These results are the first to identify that CRF may protect the brain health of breast cancer survivors within 3 years of treatment. The present study uniquely contributes to the field of cancer and cognition and emphasizes the importance of investigating how individual differences in CRF play a role in brain changes of breast cancer survivors.As breast cancer treatment is associated with declines in brain and cognitive health, it is important to identify strategies to enhance the cognitive vitality of cancer survivors. In particular, the hippocampus is known to play an important role in brain and memory declines following cancer treatment. The hippocampus is also known for its plasticity and positive association with cardiorespiratory fitness (CRF). The present study explores whether CRF may hold promise for lessening declines in brain and cognitive health of a sample of breast cancer survivors within 3 years of completion of primary cancer treatment. We explored the role of cardiovascular fitness in hippocampal structure in breast cancer survivors and non-cancer female controls, as well as performed a median split to compare differences in hippocampal volume in relatively higher fit and lower fit cancer survivors and non-cancer controls. Indeed, CRF and total hippocampal volume were positively correlated in the cancer survivors. In particular, higher fit breast cancer survivors had comparable hippocampal volumes to non-cancer control participants (Cohen’s  Breast cancer treatment is associated with declines in brain and cognitive health  and aerobic exercise are known to positively contribute to neural plasticity of the hippocampus in humans. That is, younger and older healthy humans with higher CRF levels have larger hippocampal volumes , such that breast cancer survivors with higher CRF would have comparable hippocampal volume to that of non-cancer control participants. We explored anterior and posterior subsections of the hippocampus to examine whether breast cancer status, and/or CRF, had selective effects on brain structure in breast cancer survivors. We also hypothesized that larger hippocampal volumes would be associated with better memory performance on a task that required the maintenance of a flexible and dynamic map of spatial information, a task considered to be dependent on the hippocampus . Furthermore, participants with a history of stroke, transient ischemic attack, surgery that involved removal of brain tissue, a score ≤23 on the modified Mini-Mental Status Exam (MSSE), or current use of computer-based brain training games  were excluded. The study was approved by the University of Illinois Institutional Review Board, and all participants provided informed consent. All participants also provided written consent from a physician prior to study enrollment indicating clearance to participate in both the CRF, cognitive, and MRI testing. The present study included 29 female breast cancer survivors  and 27 female controls .2 peak  protocol with 192 contiguous axial slices, collected in ascending fashion parallel to the anterior and posterior commissures, echo time (TE) = 2.32 ms, repetition time (TR) = 1900 ms, field of view (FOV) = 230 mm, acquisition matrix 256 mm × 256 mm, slice thickness = 0.90 mm, and flip angle = 9°. All images were collected on a Siemens Magnetom Trio 3T whole-body MRI scanner.Segmentation and volumetric analysis of the hippocampus were performed using a semi-automated, model-based subcortical tool  in FMRIB’s Software Library (FSL) version 4.1.9 . The volume of each participant’s brain region was measured in mm3 and converted to cm3 for presentation.A two-stage affine registration to a standard space template (MNI space) with 1 mm resolution using 12-degrees of freedom and a subcortical mask to exclude voxels outside the subcortical regions was first performed on each participant’s MPRAGE. Next, the hippocampus was segmented with 30 modes of variation. To achieve accurate segmentation, the FIRST methodology models 317 manually segmented and labeled T1-brain images from normal children, adults, and pathological populations  as a point distribution model with the geometry and variation of the shape of each structure submitted as priors. Volumetric labels are parameterized by a 3D deformation of a surface model based on multivariate Gaussian assumptions. FIRST searches through linear combinations of shape modes of variation for the most probable shape  given the intensity distribution in the T1-weighted image, and specific brain regions are extracted . Hippocampal amnesics have been found to show more “swaps” on this task, thereby failing at binding item identities to locations  a lower fit breast cancer group with CRF levels lower than, and including, the median; and (2) a higher fit breast cancer group, with CRF levels above the median. A median split analysis was also conducted for the non-cancer control group to create a lower fit and higher fit control group.Univariate ANCOVAs were conducted to compare hippocampal volume and memory performance as a function of group , with age as a covariate. Given the small sample size and exploratory nature of this study, we explored associations between CRF and hippocampal volume stratified by group. We also performed a median split based on fitness level in the cancer participants and control participants to compare hippocampal volumes between the higher fit and lower fit cancer survivors and the non-cancer controls using independent d) were calculated and reported . The following was the formula used to calculate the Cohen’s d: d = (Mean1−Mean2)/SDpooled, SDpooled is the pooled standard deviation for the samples Effect sizes . On average, the participants were 17 ± 9 months off-therapy (range = 2–33 months). Survivors were all disease and relapse free at the time of evaluation. We also included 27 non-cancer female controls. There were no significant differences between the groups in terms of age (range = 41–73 years), years of education, CRF or MSSE  breast cancer who underwent surgery, adjuvant chemotherapy treatment and/or radiation treatment  between specific cancer treatment groups. Breast cancer survivors had significantly smaller volumes in the left posterior hippocampus compared to non-cancer control participants  = 5.48, p = 0.02; when controlling for age, which was associated with hippocampal volume, r = −0.273, p = 0.04). No group differences were found for anterior hippocampal volumes  or total hippocampal volume  = 2.78, p = 0.10).All hippocampal volumes for breast cancer survivors and non-cancer control participants are shown in Table t(56) = 1.2, p = 0.2). An examination of the means suggest more “swaps” in the cancer patients  compared to control participants . Additionally, more “swap” memory errors were associated with smaller left posterior hippocampal volumes . Within condition analyses indicated that this relationship remained significant in the cancer survivors , but not the control group . Lower fit cancer survivors showed significantly smaller hippocampal volumes than higher fit control participants—in terms of total hippocampal volume (t(26) = 2.80, p = 0.010), anterior hippocampal volume (t(26) = 2.65, p = 0.014), and posterior hippocampal volume (t(26) = 2.79, p = 0.010). Lower fit cancer survivors also showed significantly smaller left posterior hippocampal volumes compared to lower fit control participants (t(27) = 2.39, p = 0.024). An effect size (Cohen’s d) of 0.87 suggested a large effect for the difference in total hippocampal volume between lower fit cancer survivors and control participants, with a negligible effect size (Cohen’s d = 0.13) for the difference in total hippocampal volume between higher fit cancer survivors and control participants.Next, we compared the hippocampal volumes of dichotomized higher fit and lower fit cancer survivors to the higher fit and lower fit control participants Table . As predr = −0.024, p = 0.9) or control participants . Additionally, higher fit and lower fit cancer survivors did not differ from higher fit and lower fit control participants in terms of “swaps” , smaller left posterior hippocampal volumes were associated with poorer memory performance on a spatial learning task of hippocampal function  suggest the importance of investigating how individual differences in CRF play a role in brain changes of breast cancer survivors. The results also parallel animal research demonstrating that wheel running following chemotherapy or radiation (one week to one month post-treatment) restores hippocampal brain health  have been found to show impaired CRF  across the survivorship continuum (Jones et al., Future work may also investigate how CRF moderates other structural and functional brain changes following cancer treatment. In addition to changes in hippocampal volume following cancer treatment, post-treatment declines in gray matter volume (de Ruiter et al., In conclusion, the present study is the first to identify that CRF holds promise for improving the brain health of breast cancer survivors within 3 years of completion of treatment. Our findings also support further research on the inclusion of physical activity, aimed to improve CRF, in treatment protocols for breast cancer survivors.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.


P=0.024). We analyzed the relationship between adiponectin and breast cancer risk in 6 subgroups. Higher circulating HMW adiponectin was also negatively associated with breast cancer risk  in the subgroups of postmenopausal women, negative family history of breast cancer, BMI>=24.0. Total adiponectin was positively associated with breast cancer (P=0.028) in the subgroup of BMI<=24.0. Higher HMW/total adiponectin ratio was negatively associated with breast cancer (P=0.019) in the subgroup of postmenopausal women. Interestingly, in the subgroup of women with family history of breast cancer, higher circulating total and HMW adiponectin were positively associated with breast cancer risk . This study showed different forms of circulating adiponectin levels might play different roles in breast cancer risk. A higher circulating HMW adiponectin is associated with a decreased breast cancer risk, especially in postmenopausal, without family history of breast cancer or BMI>=24.0 subgroups, whereas higher circulating HMW adiponectin levels is a risk factor in women with a family history of breast cancer. Further investigation of different forms of adiponectin on breast cancer risk is needed.The level of total adiponectin, a mixture of different adiponectin forms, has been reported associated with breast cancer risk with inconsistent results. Whether the different forms play different roles in breast cancer risk prediction is unclear. To examine this, we measured total and high molecular weight (HMW) adiponectin in a case-control study (1167 sets). Higher circulating HMW adiponectin was negatively associated with breast cancer risk after adjusting for menopausal status and family history of breast cancer ( Breast cancer is the most common cancer and the leading causes of cancer death among women worldwide. The latest World Health Organization (WHO) statistics show that there were 1.67 million new breast cancer cases diagnosed in 2012, which comprised 25% of all cancers diagnosed that year. In factAdiponectin, an obesity-related protein, has been reported to be associated with obesity, metabolic syndrome, and several types of cancer, including breast cancer. Adiponectin is an adipokine secreted exclusively by adipocytes and exhibits insulin-sensitizing, inflammatory-related, antiatherogenic, proapoptotic, and antiproliferative properties–7. ThreeInterestingly, results from previous epidemiologic studies for the association between adiponectin and breast cancer risk have been inconsistent, with the reason unknown. For example, in three meta-analyses regarding the relationship between adiponectin levels and breast cancer risk published in the last two years, one suggested that low circulating adiponectin levels were associated with an increased breast cancer risk, whereasHere, we hypothesized that HMW adiponectin or the HMW/total adiponectin ratio, but not total adiponectin, associated with risk of breast cancer, which may partly explain the inconsistent results from literature. To test our hypothesis, we did a large 1:1 case-control study of 1167 cases from 21 hospitals from northern China. We investigated plasma total adiponectin, HMW adiponectin and the HMW/total adiponectin ratio, and their association with breast cancer risk in the context of other known risk factors.We recruited female patients from 21 hospitals in 11 provinces in northern and eastern China from April 2012 to April 2013. The inclusion criteria for breast cancer cases were: (1) newly diagnosed and histologically confirmed breast cancer; (2) Han ethnic group; (3) age 25 to 70 years old. For the control group, the following criteria were used: (1) physical examination results were negative; (2) ultrasound scans of breast and/or mammographic screening results were negative; (3) matched age with the cases (±3 years); (4) women who had been hospitalized or had a regular physical examination in the same hospital with matched case in the same time period (±2 months); (5) no evidence of cancer or history of cancer; (6) Han ethnic group. Anyone who had a neoplastic disease at any other site, history of cancer, or other major chronic disease, was excluded from the study. Cases and controls were matched based on age, hospital, and timing of examination at 1:1 ratio. There were 1167 case-control sets included in this study.The study protocol and procedures were approved by the Institutional Review Boards at the Second Hospital of Shandong University. All participants have provided their written informed consent.Data on breast cancer risk factors was obtained by in-person interviews based on a self-designed structured questionnaire. The questionnaire contained six aspects: (1) demographic characteristics and female physiological and reproductive factors, such as age, height, weight, age at menarche, age at menopause; (2) medical and family history: primarily, breast-related diseases and family history of breast cancer; (3) lifestyle habits: smoking (including passive smoking), alcohol intake, dietary habits; (4) medication and chemical exposure history: hair dyes, antidiabetic agents; (5) breast cancer-related knowledge: risk factors for breast cancer, early signs and symptoms of breast cancer; (6) medical record: specifically, information gathered from the clinical breast examination, which included the results from visual examination, palpation and related diagnostic tests. The histological and immunohistochemical diagnosis of breast cancer patients were also collected from the medical recordPeripheral blood samples were obtained after fasting at least 8 hours early in the morning. Blood samples of the cases were obtained pre-operation and pre-therapeutic intervention, including neoadjuvant chemotherapies, radiation ad hormone therapies.After excluding subjects with inadequate information or samples, 1167 sets of cases and controls met our inclusion criteria .Total and HMW adiponectin levels were assayed from plasma using a human total adiponectin and HMW adiponectin quantitative ELISA kits with sensitivity of 0.079–0.891ng/ml, 0.086–0.989ng/ml, respectively . Each sample was assayed twice and the average of the data was used. No samples were below the detection limits. All analyses were performed at the Central Research Laboratory, the Second Hospital of Shandong University  according to the manufactory recommended protocols. Data were collected in an case-control status blind manor.P-values of continuous variables were determined by Student’s t-tests and the P-values of categorical variables were determined by Chi-Square tests. HMW adiponectin level, HMW/total adiponectin ratio were divided into two class based on a cut-off value as described below. The odds ratio (ORs) and 95% confidence intervals (CIs) were obtained by using single and multiple binary logistic regression analyses. The models were adjusted for BMI, age, diabetes mellitus, age at menarche, etc. All P-values were two-sided and P<0.05 was considered significant.All statistics except the ROC curve were performed by SAS Statistical Software , and the ROC estimate were calculated through MedCalc. Descriptive characteristics of the group variables are expressed as mean . The J), one of the main summary statistics of the ROC curve, defines the maximum potential effectiveness of a biomarker. J can be formally defined as J = maxc{SE (c)+SP (c)-1}. The cut-off value that achieves this maximum is referred to as the optimal cut-off point that optimizes the biomarker’s discriminating power when the sensitivity and specificity bear equal weight[The cut-offs for the total adiponectin, HMW adiponectin and HMW/total adiponectin ratio were assessed for the overall and corresponding subgroup by receiver operating characteristic (ROC) curve analysis, in which the sensitivity (SE) is plotted as a function of 1-specificity (1-SP). The Youden Index  of cases is 47.65 (±8.65); the mean age (±SD) of controls is 46.72 (±8.77). The characteristics of cases and controls were shown in P = 0.016). In addition, the circulating total and HMW adiponectin levels were significantly lower in controls compared to cases among those women with a family history of breast cancer .We evaluated the status of circulating adiponectin levels and the different subgroups as a continuous number factors  to furthJ: 0.039) significantly discriminated the cases from controls  after adjusting for menopause and family history of breast cancer (J: 0.091) significantly discriminated the cases from controls  (J: 0.048) significantly discriminated the cases from controls after adjusting for menopausal status  (J: 0.201) significantly discriminated the cases from controls   (J: 0.095) significantly discriminated the cases from controls   was 0.515 and the cutoff value of 1.42 μg/ml of HMW adiponectin (t cancer . In the 7–0.947) . In the 0–0.935) . In the 2–8.486) . In the 5–0.982) . Only in6–0.944) .ADIPOQ could affect the formation of HMW adiponectin, which resulted in impairment of its complement activation which means that some mutation of ADIPOQ might affect the circulating level of HMW adiponectin and its biological function[ADIPOQ may be the true relationship between HMW adiponectin and breast cancer risk for women who have positive family history of breast cancer in China. The number of women who have family history of breast cancer in this study is only 121/2334 , which also limits the power of our analysis. Further studies are needed to confirm the relationship between HMW adiponectin and breast cancer risk especially in women who have a family history of breast cancer in China.In the present study we have demonstrated the value of measuring circulating HMW adiponectin in breast cancer. Our results show that higher HMW adiponectin level is negatively associated with breast cancer risk in Chinese women. This association is independent of menopausal status and family history of breast cancer. This is in accordance with the result of a case-control investigating pheochromocytoma. Higher  function. CertainThe mechanisms of how HMW adiponectin impact the risk of breast cancer is not clear. With respect to inflammatory-related responses, HMW adiponectin is responsible for proinflammatory actions, whereas LMW adiponectin is responsible for anti-inflammatory actions. More imADIPOQ, which is considered to be the key amino acid for the formation of HMW adiponectin[Similarly, we also show the value of the HMW/total adiponectin ratio in breast cancer risk. We found that a higher HMW/total adiponectin ratio is a protective factor of breast cancer in postmenopausal women. One possible explanation for the observed changes in the HMW/total adiponectin ratio could be due to polymorphisms in Cys36 of iponectin,22. The iponectin. In addiiponectin,28. DespThe results possibly explain the inconsistent epidemiologic results that HMW adiponectin or HMW/total adiponectin ratio may be the real factor related to breast cancer risk, not the total adiponectin complex, and implicate differing pathways toward carcinogenesis, especially in special subgroups of individuals.ADIPOQ polymorphisms are necessary. In addition, due to differences between risk factors between ethnicities, our findings derived from a Han Chinese population, may not generalize to other ethnic groups.In conclusion, we found that different forms of circulating adiponectin levels may play different roles in breast cancer risk. Higher circulating HMW adiponectin is associated with a decreased breast cancer risk in Chinese women, especially in postmenopausal, without family history of breast cancer or BMI> = 24.0 subgroup. Whereas higher circulating HMW adiponectin levels is a risk factor in women with a family history of breast cancer. Higher HMW/total adiponectin ratio is a protective factor of breast cancer in postmenopausal women. Our data provides additional evidence for a biological link between menopausal status, hereditary factor, BMI and breast cancer, suggesting an independent role of different circulating adiponectin in the carcinogenesis of breast cancer. In addition, because circulating adiponectin can be influenced by a number of behavioral and drug interventions, such as fruit, weight loss, the observation in this study may help guide a preventive strategy for breast cancer–31. FurtS1 Table(DOCX)Click here for additional data file.


Physical exercise and healthy dietary habits are recommended to prevent breast cancer.Increased intake of omega-3 fatty acids associated with decreased omega-6 - resulting in higher omega-3 to omega-6 ratio compared with Western-type diet - is inversely associated with breast cancer risk. The modernized Mediterranean diet with high omega-3 to omega-6 ratio, high fiber and polyphenol intake, and consumption of low-glycemic index foods reduces overall cancer risk and specifically breast cancer risk. It has been suggested that consuming no more than one alcoholic drink per day, preferably wine, is preferable. Eliminating environmental contaminants, including endocrine disruptors, and favoring organic foods to increase polyphenol intake and the omega-3 to omega-6 ratios were also shown to be beneficial. Cholesterol-lowering statins may decrease antitumor defenses; are toxic for the mitochondria; decrease the omega-3 to omega-6 ratio; increase body mass index, insulin resistance and diabetic risk; and have been associated with an increased breast cancer risk.Therefore, as well as making lifestyle changes to decrease breast cancer risk, we argue that physicians should carefully consider (and often avoid) therapies that may increase breast cancer or diabetes risk in high-risk women and women who wish to decrease their breast cancer risk. Breast cancer (BC) remains a leading cause of death from cancer and a scientific challenge for the medical community . One criIncreasing protective factors is critical, in particular among high-risk women . The effet al. did in their recent study [As both n-3 and n-6 may contribute to BC risk individually (but in opposite directions), they may introduce confusion in their respective analyses. Thus, when analyzing the associations between n-3 and BC risk, it is critical that n-6 is included in the analyses. This is what Yang nt study . They usnt study .Thus, all the factors influencing the n-3/n-6 ratio are critical in BC risk . IncreasCYP1A1 have been studied concerning their potential implication on BC. A recent meta-analysis pointed to the A2455G G allele as a risk factor for BC among subjects of Caucasian origin [CYP1A1 polymorphisms as a potential marker of genetic predisposition to BC. In this context it is critical to recall that endocrine disruptors - such as phthalates - increase insulin resistance, diabetes and obesity [Organic plant foods contain more polyphenols than similar conventional foods -24 and on origin . Thus, f obesity -35, all In the next section, we examine the critical importance of two major factors in breast cancer risk. One is protective (the modernized Mediterranean diet) whereas statins increase risk. The effects of both can be more easily understood at the light of the factors analyzed in the “Background” section.ex nihilo cancers and more likely to be dormant cancers clinically exposed by the treatment being investigated. As the process requires a minimal length of exposure, premature termination is the best way of avoiding the cancer issue in relation to any investigated drug. However, this process leads to confusion and prevents clarification of whether the investigated drug may increase cancer risk in the non-selected general population in whom the drug is then prescribed without precaution by unaware physicians. Despite this, a meta-analysis of clinical trials published in 2006 found a 33% increase in BC incidence with statins compared with a placebo [Other substances that influence both n-3/n-6 ratio and BC risk are the cholesterol-lowering statins. The effect of statins on cancer risk is a long story and still today there is no consensus -38. The  placebo . It is n placebo , suggest placebo . In viewIn general, meta-analyses of observational studies reported no association between statin use and BC incidence. However, since high cholesterol may reduce cancer risk (see below), and as patients taking statins have spent most of their lives with high cholesterol - which is thought to lower cancer risk  - observThe next question is whether there are biological explanations for the effect of statins on BC risk. First, statins interfere negatively with the metabolism of n-3 and n-6 - that is, they decrease the n-3/n-6 ratio -48 - whiRecently, investigators curiously claimed that hypercholesterolemia is a risk factor for BC and that lowering circulating cholesterol levels (or interfering with its conversion to 27-hydroxycholesterol) may be a useful strategy to prevent and/or treat BC . HoweverThus, statins may increase BC risk through increased insulin resistance and new-onset diabetes, decreased n-3/n-6 ratio, cholesterol lowering, mitochondrial toxicity and an immunomodulatory effect. Statin use also results in skeletal muscle toxicity and decreased physical activity -58. For Regarding diabetes risk, increased fiber intake and consumption of flavonoids and n-3 are all inversely associated with diabetes risk -82. In lFinally, consumption of foods with a low glycemic impact - that is, foods with a low glycemic index (GI) - is associated with lower risks of diabetes ,88 and Bp = 0.003) [The Mediterranean diet, the traditional dietary habits of people living around the Mediterranean Sea, is a well-known healthy dietary pattern . A moder= 0.003) . There w= 0.003) . More sp= 0.003) , specifi= 0.003) , gastric= 0.003) , colorec= 0.003) , hepatoc= 0.003) , prostat= 0.003)  and brea= 0.003) -109. Thi= 0.003)  and on t= 0.003) ,111 and = 0.003) ,113, bot= 0.003) -72. Also= 0.003) . Finally= 0.003) -117, whi= 0.003) .The only limitation regarding the prevention of BC through adherence to the Mediterranean diet regards alcohol consumption. Moderate wine drinking is indeed a component of the traditional Mediterranean diet . HoweverAdhering to a healthy dietary pattern, specifically the modernized Mediterranean diet ,94, shouIn the context of the Mediterranean diet, it is critical to increase plant and marine n-3 and decrease plant and animal n-6. High flavonoid consumption - which increases marine n-3 -18 - shoNational and international guidelines recommend healthy diet and physical activity to decrease BC risk . We agreBC: breast cancer; GI: glycemic index; n-3: omega-3 fatty acids; n-6: omega-6 fatty acids; PCB: polychlorinated biphenyls.The authors declare that they have no competing interests.MdeL drafted the manuscript. PS critically revised the manuscript and gave final approval for publication. Both authors read and approved the final manuscript.


The role of alcohol and breast cancer risk in Asians has not been well studied. Recent studies suggest that even moderate alcohol intake may be associated with an increase in breast cancer risk, and this may be particularly relevant as alcohol intake is traditionally low among Asians.We investigated the association between lifetime alcohol intake  and breast cancer in a population-based case-control study of 2,229 Asian Americans diagnosed with incident breast cancer and 2,002 matched control women in Los Angeles County. Additionally, we examined the relation between current alcohol intake and serum concentrations of sex-hormones and growth factors in a subset of postmenopausal control women.P < 0.001) and almost twice as common in Japanese- than in Chinese- and Filipino-Americans (P < 0.001). Breast cancer risk increased with increasing alcohol intake among US-born Asian Americans; the odds ratios (ORs) per 5 grams per day and per 10 years of drinking were 1.21  1.00 to 1.45) and 1.12 , respectively. Regular alcohol intake was a significant risk factor for Japanese-, but not for Chinese- and Filipino-Americans. Current consumers compared with nondrinkers showed lower concentrations of insulin-like growth factor binding protein 3 (P = 0.03) and nonsignificantly higher concentrations of estrone and androgens.Regular lifetime alcohol intake was significantly higher in US-born than non-US-born Asian Americans (Regular lifetime alcohol intake is a significant breast cancer risk factor in US-born Asian Americans and Japanese Americans, emphasizing the importance of this modifiable lifestyle factor in traditionally low-risk populations. High consumption of alcohol has been associated consistently with an increased risk of breast cancer in studies conducted primarily among women of European ancestry . The rolWe recently completed a large population-based case-control study of breast cancer among Asian-American women in Los Angeles County (LAC) in which detailed information on lifetime alcohol intake  was collected. We investigated the relation between alcohol intake and breast cancer risk separately by Asian ethnicity , nativity , and by Asian ethnicity and nativity. We also examined the interrelations between alcohol intake, smoking status, body size, use of hormone therapy , and various dietary factors on breast cancer risk in LAC Asian-American women.The study population and methods used in this population-based case-control study have been described previously . In brieCases and controls were interviewed in person by trained multilingual interviewers by using a standardized, structured questionnaire. In brief, the questionnaire elicited information on race/ethnicity, migration history, education, family history of cancer, menstrual and reproductive histories, use of exogenous hormones, smoking history, lifetime physical-activity patterns, birth weight, and height and weight history. We used two separate measures to assess alcohol intake. In the beginning of the interview, by using a quantitative food-frequency questionnaire (FFQ) that was modeled after the validated diet instrument used in the Multiethnic Cohort Study in Hawaii and Los Angeles , we askeVariables on body size, use of menopausal hormones, diabetes, selected dietary factors, and dietary pattern have been reported in the first group of study participants  -11. The Blood specimens were collected from interviewed breast cancer cases and control women at the end of the interview. We conducted a cross-sectional study among a subset of postmenopausal control women in which sex hormones and growth factors were measured. Methods used to measure these biomarkers have been published in our previous studies -12. In bIn total, 2,229 cases and 2,002 controls with complete information on lifetime alcohol intake and the covariates included for adjustment were included in this study . For drinkers, the number of grams of ethanol consumed per day was estimated by multiplying the number of drinks of each specific type of alcohol consumed per week by the appropriate number of grams of ethanol per drink, and then summing across the type of alcohol and dividing by seven. Ethanol values attributed to a 12-oz serving of beer, 4-oz serving of wine, 1-oz serving of sake, and 1.5-oz serving of hard liquor were 13, 11, 4, and 14 grams, respectively.P values by conditional logistic regression methods, with matched sets defined jointly by reference age , and specific Asian ethnicity . All regression models included the following covariates: birthplace and years of residence in the United States among non-US born , education , interviewer, age at menarche , parity , current body mass index (BMI (kg/m2); quartiles of controls), years of regular  recreational physical activity , total calories (continuous), intake of soy (quartiles), green tea , and black tea , menopausal status , age at menopause , and family history of breast cancer. We conducted case-control comparisons for all subjects combined, and separately by Asian ethnicity , nativity , and by the six Asian ethnic/nativity groups, and menopausal status. To examine the potential effect modification of smoking, BMI, soy intake, folate intake, and use of menopausal hormones on association with alcohol and breast cancer, we separately constructed interaction terms between these factors and alcohol intake and used likelihood-ratio tests to assess the significance of these interaction terms. We used analysis of variance (ANOVA) and analysis of covariance (ANCOVA) to assess the relations between alcohol intake and serum hormone levels and other biomarkers in a subgroup of control women after adjusting for age, Asian ethnicity, migration history, education, age at menarche, parity, and current BMI. Hormone and other biomarker measurements were transformed logarithmically to achieve approximate normal distributions for statistical analysis. We evaluated whether the geometric mean of hormone and other biomarker levels differed by current drinking status. P values less than 0.05 are considered statistically significant, and all P values quoted are two-sided. All analyses were performed by using the EPILOG statistical software system  and the SAS statistical software .We calculated odds ratios  and their corresponding 95% confidence intervals (CIs) and P < 0.0001). The percentage of current drinkers was highest in Japanese women (33.3%), intermediate in Chinese (21.9%), and lowest in Filipino (18.3%) (P < 0.0001). The percentage of current drinkers was also higher in US-born Asians (29.2%) than in non-US-born Asians (21.8%) (P = 0.0005). However, among current drinkers, no significant differences were found in the frequency of drinking (times per year) or average amount of alcohol consumed per day by Asian ethnicity, by nativity, or by Asian ethnicity and nativity combined. Lifetime alcohol-intake (defined as at least weekly for 6 months or 26 times per year) patterns also differed between the six Asian ethnic-nativity groups (P < 0.0001). Regular lifetime alcohol drinking was almost twice as common in Japanese (26.7%) compared with Chinese (13.7%) and Filipino (14.1%) control women (P < 0.0001). The percentage of regular lifetime drinking was higher in US-born Asians (24.2%) compared with non-US-born Asians (14.5%) (P < 0.0001). However, among regular drinkers, no significant differences were found in the amount and duration of drinking between the three Asian groups or between US-born and non-US-born Asian Americans.Table P = 0.062) and increased with increasing frequency of drinking (P trend = 0.053). The risk per 5 g/day of intake was 1.32 . In US-born Filipino women, breast cancer risk was nonsignificantly elevated in association with current alcohol intake .Current alcohol intake was unrelated to breast cancer risk in all subjects combined . However, risk patterns differed by Asian ethnicity and nativity Table . In ChinP trend = 0.022). Breast cancer risks in non-US-born Japanese and US-born Filipinos were similarly increased in association with lifetime alcohol intake; the OR per 5 g/day of alcohol intake was 1.23 (0.86 to 1.77) and 1.90 , respectively.Results on breast cancer risks in relation to lifetime alcohol intake are shown in Table P trend = 0.048), whereas the corresponding OR was 0.91  in non-US-born women (P interaction = 0.12). The risk estimates did not differ significantly within each of the three Asian ethnic groups by nativity. The OR per 5 g/day of lifetime alcohol intake in Japanese, Chinese, and Filipino women was 1.21 , 0.95 , and 0.85 , respectively . None of the other factors significantly modified the alcohol/breast cancer association in Japanese Americans. Results were similar when we investigated the alcohol/breast cancer associations by potential modifiers in US-born Asian Americans (data not shown).We investigated the relation between lifetime alcohol intake and breast cancer risk in Japanese Americans by various potential modifiers, including smoking (never versus ever), intake of soy and folate, BMI, and use of menopausal hormones  Table . The inc+) tumors but not among those with ER negative (ER-) tumors. Alcohol intake was positively associated with both PR+ and PR- breast cancer, although the findings were statistically significant only for those with PR+ tumors. Further analysis by ER and PR status combined showed that increased risks were found among Japanese-American women with ER+/PR+ tumors and those with ER+/PR- tumors. The risk associated with 10+ years of drinking was 1.56 (P trend = 0.034) for ER+/PR+ tumors and 3.43 (P trend = 0.02) for ER+/PR- tumors. No increased risk was found for those with ER-/PR- tumors. The alcohol/breast cancer associations by hormone-receptor status in US-born Asian Americans (data not shown) were generally similar to the risk patterns observed in Japanese Americans.Table P = 0.03), but differences in IGF-1 levels were not observed. Current alcohol consumers  showed 10% to 16% higher levels of estrone and androgens  than did nondrinkers, but these differences were not statistically significant. Current alcohol drinkers also showed borderline statistically significantly higher (17% to 19%) concentrations of SHBG (P = 0.09) and adiponectin (P = 0.10) than did nondrinkers.Table To our knowledge, this represents one of the most comprehensive analyses of lifetime alcohol intake and breast cancer risk in large numbers of Asian Americans that considered frequency, amount, duration, timing, and types of alcoholic beverages. Our results emphasize the heterogeneity of the Asian-American population and the need to study breast cancer risk factors separately by Asian ethnicity and by nativity. Regular lifetime alcohol intake is a significant risk factor in US-born Asian Americans but not in non-US-born Asian Americans. Our results by Asian ethnicity show that the prevalence of lifetime alcohol intake is significantly higher in Japanese than in Chinese and Filipino women Table  and thatIn a population-based case-control study that we and colleagues conducted in the 1980s, alcohol intake was unrelated to breast cancer risk in Chinese, Japanese, and Filipino Americans residing in California and Hawaii  for ever drinking, defined as at least one drink per year) . The perIn a cohort study conducted among multiethnic health-care enrollees at Kaiser Permanente, breast cancer risk in Asian Americans was significantly increased among regular alcohol consumers. Compared with Asians who were nondrinkers, the RRs among consumers of less than one drink per day, one to two drinks per day, and more than three drinks per day were 1.0 , 1.3 , and 3.5 , respectively, but this study also lacked information on the prevalence of drinking, other parameters of drinking, and the composition of Asians that were investigated .Reasons for the significant effect of alcohol intake on breast cancer risk in Japanese Americans but not in Chinese and Filipino women are not apparent but may be related, in part, to the higher prevalence of alcohol intake among Japanese women in Asia and in the United States. Misclassification of alcohol intake cannot be ruled out, and this may be particularly relevant among non-US-born Asians, who were more likely to report increases in alcohol intake after migration (data not shown). Lifetime alcohol intake was unrelated to breast cancer risk for Chinese women in LAC, in agreement with findings from population-based case-control results from Shanghai, China ,16. Althet al. [Results on alcohol intake and breast cancer risk in Japan are mixed with null findings in most of the hospital-based case-control studies . Althouet al.  and the et al.  Cohorts,et al. . Similaret al. . It is oet al.  and withet al. -24.All types of alcoholic beverages are implicated in our study. Most previous studies on alcohol intake and breast cancer risk conducted in Western populations did not find significant differences by type of alcoholic beverages  ,26,27.Although several risk factors  have been implicated as potential modifiers of the alcohol/breast cancer association ,28-30, t+, PR+, and ER+PR+ tumors, which are consistent with the results reported in other studies conducted in Western populations [+/PR- was particularly prominent and is supportive of findings reported in the Nurses' Health Study and a study in Shanghai, China [In our study, the alcohol/breast cancer associations in Japanese Americans and US-born Asian Americans were statistically significant for women with ERulations ,32. Intei, China ,16.A favored hypothesis is that alcohol intake is associated with increases in sex hormone concentrations, which might contribute to the increase in breast cancer risk . Our croNotwithstanding this, several limitations should be noted. The overall participation rate was modest (61% among cases and 64% among controls). Although our refusal rate (23%) is comparable to rates reported in other US studies, some 14% of the identified cases had moved outside of LAC . A methodologic concern is the comparability of cases we interviewed and those we did not interview in terms of alcohol intake. Nevertheless, we have reasonable confidence in our findings among the respondents because we have two separate measures of alcohol intake, and the results were similar. One measure was based on responses obtained from the FFQ, and the intake of beer, wine, and hard liquor was asked along with the other more than 100 food items/groups included in our questionnaire. A second measure was based on lifetime history assessment of alcohol intake.Misclassification of exposure is another concern in this and other case-control studies. However, our findings on alcohol intake by hormone-receptor status are generally compatible with published results from cohort studies ,32. ThisFinally, although the sample size of our cross-sectional study among control women was modest, our findings of elevated estrone, androgen, and adiponectin levels among current alcohol consumers compared with nonconsumers are also compatible with larger studies conducted in Caucasian women .Alcohol-drinking habits differ by Asian ethnicity and nativity, and their effects on breast cancer risk differ accordingly. Analyses by nativity and Asian ethnicity revealed a statistically significant alcohol/breast cancer association in US-born Asian Americans and Japanese Americans, emphasizing the growing importance of this risk factor in traditionally low-risk populations as alcohol intake has become more prevalent. Because alcohol intake is one of the few modifiable breast cancer risk factors, Asians and other traditionally low-risk populations should be aware of the risk associated with even moderate amounts of intake. Further studies are also needed to elucidate the mechanisms of the effect of alcohol intake on breast cancer risk in Asians and in the non-Asian populations.Adione: androstenedione; Adj: adjusted; ANOVA: analysis of variance; BMI: body mass index; CI: confidence interval; CSP: Cancer Surveillance Program; DHEAS: dehydroepiandrosterone sulfate; E1: estrone; E2: estradiol; ER: estrogen receptor; FFQ: food-frequency questionnaire; IGF-1: insulin-like growth factor-1; IGFBP-3: insulin-like growth factor-binding protein 3; LAC: Los Angeles County; OR: odds ratio; PR: progesterone receptor; SHBG: sex-hormone-binding globulin; SEER: Surveillance, Epidemiology, and End Results; T: testosterone.The authors declare that they have no competing interests.AW was responsible for the design and implementation of study and supervised the data-collection activities. Data management was conducted by CT. CT, CV, and PR conducted data analyses under the supervision of AW. Laboratory measurements were conducted under the supervision of FS. All authors read and approved the manuscript.


To explore the barriers to cervical cancer screening, focusing on religious and cultural factors, in order to inform group-specific interventions that may improve uptake of cervical cancer screening programmes.We conducted four focus group discussions among Muslim and Christian women in Nigeria.Discussions were conducted in two hospitals, one in the South West and the other in the North Central region of Nigeria.27 Christian and 22 Muslim women over the age of 18, with no diagnosis of cancer.Most participants in the focus group discussions had heard about cervical cancer except Muslim women in the South Western region who had never heard about cervical cancer. Participants believed that wizardry, multiple sexual partners and inserting herbs into the vagina cause cervical cancer. Only one participant knew about the human papillomavirus. Among the Christian women, the majority of respondents had heard about cervical cancer screening and believed that it could be used to prevent cervical cancer. Participants mentioned religious and cultural obligations of modesty, gender of healthcare providers, fear of disclosure of results, fear of nosocomial infections, lack of awareness, discrimination at hospitals, and need for spousal approval as barriers to uptake of screening. These barriers varied by religion across the geographical regions.Barriers to cervical cancer screening vary by religious affiliations. Interventions to increase cervical cancer awareness and screening uptake in multicultural and multireligious communities need to take into consideration the varying cultural and religious beliefs in order to design and implement effective cervical cancer screening intervention programmes. We identified several group-specific barriers to successful cervical cancer screening among Nigerian women and showed that religious and cultural factors have significant impact on health-seeking behaviours that should not be underestimated.Our findings have the potential to influence the implementation and uptake of cervical cancer screening in multicultural societies.Participants in our study were relatively well educated compared with the general population and may have provided responses that are not generalisable.We would need to further evaluate our findings from this qualitative study in a larger population-based survey.Cervical cancer is the fourth most common cancer in women, with an estimated 528 000 new cases occurring globally in 2012.4The incidence of cervical cancer in developed countries has fallen significantly in recent decades due to the implementation of population-wide, cytology-based screening programmes.9There are several barriers to the uptake of cervical cancer screening in LMICs; however, few studies have evaluated these barriers, particularly those related to cultural and religious differences in complex societies such as Nigeria. These barriers include low levels of knowledge of cervical cancer, limited awareness of prevention and early detection methods, fear of stigma associated with cancer diagnosis, concerns about spousal disapproval of screening, and concerns about violations of religious and cultural obligations of modesty during screening procedures.11It is imperative that these barriers are reduced or eradicated and appropriate mechanisms are instituted to enhance the use of screening services.We used focus group discussions (FGDs) so that we could elicit new information, free from researchers’ preconceived expectations in order to learn about group and cultural norms and behaviours associated with cervical cancer prevention among Nigerian women.Participants were recruited through purposive sampling. Participants were eligible if they were (1) women resident in the North Central or South Western regions of the country, (2) age 18 or older, (3) not currently suffering from cervical cancer and (4) self-identified as Muslims or Christians. We did not exclude women who had family or close acquaintances with a present or past diagnosis of cervical cancer. We conducted in-person visits to churches, markets and the general outpatient clinics of participating hospitals to identify potential participants. Potential participants were screened by a brief in-person interview to assess eligibility, and eligible participants were provided venue and time details for the FGD. Six of 55 women (11%) who were approached to participate in the FGDs declined. All of these women cited time constraints as their reason for declining.We conducted four FGDs between August and October 2014, two at each of the hospitals where the study was implemented. In order to encourage free exchange of ideas, focus groups were conducted according to the faiths of the participants, one for Muslims and the other for Christians and we achieved a heterogeneous (by age and socioeconomic status) group with at least 10 participants in each FGD. All participants provided written informed consent.The focus groups were conducted by FIM (a physician), EJ-A (a physician-epidemiologist) and PB (a nurse), all of whom, along with CA (physician-epidemiologist), have more than 4 years of experience in the design and conduct of qualitative research. FIM and EJ-A have had postgraduate training in qualitative research methodology at the West African Bioethics Training Program (PI—CA). EJ-A and CA have published papers using qualitative research methodology. All these researchers, except CA are women. AA, LO and OO are male gynaecologists who provide cervical cancer screening at the research sites and participated in the implementation of the research. None of the researchers had any relationship with the study participants before the start of the study.All four FGDs were carried out in English language using pidgin or local terms when necessary and lasted approximately 60–90 min without interference or the presence of other people. At each FGD, using an FGD guide that we developed on the basis of previous literature and using predetermined domains relevant to the objectives of the study, one of the two researchers (FIM or EJ-A), assisted by PB, moderated the discussions. We pilot-tested the FGD guide among 15 women in Abuja identified through purposive sampling, before the start of the study. We informed participants that the reason for carrying out the research study was to determine barriers that might exist to cervical cancer screening, especially related to religious and cultural factors, in an attempt to ascertain ways of improving participation rates in cervical cancer screening programmes. We then addressed all questions they had, after which we took informed consent. We audiorecorded each FGD, and two independent members of the research team transcribed the recordings. Handwritten notes were also taken during the interviews and were used to supplement the audio recordings. The sample size was determined based on data saturation.13The transcribed data were analysed based on the content analysis technique using a combination of deductive and inductive processes with Atlas.ti V.7.5.2 software for qualitative analysis. Transcripts were not returned to the participants for any comments or corrections. Two of the authors, ED and EJ-A, created a priori codes based on our research objective, as a general framework, while allowing for emergent concepts from the discussions. For each code, a description of the code was written in the code manager to provide contextual information. Coding was an iterative process, with the first level of coding generating initial codes which were evaluated by ED and EJ-A for a second and third level of coding. Related codes were grouped together using prefixes related to the study objective (using shared characteristics), and codes were colour coded using the shared prefix titles for each specific objective. We grouped codes into families according to shared themes. ED and EJ-A created semantic networks representing hierarchical relationships between concepts after a review of the codes. We analysed each code to identify emerging opinions and themes for the research objective. We kept detailed reflective and thematic memos during the process of coding to provide contextual information that developed during the coding process. All the authors reviewed the codes at a data analysis review meeting and subsequently modified and agreed on a set of codes. We used the query tools and Boolean operators to interrogate the codes and obtain the results that we present in this paper. We used the consolidated criteria for reporting qualitative research (COREQ-32) in describing the results.14We used the Word Cruncher and Word Cloud tools in Atlas.ti for content analysis to improve the quality of codes by identifying themes that may not have been previously coded. These tools determine the relative frequency of occurrence of all words in all four FGD transcripts. We did not identify any missed themes using this process.Ethics approval was obtained from the National Health Research Ethics Committee of Nigeria (NHREC/01/01/2007--01/08/2014).A total of 49 women  participated in this study. The mean (SD) age of participants was 33 (9.9) years. Most of the participants (83.7%) had completed at least 12 years of formal education. The majority (63.3%) were married, and 59.0% were employed. About one-third of the participants (38.8%) had been screened for cervical cancer in the past. Most participants had heard about cervical cancer . The mosAmong participants who had heard about cervical cancer, most did not understand the part of the body affected by it or where the cervix is located. A few participants identified cancer of the cervix by describing the cervix as the mouth of the womb or the birth canal. Several participants believed it was the same condition as cancer of the breast, while a few others believed it was cancer of the uterus. Some other discussants thought that it was cancer of the hips. During the FGDs, we found that, when some participants volunteered the names ‘cancer of the mouth of the womb’ or ‘cancer of the birth canal’, several other participants in the FGDs, who had heard of cervical cancer but did not know what part of the body was affected, were able to identify the location of the cervix.I heard that…On that talk show somebody say is…They use to send it, maybe it is a kind of charm, if a woman offend a man, the man now charm her that she will not have sex again. Then that place will now start to decay. That was what they said. Abuja Christian FGD participantDiscussants had some misconceptions about the cause of cervical cancer . These v…I think you know women have a lot of…like herbs that they insert into their vagina. So me I felt…you know sometimes you see tablets, sometimes it's these local herbs or something. The first time I learnt about it, from I think a friend was telling me. That like in Niger (a State in Northern Nigeria), you know they are used to buying these women herbs. That most of women there have cervical cancer. Abuja Muslim FGD ParticipantAmong the Muslim women in the Abuja FGD, various vaginal health practices were thought to cause cervical cancer . These pshe was talking about sexual intercourse, having a multitude of partners even though in one partner but it is not safe for you because he may have other girl friends, Which he can contract from them too. Abuja Muslim FGD participantMost respondents believed that having multiple sexual partners would increase the risk of having cervical cancer.In addition to the causes mentioned above, one of the Abuja Christian FGD participants also mentioned that it could be hereditary.I think they said irregular menses, or at times, heavy flow of menstrual blood. That is one. I think that is what I heard. Ondo Christian FGD participantOffensive discharge, bleeding during sexual intercourse. Abuja Christian FGD participant.Although most participants in the FGDs did not demonstrate a good understanding of the part of the body affected by cervical cancer, they were able to mention some of the symptoms of cervical cancer. From all FGDs, except the Ondo Muslim FGD, abnormal vaginal bleeding was recognised as a symptom of cervical cancer by the majority of the participants . Some reI think if you go early enough and you do your screening you will know when if you have it at all you will know early, and from there you start the treatment. Which is easier than you knowing it when it's late. Abuja Christian FGD participantThere was limited knowledge of the use of screening as a means of preventing cervical cancer . This diWhile many of the Muslim women in Ondo had not heard of cervical cancer screening, Muslim women in Abuja had heard about screening for cervical cancer; however, they had limited knowledge of its use for prevention. Some of the Muslim FGD participants in Ondo said that the only screening they had heard of was for breast cancer.Among the participants who knew about cervical cancer screening, the majority believed that it is only required for premenopausal women who are sexually active and that the screening interval should be yearly.Another way is that if a woman have delivered the children she wanted, I think the womb can be removed. Abuja Christian FGD participantRegardless of location, the Christian women identified treatment options for cervical cancer to include early detection, screening, chemotherapy, ‘spirituality,’ ‘exercise.’ One participant noted that preventive hysterectomy was also an option sayingI have seen on breast cancer but not heard of cervical cancer. Abuja Christian FGD participantParticipants in Abuja did not feel that there was any effective traditional treatment for cervical cancer, although one participant noted that traditional treatment was available for breast cancer but not for cervical cancer sayingYes it can be treated if it has not damaged the womb. If it is still around the cervix and it has not gone very far, it can be treated. Ondo Christian FGD participantMost Muslim FGD participants in Abuja believed that cervical cancer can be treated, and a few participants claimed awareness of traditional treatment modalities for it. Participants who were aware of traditional treatment modalities for cervical cancer provided further insight by noting that, when women had symptoms suggestive of cervical cancer, they started traditional treatment before visiting a healthcare facility. In these instances, such participants noted that they could not tell much about the efficacy of the traditional treatment, as they were not certain if what was being treated was indeed cervical cancer. In the Christian FGD in Ondo, participants noted that cervical cancer could be treated if diagnosed early.These participants did not believe that traditional medicine could be used to treat cervical cancer.This awareness of cervical cancer is limited to the city… Ondo Christian FGD participantAll participants, except the Muslim women in Ondo, opined that cervical cancer was becoming a significant problem in Nigeria, as they hear about the disease more commonly now than in the past. One respondent described rural–urban disparities in the awareness of cervical cancer sayingit is all about having sex and many multiple sexual partners. Abuja Christian FGD participantAll participants, except those in the Muslim FGD in Ondo, believed that they could develop cervical cancer as long as they were engaged in sexual relationships and with increasing age. One participant saidAlthough most participants believed that they have some personal risk of developing cervical cancer, several expressed unwillingness to be screened. Some of the barriers to screening that respondents described included modesty concerns, gender of healthcare providers, fear of status disclosure, fear of contracting other illnesses in the hospitals, discomfort during the screening process, lack of awareness of screening programmes, denial of disease condition, discrimination, and requiring husband’s permission before screening. These barriers varied by religion across the geographical regions.Islamically it is not good to expose yourself outside, except to your husband. Ondo Muslim FGD participantAll FGD participants identified cultural norms of modesty as a barrier to seeking cervical cancer screening; however, the participants in the Muslim FGDs were more emphatic about this barrier, citing an additional religious basis for their concern. A participant put it this wayEven in our religion, our mentor in Islam, Muhammadu Rasurulillahi has even told us—When you are in community and you can perceive a kind of a sickness that is being spread among the people or even in the forest that you should leave that place and go to area where you will not contact it. Ondo Muslim FGD participantA participant noted that there can be exceptions to this norm in cases of illness and explained how Islam teaches the practice of preventive measures.Normally….Muslim women do not like to open themselves to the other… man. I prefer female doctors to attend to the Muslim woman. To me, I prefer to go female hospital, because they will see our private parts. I don't really, really like it at all at all. Ondo Muslim FGD participant.The participants in the Muslim FGD in both geographical regions expressed a strong preference for a female healthcare provider.The way they are treating us in the hospital, as if we are not part of the community. Even the female doctors in the hospital, before they even attend to you, they will already be abusing you from head to toe as if you don't know anything, as if you are not part of the community. If you want us to go for screening in the hospital, these women that are coming, at least they should be kind to them and be patient with them. Ondo Muslim FGD participantSome participants further explained that they had failed to go through screening in the past when they realised the service was to be provided by a male healthcare provider. Participants in the FGD for Muslim women in Ondo claimed that Muslim women face some discrimination at healthcare facilities because their mode of dressing readily identifies their faith.Among all the Christian FGD participants, while there was a preference for female healthcare providers, they did not mind being attended to by a male healthcare provider. All participants opined that they would be more comfortable if there was a female chaperone present in the examination room.Some women will not want any other person to know their status. You know if you have infection, that tendency of thinking that so they know I am carrying this thing…. Ondo Christian FGD participantSome respondents expressed concerns about confidentiality of results.I may be thinking maybe, I will contact another disease. Like this Ebola we have been hearing this time around now. Most of the doctor that have been treating the patients, they are the ones catching the disease. If I go for screening now, maybe something may have happen, I don't know. That is the part of the reason that have been scaring us from going. Ondo Muslim FGD participantParticipants expressed a lack of confidence in the healthcare system and opined that they could be infected with other diseases either from the screening equipment or from other sources or procedures within the healthcare facility.Most participants said that they required their husband’s permission before being screened. This view was more prevalent among the Muslim respondents. Some felt they needed to let their husbands know before attending screening clinics because of financial reasons, stating that the husband would need to provide the funds. One participant noted that it would be important to inform her husband because this would make disclosure and discussion of abnormal results, if found during screening, easier. Other reasons proffered for requiring their husband’s permission were religious obligation and trust in their spouse’s opinion.Because the reason is that when you give us the thing to screen at home we won't have something to open it (private part) very well. And we may not do it properly. Ondo Muslim FGD participant.Most participants were not aware that there were screening options that allow the participant to take the cervical samples by themselves. However, when they considered this option, the majority expressed a preference for a healthcare provider to take the samples in a healthcare facility as opposed to self-sampling. The main reason for this preference was the belief that they would be unable to take adequate samples of good quality even with instructions.The majority of the FGD participants (61.2%) had never been screened for cervical cancer. Participants attributed this low level of screening uptake to modesty concerns, lack of awareness of screening, lack of husband's permission to be screened, fear of a positive result, and belief that it is better to be ignorant of the disease than to go in search of it. However, several participants who had not been screened for cervical cancer were willing to be screened if a free screening test was provided. They also offered suggestions on how cervical cancer screening could reach a wider range of women by the use of mobile screening clinics, dissemination of information in churches and mosques, and use of text messages via mobile phones.Our study shows that awareness of cervical cancer was not uniform among different groups of women in our population. When compared with the Christian FGD participants, the Muslim women were less likely to be aware of cervical cancer especially in the Ondo South Western FGD, where none of the participants were aware of cervical cancer. This finding may be because there have been more public health campaigns in churches and at Christian gatherings. It may also be a reflection of the scope of social and ancillary programmes that accompany the practices of Christianity compared with Islam in our study communities. We also found a higher prevalence of reluctance to engage with the healthcare system among Muslim participants. There is a need to provide educational campaigns that are specifically designed to reach Muslim women, as recommended by others.Most of the women in our study were aware of cervical cancer, but only a third had ever been screened and only one participant had ever heard of the association between HPV and cervical cancer. This is similar to findings from other low-resource settings, which found that the knowledge of women about cervical cancer is ‘elementary’ at best and that there was a high prevalence of ignorance about causes, symptoms and treatment options for cervical cancer.Some of the women in our study knew cancer of the cervix as ‘cancer of the mouth of the womb’ or ‘cancer of the birth canal’. To be successful, public health messages to promote cervical cancer screening should build on names and terminologies that are already in use in the community. Our study participants stated that their main sources of information on cervical cancer were the mass media and hospital health talks. This is similar to the findings from other studies carried out in Nigeria and Ethiopia.Several participants recognised the role of a sexually transmitted infection in cervical cancer, but only one participant mentioned an association with HPV. With increasing use of HPV DNA testing as primary modality for cervical cancer screening in high- and middle-income countries and the role of HPV vaccination in prevention of cervical cancer, there is a need to improve awareness of the association of HPV with cervical cancer in order to enhance the uptake of these modern prevention and screening interventions in this population.Beliefs that cervical cancer may be caused by charms deployed by men who are unhappy with their female sexual partners were more prevalent among Christians in this study. These beliefs may reflect the growth of evangelical Christianity with its emphasis on the spiritual nature of illnesses in recent decades in Nigeria.There was a prevailing notion among several participants that cervical cancer screening is only used for detection of cancer that is already present and the cancer may have a poor outcome even if treated. This limited knowledge of cervical cancer treatment, and its options, coupled with fear of receiving a diagnosis of cervical cancer during screening was a strong deterrent to accessing cervical cancer screening services. Other studies have found that the lack of awareness of cervical cancer and its causes, symptoms and treatment among women in Sub-Saharan Africa decreases their cervical cancer screening participation rates and increases their risk of developing cancer.Although the majority of participants in the FGDs recognised their personal risk of cervical cancer, several expressed an unwillingness to be screened because of cultural and religious norms of modesty. This was expressed in several forms such as the lack of desire to disrobe for the pelvic examination necessary for cervical cancer screening in the clinic and concerns at being attended to by male healthcare providers. These concerns were more pronounced among the Muslim participants, and they related it to the teachings of their faith. Our finding on the preference for a female doctor among the Muslim women in our sample is similar to reports from a predominantly Muslim population in Kuwait where 78% of respondents expressed their preference for examination by a female doctor.Most participants indicated that they would need spousal financial and emotional support before attending screening services. In Africa, men have an important role to play in improving uptake of screening programmes and health interventions, so health education programmes for women's health need to engage spouses in order to increase their chances of success.An unexpected finding in our study was the perception of discrimination at healthcare facilities by Ondo FGD Muslim women who suggested that this prevents them from seeking care. This is an important finding especially since these same women were unaware of cervical cancer. Participants opined that their mode of dressing, which involves the wearing of a veil and long loose black gowns (the hijab), triggers a discriminatory response from healthcare providers. The Muslim women mentioned that they already feel that they are being discriminated against when they attend services such as the antenatal clinic. This therefore discourages them from returning to hospitals for other, particularly non-critical, services. Healthcare providers need to remain ethical and treat all patients equally. Perceived racial, ethnic, religious or cultural discrimination may alter health behaviour including cancer screening, leading to group-specific cancer health disparities.Participants in our study also showed evidence of low levels of trust in the healthcare system. There was concern about disclosure of status based on the screening result and fear of contracting other diseases while in the hospital environment. While there have been several studies of disclosure of status and its impact in the context of HIV/AIDS,We explored the attitude of our FGD participants to potential use of self-sampling for cervical cancer screening in Nigeria in this study. Participants expressed concerns about being able to take adequate samples and would rather have the samples taken by a trained provider in a healthcare facility. Similar concerns have been found in other studies and highlight the need to ensure that women are adequately trained before introduction of self-sampling techniques for cervical cancer screening.36Limitations of our study include the possibility that the FGD environment may have caused some participants to give answers they perceive to be more ‘socially acceptable’, while more reticent participants may have shied away from participation. There may also have been some selection bias in recruiting participants for the FGDs. Participants in our study were relatively well educated and they may have provided responses that are not generalisable to the general population. Another limitation to our study is the sample size; although we conducted two FGDs in each geographical region, we acknowledge that our findings of distinct experiences and perceptions among Muslim women in Ondo require further exploration. It is our plan to explore this further in a population-based survey.Our study adds valuable information to the knowledge, attitudes and practices of cervical cancer screening in Nigeria. We identified several barriers to successful cervical cancer screening among Nigerian women, some of which varied by religion. We showed that religious and cultural factors could have significant impact on health-seeking behaviours that should not be underestimated, and that there were significant differences in attitudes to cervical cancer screening among the two major religious groups in Nigeria. Our next steps are to further evaluate our findings from this qualitative study in a larger population survey.


Smoking has recently been established as a risk factor for rectal cancer. We examined whether the smoking-related increase in rectal cancer differed by gender.χ2.We followed 602,242 participants (49% men), aged 19 to 67 years at enrollment from four Norwegian health surveys carried out between 1972 and 2003, by linkage to Norwegian national registries through December 2007. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by fitting Cox proportional hazard models and adjusting for relevant confounders. Heterogeneity by gender in the effect of smoking and risk of rectal cancer was tested with Wald trend <0.05), number of cigarettes smoked per day (both ptrend <0.0001), smoking duration in years  and number of pack-years smoked (both ptrend <0.0001)]. The test for heterogeneity by gender was not significant between smoking status and the risk of rectal cancer .During a mean follow-up of 14 years, 1,336 men and 840 women developed invasive rectal cancer. Ever smokers had a significantly increased risk of rectal cancer of more than 25% for both men  and women  compared with gender-specific never smokers. Men smoking ≥20 pack-years had a significantly increased risk of rectal cancer of 35% , whereas for women, it was 47%  compared with gender-specific never smokers. For both men and women, we observed significant dose–response associations between the risk of rectal cancer for four variables [Age at smoking initiation in years (both pSmoking increases the risk of rectal cancer to the same extent in women as in men. An expert group at the International Agency for Research on Cancer (IARC) recently re-evaluated the carcinogenetic effects of smoking in humans, and concluded that smoking is a risk factor for both colon and rectal cancer . In a reThe variation in the smoking epidemic by country and gender was first described in a model focusing on the four stages of the tobacco epidemic in Western countries  and lateDuring the last 50 years, the incidence rate of rectal cancer has increased dramatically in Norway. It was about 5 per 100,000 for women and 6 per 100,000 for men in the late 1950s. In 2007, which was the end of the follow-up period in our study, the risk had more than doubled to 12 per 100,000 for women and 17 per 100,000 for men  and rectal cancer with never smokers as the reference group. All analyses were done by gender. Entry time was defined as age at enrollment and exit time was age at diagnosis of rectal cancer, the date of any incident cancer diagnosis , emigration, death, or the end of follow-up , whichever occurred first. The possible confounders included in the final models, selected a priori, were age at enrollment(continuous), level of physical activity , BMI(continuous), all at enrollment, and duration of education in years . Tests for linear trends were obtained by creating an ordinal exposure (including never smokers) variable with equally spaced scores and including it in the models.We used the χ2 test. Two-sided p -values of <0.05 were considered statistically significant. All analyses were conducted using STATA version 12.0 .We excluded 8,151 (99% men) participants who reported smoking only cigar or pipe and did a sensitivity analyses in this sub cohort. We had information on alcohol consumption for 37%  of the total analytical cohort and did sensitivity analyses for the risk of rectal cancer by gender for this subcohort (49% men) with and without adjustment for alcohol consumption. Heterogeneity by gender in the effect of smoking and risk of rectal cancer was tested with the Wald During a mean follow up period of 14 years and 8.6 million person-years of observation, 2,176 (61% men) histologically confirmed invasive rectal cancer cases were ascertained. Mean age at rectal cancer diagnosis for men varied from 57 years in the 40 years cohort to 66 years in the CONOR and the Oslo study I and for women, it varied from 55 years in the 40 years cohort to 66 years in the CONOR study. At enrollment, 67% of men and 59% of women were ever smokers (Table trend <0.05), number of cigarettes smoked per day (both ptrend <0.0001), smoking duration in years  and number of pack-years smoked (both ptrend <0.0001)] and rectal cancer . These estimates did not differ materially when we excluded participants who smoked only cigars or pipes (data not shown).Table er Table . The tesIn the sensitivity analyses for men with information on alcohol consumption most of whom were enrolled after 1995, the risk estimate of rectal cancer incidence was 13%  with adjustment for alcohol consumption and 12%  without adjustment for alcohol consumption among ever compared with never smokers. The same analyses among women rendered a risk estimate of 37%  with adjustment for alcohol consumption and 39%  without adjustment for alcohol consumption.Table Our study shows that ever smokers had a significantly increased risk of rectal cancer, and that this risk is similar for men and women. A possible causal interpretation of our results is supported by the presence of a consistent dose–response association between the various measures of smoking exposure  and the risk of rectal cancer for both genders. Men and women ever smokers also had an increased risk of rectal cancer within the different categories of possible confounding variables, such as BMI, duration of education and level of physical activity.To our knowledge, this prospective analysis of smoking and the risk of rectal cancer includes the largest number of rectal cancer cases investigated to date. It is also the first to compare this association in detail by gender. In the present report, the association between cigarette smoking and rectal cancer was similar for men and women. Previously, we reported from the same cohort that smoking increased the risk of colon cancer to a greater extent for women than men . Our preTwo meta-analyses, one including 36 prospective cohort studies reported a non-significant almost 20% increased risk of rectal cancer for both former and current smokers  while thIn studies reporting risk estimates by cancer site, the association between smoking and rectal cancer has generally been stronger than that with colon cancer among both men and women. Similarly, stronger relative risk among ever smokers for proximal compared to distal colon cancer has been documented . In our Colorectal cancer is considered a complex collection of diseases with different etiologies . SmokingOur study has several major strengths. It is based on a large prospective cohort population from Norway comprising both men and women, with a long and virtually complete follow-up. The long follow-up period resulted in a large number of cases, and gave us more stable risk estimates and results that are less prone to chance. We were able to stratify all the analyses according to different measures of smoking exposure and were able to conduct all analyses separately by gender. Also, smoking histories were obtained at enrollment and, therefore, are not subject to recall bias. We have a high proportion of men and women ever smokers. In addition, we focused our analyses on the comparison between ever versus never smokers. Thus, it is only never smokers that could have possibly changed their smoking status during follow-up. As very few Norwegians start to smoke after the age of 30 and the mean age at enrollment for our study is more than 40 years, we are confident that possible changes in smoking status among never smokers during follow-up did not influence our risk estimates. We had information on, and were able to control for, established risk factors for rectal cancer, many of which varied according to smoking status. Rectal cancer screening was not in place in Norway during our study period, thus reducing detection bias. Also, two previous reports confirmed the internal validity of the association between smoking exposure and the risk of breast  and coloOur study has also several limitations. We lacked information on family history of rectal cancer and on dietary factors, such as alcohol and red meat consumption, which are established risk factors for rectal cancer. Increased consumption of alcohol and red meat are factors that may partly explain the steep increase in rectal cancer incidence for both genders. Alcohol consumption is higher among men than women in Norway . Thus, tSimilarly, information on the use of COX inhibitors, such as aspirin, which has preventive effects on rectal cancer development  was not Smoking increases the risk of rectal cancer to the same extent in women as in men.BMI: Body mass index; CI: Confidence interval; CONOR: Cohort of Norway; EPIC: European Prospective Investigation into Cancer and Nutrition; IARC: International Agency for Research on Cancer; ICD: International classification of diseases; HR: Hazard ratio; SD: Standard deviation.The authors declare that they have no competing interests.RP carried out the statistical analysis and drafted the manuscript. ITG, EW and EB contributed to the planning of the manuscript, statistical analysis, interpretation of the data and critical revision of the manuscript. AT contributed with statistical analysis interpretation of data and critical revision of the manuscript. LM contributed with interpretation of the data and critical revision of the manuscript. All authors read and approved the final version of the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/14/321/prepub


The aim of this study was to study the risk of breast cancer in men on 5-ARI, in men with benign prostatic hyperplasia (BPH) not on 5-ARI, and in men without BPH.We performed a population-based cohort study in Sweden with data from The Prescribed Drug Register, The Patient Register, and The Cancer Register. Men on 5-ARI, men on α-blockers, or men who had undergone a transurethral resection of the prostate (TUR-P) prior to or during 2006–2008 were included as exposed to BPH and a specific treatment thereof. For each exposed man, five unexposed men were selected. Risk of breast cancer was calculated in Cox proportional hazard models.There were 124,183 exposed men and 545,293 unexposed men, and during follow-up (median 6 years), 99 men with breast cancer were diagnosed. Compared to unexposed men, men on 5-ARI had a hazard ratio (HR) of breast cancer of 0.74  0.27–2.03), men on α-blockers had HR 1.47 (95 % CI 0.73–2.95), and men with a TUR-P had HR 1.99 (95 % CI 1.05–3.75).No increased risk of breast cancer was observed for men on 5-ARI. However, the increased risk of breast cancer among men who had undergone a TUR-P, a strong indicator of BPH, suggests that the endocrine milieu conducive to BPH is associated with male breast cancer. The mode of action of 5-ARI is to inhibit the conversion of testosterone to dihydrotestosterone (DHT), the most potent androgen in the prostate . This inThe aim of this study was to assess the risk of breast cancer in men on 5-ARI and in men with BPH not treated with 5-ARI using data from nationwide, population-based healthcare registers and demographic databases in Sweden.1-adrenergic receptor blocker (α-blocker), or who had undergone a transurethral resection of the prostate (TUR-P) prior to or during the study period, were included. The use of α-blockers, another class of drugs for the treatment of LUTS that block receptors in the smooth muscle in the prostate, and the receipt of a TUR-P were used as indicators of BPH. For each man with an exposure to 5-ARI, α-blocker, or a TUR-P, five unexposed men of same age (±1 year) as the exposed man in each subgroup were randomly selected from the same county of residence. This was done by identifying men without these exposures in the Register of the Total Population and Population Changes held at Statistics Sweden. Unexposed men were required to be alive at the index date of the exposed.This investigation was conducted as a cohort study in the male population in Sweden with study men identified from 1 January 2006 to 31 December 2008. All men with a filled prescription for a 5-ARI or an αWe were not able to find five unexposed men from the same county and in the same age for all men, so some men have less than five controls. Follow-up started at 1 January 2006 for men exposed prior to that date, and for men who started exposure later, follow-up started at the date of surgery or first filled prescription. For unexposed men, follow-up started at the same date as their index man. No men with prevalent prostate cancer were included, and if a prostate cancer was detected during follow-up, this was ignored. Follow-up ended at the date of diagnosis of breast cancer, date of emigration, date of death, date of androgen deprivation therapy for prostate cancer, or 31 December 2011, whichever date came first.Data on filled prescriptions for the 5-ARI finasteride and dutasteride [Anatomic Therapeutic Chemical classification system (ATC) code G04CB] and all types of α-blockers (G04CA01 to 4) used for the treatment of LUTS were extracted from The Prescribed Drug Register, which includes all prescriptions dispensed since July 2005 in Sweden . We alsoAs of 1987, the National Patient Register collects information on inpatient care including surgical procedures, and discharge diagnoses coded according to International Classification of Diseases (ICD-9 and subsequently ICD-10) . From thWe performed two Cox proportional hazard models  with theFirst we estimated the risk of breast cancer in relation to exposures determined at study entry, α-blockers, TUR-P, or 5-ARI compared to non-exposed men. No adjustments for potential confounders were made in this analysis, and subsequent changes in exposures were ignored.In the second analysis, subsequent exposures to α-blockers, TUR-P, or 5-ARI were taken into account using time-dependent covariates. This analysis was performed as both a univariable and a multivariable analysis, including potential confounders such as the use of antidiabetic drugs and statins. This second analysis was first performed for (A) the full study group, (B) men unexposed at entry to the study, (C) men exposed to α-blockers/TUR-P at entry to the study, and (D) men exposed to 5-ARI at entry to the study. Stratification was done in order to assess all potential associations between exposure to BPH and male breast cancer. We performed a sensitivity analysis where all men with a prostate cancer diagnosis during follow-up were censored. Third, we studied the time between the start of 5-ARI exposure and the date of breast cancer diagnosis. Finally, we performed a meta-analysis of the current study and the two previous studies on 5-ARI and breast cancer.In total, 669,476 men were included in the study, with a mean age of 70 years at the study start for non-exposed men, 66 years for men on α-blockers, 74 years for men who had undergone TUR-P, and 72 years for men on 5-ARI Table . A majorDuring the study period, 99 men were diagnosed with breast cancer, with a mean age of 78 years (standard deviation ± 9.0 years). Compared to the unexposed, men on 5-ARI had a non-significant decrease in the risk of breast cancer, HR 0.74 (95 % CI 0.27–2.03); men on α-blockers had a non-significant increase, HR 1.47 (95 % CI 0.73–2.95); and men who had undergone a TUR-P had a significantly increased risk, HR 1.99 (95 % CI 1.05–3.75) .In the meta-analysis, we found an unaltered risk of male breast cancer, RR 0.85 (95 % CI 0.59–1.24) Fig. .Fig. 3MeIn this nationwide, register-based, and population-based study, men on 5-ARI had a non-significant decrease in risk of breast cancer, whereas men on α-blockers had a non-significant increase and men who had received a TUR-P had a significantly increased risk of breast cancer.Strengths of our study include the very high capture rate of the entire male population of Sweden in all registers that were used. The Prescribed Drug Register has an extremely high capture rate with less than 0.3 % incomplete records, and the Patient Register has a high capture rate for inpatient surgery , 13. LimMale breast cancer is a rare disease with an annual incidence rate of 1 per 100,000 men , and preEach exposure in our study is an indicator of LUTS, and the most common cause for LUTS in elderly men is prostatic enlargement due to BPH, but LUTS may also have other causes, so LUTS is not synonymous with BPH. However, a large proportion of men who undergo a TUR-P have obstructive symptoms due to prostatic enlargement, and in general these men have more severe symptoms and larger prostates than men who are pharmaceutically treated , 21. ManWe suggest that our observation of an increased risk of breast cancer in men with BPH who had undergone a TUR-P is due to a decreased ratio of testosterone to estrogen. In line with this speculation, the increased ratio caused by 5-ARI in men with BPH could be the mechanism behind the unaltered risk of male breast cancer in men with BPH on 5-ARI.We found no increase in the risk of breast cancer for men on 5-ARI, but there was an increased risk for men who had undergone a TUR-P, a strong indicator for BPH. Given the very low incidence of breast cancer and the null results from our cohort study and two large case–control studies, we suggest that the concern for breast cancer should not influence the selection of treatment for BPH.