significant success of the Breast Cancer Association Consortium  and of the Consortium of Investigators of Modifiers of BRCA1/2 . A meta-analysis of genome wide association studies (GWAS), which combined data from 122,977 breast cancer cases and 105,974 controls, resulted in the identification of a total of 172 risk-associated SNPs explaining about half of the familial relative risk [the risk of first-degree relatives of breast cancer patients of developing the disease;  Group, described in this e-book by Lesueur et al., is one of the larger studies within CIMBA. GEMO was initiated in 2006 and today involves 32 clinics and 17 diagnostics laboratories that, as of April 2018, collected 5,303 participants.The identification of common SNPs associated with breast cancer risk and of those that modify the breast cancer risk in individuals with disease; , bringinBRCA1/2 and in other established or candidate breast cancer genes have uncertain clinical significance. These VUSs, which are typically rare missense variants, represent a serious clinical problem as carrier risk estimates are often unclear. The Evidence-based Network for the Interpretation of Germline Mutant Alleles  was formed to determine the clinical significance of variants in BRCA1/2 and other known or suspected breast cancer genes (Zuntini et al., investigated whether co-segregation analyses, integrated with functional data and in silico predictions, could improve VUSs interpretation and counseling in carrier families. In the second study, Caleca et al., used an in vitro assay specifically designed to test the BRCA2 and PALB2 gene products interaction and showed initial pathogenicity evidence for two very rare missense variants in these genes. A special class of VUS are those suspected to cause mRNA splicing defects. One of the ENIGMA working groups was established to improve the clinical classification of likely spliceogenic variants. Members of this working group contributed articles exploring some of the aspects of this variant class. For example, Fraile-Bethencourt et al. identified eight spliceogenic variants in exon 16 of BRCA2 by minigene assay, highlighting the efficiency of this approach for clinical classification. In silico tools for splicing defect prediction may play a key role in VUS analysis. Moles-Fernández et al. used 99 in vitro-validated variants to evaluate the performance of six commonly used splicing in silico tools. Finally, Farber-Katz et al. conducted analyses of BRCA1/2 variants using a novel RNA-massively parallel sequencing assay capable to perform quantitative and qualitative analysis of transcripts. Similarly, Lattimore et al. utilized targeted RNA-seq to re-assess BRCA1/2 mRNA isoform expression patterns in lymphoblastoid cell lines. Recommendations from these two studies will facilitate the application of targeted RNA-seq approaches for the quantitative characterization of BRCA1 and BRCA2 germline splicing alterations.As discussed above, many variants in er genes . To thisBRCA1/2 on breast cancer risk, much has been learned and through the tremendous international, multi- and inter-disciplinary efforts of consortia such as BCAC, CIMBA, and ENIGMA. The next decade promises to illuminate many new aspects of breast cancer risk prevention on families and in the general population.In summary, articles in the present e-book move the field of breast cancer genetics in several aspects, ranging from characterizing genetic variation in new populations to developing and applying tools for variant re-classification. Since the discovery of the role of PP and LC-C wrote this manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


This study aimed to explore the effect of dietary magnesium intake on breast cancer risk both directly and indirectly via its effect on inflammatory markers C-reactive protein (CRP) and interleukin-6 (IL-6). This case-control study recruited 1050 case patients and 1229 control subjects. Inflammatory marker levels of 322 cases and 322 controls, randomly selected, were measured using ELISA, and data on dietary magnesium intake were collected using a food frequency questionnaire. Multivariable logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI), and path analysis was used to investigate the mediating effect. A higher magnesium intake was associated with a lower breast cancer risk . A positive association was found between the CRP level and breast cancer risk . However, IL-6 was not found to be associated with breast cancer risk. Path analysis revealed that dietary magnesium affected breast cancer risk both directly and indirectly by influencing the CRP level. The results indicate that a direct negative association and an indirect association through influencing the CRP level were observed between dietary magnesium intake and breast cancer risk. Magnesium deficiency has been reported to be associated with the risk of some diseases, including cardiovascular disease, diabetes mellitus, metabolic syndrome, as well as various types of cancers8. Some studies have linked magnesium deficiency to the development and prognosis of breast cancer10, but this finding is inconsistent across studies. The bioavailability of magnesium depends largely on food sources8. Although a variety of foods and food groups, including green vegetables, beans and unrefined whole grains, are rich in magnesium, the daily intake of magnesium remains below the recommended daily allowance and does not meet even the estimated average requirement (EAR)11. The National Health and Nutrition Examination Survey reported that the magnesium intake of approximately 70% of American adults is insufficient because of increased consumption of refined foods, which are poor sources of magnesium12. Therefore, it is essential to investigate the effect of magnesium deficiency on breast cancer risk.Breast cancer is the most common cancer among women, accounting for 25% of all female cancer cases13. In particular, there is evidence that magnesium deficiency is associated with inflammatory response, although the underlying mechanisms are still unclear18.Magnesium plays essential roles in several biological reactions, such as inflammation, DNA replication and repair, cell proliferation and signalling transduction, most of which are linked to tumourigenesis19. Although studies have suggested that the development of approximately 20% of all cancers is linked to chronic low-grade inflammation, the varying effects of inflammation on the onset of different types of cancer are still not completely clear21. Elevated levels of C-reactive protein (CRP) and several cytokines are associated with chronic low-grade inflammation23. The CRP level is widely used as a classic biomarker of systemic inflammation in epidemiological studies as it is sensitive to acute inflammation and also shows a moderate increase in chronic inflammation26. The use of CRP level as a chronic inflammatory biomarker has some advantages, such as wide availability of assays and temporal stability28. There is growing evidence that an increased CRP level is associated with the risk of colorectal and lung cancers, but evidence about the association of CRP level with breast cancer risk is inconsistent35. Interleukin-6 (IL-6) is a major pleiotropic pro-inflammatory cytokine that also reflects the systematic chronic inflammatory status. IL-6 bridges the signal transducer and activator of transcription 3 (Stat-3) and nuclear factor-kappa B (NF-κB)- dependent signalling pathways, which regulate both inflammatory response and tissue metabolism36. To date, very few epidemiological studies have assessed the role of IL-6 in the risk of breast cancer39.A possible relationship between inflammation and cancer was first suggested when Rudolf Virchow found the presence of leukocytes in tumours in 1863Based on the above-mentioned findings, we speculated that magnesium deficiency affects breast cancer risk by regulating the systematic inflammatory status. Accordingly, this study aimed to investigate the direct association of dietary magnesium intake and inflammatory marker levels with breast cancer risk among Chinese women and to explore the indirect association of dietary magnesium with breast cancer risk through the modulation of chronic low-grade inflammation (i.e. changes in serum CRP and IL-6 levels).).In this case–control study, 1050 case patients and 1229 control subjects completed a food frequency questionnaire (FFQ). Data on the diet and serum samples of 941 and 1006 of these cases and controls were available, respectively, and 322 cases and 322 controls were randomly selected from them. The serum samples of these selected participants were used to measure serum IL-6 and CRP levels. The IL-6 levels of 312 cases (96.9%) and 302 controls (93.79%) and CRP levels of 315 cases (97.83%) and 307 controls (95.34%) were within the standard curve of the assay, whereas those of the remaining cases and controls were beyond the standard curve . A marginal positive association was observed between the IL-6 level and breast cancer risk when IL-6 levels were categorised into two groups based on the 1.5-pg/mL cut-off value . However, the association became non-significant after adjusting for potential confounders. Compared with participants with CRP values ≤3000 ng/mL (the lower group), those with CRP values >3000 ng/mL (the higher group) had a 1.43 times higher breast cancer risk (95% CI = 1.04–1.97). The association in the adjusted model remained significant with an OR of 1.43 and a 95% CI of 1.02–2.01.The odds ratios (ORs) and 95% confidence interval (CIs) of dietary magnesium intake, IL-6 level, CRP level and overall breast cancer risk are shown in Table The results of the stratified analyses according to menopausal status, BMI and sex hormone status are shown in Table P value in this model was 0.55, indicating that this model could appropriately fit the data. The total effects of magnesium and calcium intake on breast cancer risk were −0.22  and −0.03 , respectively. Direct and indirect effects of dietary magnesium were statistically significant for breast cancer risk with estimates of −0.21 and −0.01, and the CRP level played a mediating role in the association between dietary magnesium intake and breast cancer risk.Table This study showed that dietary magnesium intake was inversely associated with breast cancer risk and that higher CRP level was a risk factor for breast cancer development. Path analysis revealed that the serum CRP level, but not the serum IL-6 level, mediated the association between dietary magnesium intake and breast cancer risk.2. Magnesium deficiency has been found to be involved in both the risk and prognosis of cancers, including breast cancer41. Some studies have focused on the effect of dietary magnesium on the prognosis of breast cancer10. Their results suggest that higher dietary magnesium intake is inversely associated with mortality among breast cancer patients.This study focused on the association between dietary magnesium intake and breast cancer risk because diet is an easy target for intervention. The results showed an inverse association between dietary magnesium intake and overall breast cancer risk. To date, few epidemiological studies have investigated the association between dietary magnesium intake and breast cancer risk. Consistent with our result, an Italian case–control study found that the serum magnesium level was significantly lower among breast cancer patients than among control subjects41. In particular, dietary magnesium has been reported to play a crucial role in the regulation of systematic chronic low-grade inflammation, especially the circulating CRP level18. A meta-analysis including seven cross-sectional studies suggested an inverse association between dietary magnesium intake and serum CRP levels14. Another meta-analysis of 11 randomised controlled trials indicated that magnesium supplementation reduces circulating CRP levels in individuals with inflammation (CRP levels >3000 ng/mL)15. These findings indicate that magnesium intake may play a protective role in the management of inflammation, which may be one of the mechanisms of tumourigenesis. Therefore, the present study also explored how dietary magnesium affects breast cancer risk through inflammation. This was the first study to explore dietary magnesium together with inflammatory markers as the risk factor for breast cancer. The results showed that dietary magnesium intake affected breast cancer risk both directly and indirectly by modifying the CRP level. This result supports the hypothesis proposed in previous experimental studies that the potential beneficial effect of dietary magnesium intake on breast cancer prevention may, at least in part, be explained by the inhibition of inflammation41.Several experimental studies have suggested that magnesium affects tumourigenesis through two mechanisms, namely inflammation and free radicals-induced oxidative stress, both of which may cause DNA damage, subsequently leading to tumour onset43. In particular, IL-6 has been proven to activate NF-κB and STAT3 pathways to facilitate a tumour micro-environment43. However, there is little evidence from observational studies investigating the effect of IL-6 level on breast cancer risk39. Consistent with our result, a combined analysis of two prospective studies revealed no significant relation between the IL-6 level and overall breast cancer risk39. In contrast with our result, a Korean case–control study found that the IL-6 level was significantly higher in breast cancer patients than in control subjects37. Given these contradictory results, more epidemiological studies with larger sample sizes should be conducted to explore the effect of IL-6 level on breast cancer risk.The signalling pathways linked to both STAT3 and NF-κB have been suggested to play important roles in the communication between inflammatory cells and cancer cells45. CRP is a classic inflammatory marker that is highly sensitive to inflammatory response26. Several studies have attempted to investigate the association between the circulating CRP level and breast cancer risk, most of which have reported consistent results52; however, few such studies have been conducted on Chinese populations. To date, four meta-analyses have summarised previous studies51, three51 of which consistently supported a positive association between the CRP level and breast cancer risk as observed in our study. The other meta-analysis including 12 prospective studies suggested a marginal association between the CRP level and breast cancer risk39. A cohort study comprising 17 402 Chinese females showed that women with high CRP levels (>3000 ng/mL) at baseline had a significantly higher breast cancer risk  than women with low CRP levels (<1000 ng/mL)52. Thus, the results of the present study support the hypothesis that high CRP levels (>3000 ng/mL) are a risk factor for breast cancer among Chinese women.Fundamental experiments have revealed that the moderately high levels of pro-inflammatory markers in chronic inflammatory status are responsible for the formation of an inflammatory micro-environment, which affects the process of epithelial–mesenchymal transition56. One plausible reason is that women with more adipose tissue are more sensitive to the effect of inflammation; thus, even if dietary magnesium has only a small anti-inflammatory effect, it is likely to affect breast cancer risk in overweight or obese women.The present study found an inverse relationship between dietary magnesium intake and breast cancer risk among overweight or obese women but not among women with normal weight. It is well-known that obesity is highly correlated with inflammatory response and increased free radical levels58. Differences in the oestrogen biosynthesis mechanisms may account for the different effects of inflammatory marker levels on breast cancer risk between pre- and postmenopausal women61. Dietary calcium intake has been suggested to have an interactive effect with magnesium on breast cancer risk. The protective effect of magnesium on breast cancer was stronger among women with adequate calcium intake than among those with calcium deficiency, although the association was non-significant partially due to the small sample size. Magnesium and calcium belong to the same family in the periodic table and share similar metabolic pathways62. A previous study on postmenopausal women suggested that compared with an adequate magnesium intake, dietary magnesium deficiency increases calcium retention63. The findings on the association between calcium intake and breast cancer risk remain controversial64.Stratified analyses by menopausal status revealed a negative relationship between dietary magnesium intake and breast cancer risk among premenopausal women. Oestrogen is derived mainly from the ovaries in premenopausal women and from aromatase in postmenopausal women; both of these sources have been found to be regulated by pro-inflammatory cytokines in distinct ways66, was not included in the calculation of dietary magnesium values. However, all study participants were natives of Guangdong province or had lived in Guangdong for at least 5 years, indicating that they shared similar water sources. In addition, we collected information about supplements and noted that few patients took magnesium supplements. Thus, magnesium from hard water and supplements may not have significantly affected the result. Third, selection bias and recall bias are inevitable in hospital-based case–control studies. To minimise selection bias, all control subjects were carefully recruited to exclude any diagnosis potentially related to breast cancer or dietary changes. In addition, the relatively high response rate also helped to reduce selection bias. To reduce recall bias, cases were interviewed immediately after breast cancer diagnosis. Moreover, food photographs were used to assist participants with the quantification of dietary intake. Fourth, it should be noted that it was impossible to include all mediators in the path model in which the estimates of direct and indirect effects might be affected. Moreover, the path model was based on the assumption that inflammatory response plays a mediating role, which should occur before the onset of breast cancer. However, this model could not completely avoid inverse causality due to the case–control design of the study. Thus, further prospective studies should be conducted to explore the mediating role of chronic inflammation in the association between dietary magnesium intake and breast cancer risk.To the best of our knowledge, this was the first study to explore the indirect effect of dietary magnesium on breast cancer via its influence on inflammatory marker levels and to assess the association between dietary magnesium intake and breast cancer risk among Chinese women. Despite its strengths, some limitations should be acknowledged. First, the sample size used for measuring inflammatory marker levels was relatively small, which may have affected the power of the test. Second, magnesium from hard water and supplements, which are also regarded as important sources of magnesium conducive to human bodyIn conclusion, this study indicated that a higher dietary magnesium intake was associated with a lower breast cancer risk both directly and, in part, indirectly via reduction in the CRP level. The results also provided evidence of a positive association between the CRP level and breast cancer risk among Chinese women.67. Study cases included patients admitted to the surgical units of the First Affiliated Hospital of Sun Yat-sen University and Guangdong Women and Children Hospital between September 2011 and July 2016 and were recruited based on their fulfilment of the inclusion and exclusion criteria. Patients were included if they were female, 25–70 years old, native of Guangdong province or had lived in Guangdong for at least 5 years and had been diagnosed with incident, primary, histologically confirmed breast cancer no more than 3 months before the study. Patients with a prior history of any cancer or who did not understand or speak Mandarin/Cantonese were excluded. Control subjects without breast cancer were frequency matched by age  to the case patients and were simultaneously recruited from the First Affiliated Hospital of Sun Yat-sen University. The remaining inclusion criteria for control subjects were similar to those for case patients. Control subjects were excluded if they were diagnosed with inflammatory disease, including chronic nasosinusitis, chronic otitis media, chronic tonsillitis or maxillary sinusitis.This hospital-based case–control study was conducted from September 2011 to July 2016, the details of which have been described elsewhereThis study followed the tenets of the Declaration of Helsinki, and all procedures involving humans were approved by the ethical committee of the School of Public Health, Sun Yat-sen University. All participants provided written informed consent for participation in the study before the interview.2). Postmenopausal status was defined as at least 1 year since the last menstrual cycle. Relevant medical information, medical diagnosis, histological findings and ER and PR statuses were obtained from the hospital medical records.During hospitalisation, all participants were interviewed in person by trained interviewers using a structured questionnaire that included questions on demographic information, lifestyle factors , self-reported weight and height, menopausal status, diseases, reproductive history and family history of cancer. Regular smoking was defined as ever smoking at least one cigarette per day for more than six consecutive months. Passive smoking was defined as exposure to second-hand tobacco smoke for at least 15 min per day during the previous year. Regular drinking was defined as drinking alcohol at least once per week during the previous year. Leisure-time physical activity was classified into never, seldom (1 time/week) and often (≥1 time/week). BMI was calculated by dividing weight (kg) by height squared  was used to measure IL-6 levels, and an ELISA kit  was used to measure CRP levels. Serum samples from both cases and controls were subjected to the same tests, run in the same batch of 96 samples , and assayed in a random order to reduce inter-assay variation and systematic bias. The mean intra- and inter-assay coefficients of variation were 4.9 and 6.0% for the IL-6 level and 5.0 and 5.0% for the CRP level, respectively.70, magnesium levels were classified as low (<280 mg/day) or high (≥280 mg/day) based on EARs, and calcium levels were categorised as low (<800 mg/day) or high (≥800 mg/day) based on adequate intake values. According to the Centers for Disease Control and Prevention/American Heart Association criteria, CRP levels were classified as low (≤3000 ng/mL) or high (>3000 ng/mL); this classification was originally created for the risk assessment of cardiovascular disease and has subsequently been used to explore the effect of inflammation on the development of various diseases27. Similarly, IL-6 levels were also categorised as low (≤1.5 pg/mL) or high (>1.5 pg/mL). As no guideline is available for the categorisation of IL-6 levels, the average value among healthy populations obtained from data in the literature was chosen as the cut-off value71. T-test was used to determine the differences in age, age at menarche and age at first live birth between the cases and controls. Wilcoxon rank-sum test was used to evaluate the differences in magnesium, calcium, phosphorus, dietary fibre, energy, carbohydrate, protein, fat, IL-6 and CRP levels between the two groups. Chi-square test was used to compare the categorical variables between the groups. Multiple unconditional logistic regression analysis was used to estimate the OR and 95% CI of the associations between dietary magnesium intake, serum IL-6 level, serum CRP level and breast cancer risk. The groups of participants with the lowest levels were used as reference groups. The values of Model 1 were shown as crude OR and 95% CI. Model 2 was adjusted for age at menarche, BMI, educational level, passive smoking, physical activity, parity, first-degree relative with cancer and history of benign breast disease to investigate the association between magnesium intake and breast cancer risk. Model 3 was further adjusted for the confounders from Model 2 in addition to the intake of energy, fat, calcium, phosphorus and dietary fibre. The associations between IL-6 levels, CRP levels and breast cancer risk were examined after adjusting for passive smoking, BMI, first-degree relative with cancer, history of benign breast disease and income level. Confounders were selected by comparing baseline characteristics between the cases and controls and between the current study and previous studies that evaluated the risk factors for breast cancer. Dietary magnesium intake was also classified into quartiles to explore the dose–response relationship with breast cancer risk, and then, linear trend was evaluated by entering the median value of magnesium intake for each quartile in the multiple regression model. Stratified analyses by menopausal status , sex hormone status , BMI  and calcium intake (<800 mg/day and ≥800 mg/day) were also performed72. The interactive effect was calculated by including an interaction term in the multiple regression model.Based on Dietary Reference Intakes for Chinese residents73. The model evaluation criterion was posterior predictive P value ranging from 0 to 1 with an acceptable quantity of 0.5 or close to it74.Path analyses were performed to investigate whether the inflammatory factors IL-6 and CRP were potential mediators contributing to the associations between dietary magnesium intake, calcium intake and breast cancer risk in Chinese women. Maximum likelihood is the most popular method in path analysis that is based on the assumption of multivariate normality. In this study, Mardia’s coefficient of multivariate kurtosis was 13.66 and the critical ratio was 19.91. Both values less than 1.96 indicated significant non-normality; thus, Bayesian structural equation modelling was used to evaluate the overall presented path analysis, and estimations were conducted based on the Markov Chain Monte Carlo algorithmP values are two sided, and P values of <0.05 were considered as statistically significant. Statistical analyses were performed using SPSS 20.0 and AMOS 17.0.All


Epidemiologic studies have demonstrated a relationship between selenium status and cancer risk among those with low selenium levels. It is of interest to prospectively evaluate the relationship between selenium and cancer among women who reside in a region with ubiquitously low selenium levels.n = 97) and controls (n = 184) were women with no cancer at baseline or follow-up. Serum selenium was quantified using mass spectroscopy.We performed a nested case-control study of baseline serum selenium levels and cancer risk using data and biological samples from 19,573 females that were participants in a biobanking initiative between 2010 and 2014 in Szczecin Poland. Cases included women with any incident cancer (P = 0.007). The risks for women in the two middle categories were similar and suggests that the normal range be between 70 μg/L and 90 μg/L. There was evidence for an increased risk of cancer among women in the highest category of selenium levels , but this association did not achieve statistical significance .The odds ratio associated being below the cutoff of 70.0 μg/L compared to a level above 70.0 μg/L was 2.29 (95% CI 1.26–4.19; Results from this study suggest that suggest that the optimum serum level of selenium in women living in Poland should be between 70 μg/L and 90 μg/L. Selenium is an essential trace element with numerous health-related functions . It has We have previously reported low serum selenium levels in patients with colon, lung and laryngeal cancer in Estonia and Poland, two regions of Europe known to have inherently lower selenium levels compared to North American countries , 14, 15.BRCA1 founder mutations ; as part of the testing protocol, the patients were asked permission to store the residual serum to be included in the biobank. Each subject provided written consent for biobanking for research purposes. Patients were asked to fast for four hours prior to blood collection (10 cc). Blood samples were taken between 8 am and 2 pm and was centrifuged within 30 to 120 min to separate the serum from the cellular fraction. The serum samples were stored at -80o until the selenium assay was conducted. For most patients, blood was taken once, but for some, samples were taken on multiple occasions corresponding to different visits. In the present study, if more than one sample was available, we used the first sample for the selenium assay. A total of 33,062 participated in the biobank of whom 19,573 were women with no previous cancer diagnosis at the time of blood collection.A large biobanking initiative began in 2010 as an adjunct study to complement the clinical records maintained on patients seen at the Cancer Genetic Outpatient Clinic of the University Hospital of the Pomeranian Medical University in Szczecin, Poland. Each patient who attended the outpatient clinic was invited to participate. Patients who attended the clinic were referred by their family doctor or a specialist for the evaluation of cancer risk and for genetic testing, including women at all levels of risk. The vast majority of patients who attended the clinic underwent genetic testing for three Polish BRCA1 mutation.All patients were followed for new cancers through a systematic review of pathology records for incident cancers at the three major cancer hospitals in the Szczecin region. Subjects in the biobank were linked to the records of the pathology department using a unique eleven digit identification number (PESEL). Women at high risk for breast cancer were eligible to be enrolled in a screening protocol which included annual mammography, breast ultrasound, CA125 and trans-vaginal ultrasound. MRI screening was restricted to women with a Study subjects for the present nested case-control study were women at risk for breast cancer who attended the Cancer Genetics Outpatient clinic between 2010 and 2014. Cases were women with any incident cancer identified from among the women enrolled in the biobank who had no history of cancer at the time of the blood draw. For each case, we selected two controls from among those women with no cancer at baseline or at follow-up. Cases and controls were matched on year of birth (within two years), smoking status  and family history of cancer (number of affected first-degree relatives).3 . Calibration curves were created using five different concentrations: 1 μg/l, 10 μg/l, 20 μg/l, 50 μg/l and 100 μg/l. Germanium  was used as an internal standard and ClinChek® Plasma Control Level I  was used as a reference material. Before analysis all samples were centrifuged  and the supernatant was diluted 20 times with 1% Suprapur® HNO3 . Technical details, optimal plasma operating and mass-spectrometer acquisition parameters are available on request.Serum selenium levels were measured by inductively coupled mass spectroscopy  using methane for reduction of polyatomic interferences. Calibration standards were prepared by dilution of 10 mg/l Multi-Element Calibration Standard 3  with 1% Suprapur® HNO2 test or t-test, as appropriate. We created four categories of serum selenium levels based on the distribution of the controls . Given that we had no preconceived notion of the normal or optimal level of selenium, we selected the highest category (> 80–90 μg/L) as the reference level. Unconditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) for any cancer according to selenium category. We also performed a secondary analysis limiting the cases to breast cancer only. Analyses were performed using SAS version 9.2  and all P-values are two-sided.Differences between cases and controls were compared using the χThe cohort of 19,573 eligible women accumulated a total of 57,036 person-years from the date of blood draw until December 31, 2014. For the current nested case-control study, we included 97 women with a cancer diagnosis  and 184 unaffected women . The mean age of the female subjects at the time of blood draw was 48.6 years (range 25 to 93 years)(Table P = 0.19).The distribution of the selenium levels in the 97 cases and 184 controls is presented in Fig. P = 0.01). The odds ratio associated being below the cutoff of 70.0 μg/L compared to a level above 70.0 μg/L was 2.29 . The risks for women in the two middle categories were similar and suggests that the normal range be between 70 μg/L and 90 μg/L. There was evidence for an increased risk of cancer among women in the highest category of selenium levels , but this association did not achieve statistical significance .Selenium was categorized into four categories based on the distribution in the control subjects. A case was much more likely to be in the lowest category of selenium (≤70 μg/L) than a control (30.9% versus 16.3%)(Table P = 0.05). Similarly, there was suggestive evidence for an increased risk of breast cancer among women with a selenium levels above 90 μg/L .Findings were similar when the analysis was limited to breast cancer cases Table . Women iBRCA1 mutation and those with a mutation were excluded. Only 15% of the study subjects had a first-degree relative with breast cancer. Furthermore, the number of observed cases of breast cancer did not exceed the expected number (53 versus 69); however, it is possible that in our follow-up scheme that not all new cases of breast cancer were identified particularly if they were treated in a hospital outside of the Szczecin region.The results of this nested case-control study of 281 women residing in Szczecin, Poland suggests that low serum selenium levels (≤ 70 μg/L) are associated with a statistically significant two-fold increase in cancer risk. Findings were similar in an analysis restricted to breast cancer. Breast cancer was the most commonly diagnosed cancer in this cohort of women; however, most of these women were not at increased risk given that all the particpants had been tested for a Of interest is the potential U-shaped relationship between selenium status and cancer risk. Although not statistically significant, there was suggestive evidence for an increased risk of cancer among those women in the highest category of serum selenium levels . A similar U-shaped relationship has previously been reported between selenium status, cancer incidence and all-cause mortality , 16, 17., suggested that individuals with blood selenium levels of 122 μg/L should not be supplemented [With respect to breast cancer, prospective studies have generally reported no association between blood or toenail selenium levels and risk , 20–23. Because of this geographic variability in soil selenium levels, dieteray intake in Europe tends to be lower than in the United States , 24. UsiThere are several strengths of our study including the large number of unaffected women enrolled in the biobanking inititive, complemented by the collection of detailed individual participant information and fasting blood samples. We were able to assess serum selenium status which reflects short-term selenium exposure and is an accurate assessment than dietary intake which is heavily influenced by the selenium content in the soil , 27. PreThe results of the current nested case-control study suggests that the optimum level of serym selenium in women living in Poland should be between 70 μg/L and 90 μg/L and among women with low selenium levels, supplementation may easily achieve a selenium level within in this range. Approximately one third of Polish women have a level of selenium below 70 μg/L . HoweverThe data presented here are observational and cannot be used to infer causality but suggest that further studies - including potentially a randomized trial - are rational. It is also important to determine to what extent selenium levels in a woman are stable over time and if the monitoring of levels after supplementation is recommended. The observation of an increased risk among women with high selenium levels is intriguing and suggests that caution need be applied to keep the selenium level between 70 and 90 μg/L. It is important that these observations be expanded in Poland and replicated in other cohorts. Our on-going follow-up of this population of women will help confirm these findings and define a safe and accuratre level of supplementation for women living in Poland.