Bettina F. Drake

Effect of Vitamin D Supplementation on Blood Pressure in Blacks

Blacks have significantly higher rates of hypertension than whites, and lower circulating levels of 25-hydroxyvitamin D. There are few data about the effect of vitamin D3 (cholecalciferol) supplementation on blood pressure in blacks. During 2 winters from 2008 to 2010, 283 blacks (median age, 51 years) were randomized into a 4-arm, double-blind trial for 3 months of placebo, 1000, 2000, or 4000 international units of cholecalciferol per day. At baseline, 3 months, and 6 months, systolic and diastolic pressure and 25-hydroxyvitamin D were measured. The 3-month follow-up was completed in 250 (88%) participants. The difference in systolic pressure between baseline and 3 months was +1.7 mm Hg for those receiving placebo, −0.66 mm Hg for 1000 U/d, −3.4 mm Hg for 2000 U/d, and −4.0 mm Hg for 4000 U/d of cholecalciferol (−1.4 mm Hg for each additional 1000 U/d of cholecalciferol; P=0.04). For each 1-ng/mL increase in plasma 25-hydroxyvitamin D, there was a significant 0.2-mm Hg reduction in systolic pressure (P=0.02). There was no effect of cholecalciferol supplementation on diastolic pressure (P=0.37). Within an unselected population of blacks, 3 months of oral vitamin D3 supplementation significantly, yet modestly, lowered systolic pressure. Future trials of vitamin D supplementation on blood pressure are needed to confirm these promising results, particularly among blacks, a population for whom vitamin D deficiency may play a more specific mechanistic role in the pathogenesis of hypertension.

Effect of Vitamin D Supplementation on Blood Pressure in BlacksNovelty and Significance

Blacks have significantly higher rates of hypertension than whites, and lower circulating levels of 25-hydroxyvitamin D. There are few data about the effect of vitamin D3 (cholecalciferol) supplementation on blood pressure in blacks. During 2 winters from 2008 to 2010, 283 blacks (median age, 51 years) were randomized into a 4-arm, double-blind trial for 3 months of placebo, 1000, 2000, or 4000 international units of cholecalciferol per day. At baseline, 3 months, and 6 months, systolic and diastolic pressure and 25-hydroxyvitamin D were measured. The 3-month follow-up was completed in 250 (88%) participants. The difference in systolic pressure between baseline and 3 months was +1.7 mm Hg for those receiving placebo, −0.66 mm Hg for 1000 U/d, −3.4 mm Hg for 2000 U/d, and −4.0 mm Hg for 4000 U/d of cholecalciferol (−1.4 mm Hg for each additional 1000 U/d of cholecalciferol; P=0.04). For each 1-ng/mL increase in plasma 25-hydroxyvitamin D, there was a significant 0.2-mm Hg reduction in systolic pressure (P=0.02). There was no effect of cholecalciferol supplementation on diastolic pressure (P=0.37). Within an unselected population of blacks, 3 months of oral vitamin D3 supplementation significantly, yet modestly, lowered systolic pressure. Future trials of vitamin D supplementation on blood pressure are needed to confirm these promising results, particularly among blacks, a population for whom vitamin D deficiency may play a more specific mechanistic role in the pathogenesis of hypertension.

Impact of Obesity on Cancer Survivorship and the Potential Relevance of Race and Ethnicity

Evidence that obesity is associated with cancer incidence and mortality is compelling. By contrast, the role of obesity in cancer survival is less well understood. There is inconsistent support for the role of obesity in breast cancer survival, and evidence for other tumor sites is scant. The variability in findings may be due in part to comorbidities associated with obesity itself rather than with cancer, but it is also possible that obesity creates a physiological setting that meaningfully alters cancer treatment efficacy. In addition, the effects of obesity at diagnosis may be distinct from the effects of weight change after diagnosis. Obesity and related comorbid conditions may also increase risk for common adverse treatment effects, including breast cancer-related lymphedema, fatigue, poor health-related quality of life, and worse functional health. Racial and ethnic groups with worse cancer survival outcomes are also the groups for whom obesity and related comorbidities are more prevalent, but findings from the few studies that have addressed these complexities are inconsistent. We outline a broad theoretical framework for future research to clarify the specifics of the biological-social-environmental feedback loop for the combined and independent contributions of race, comorbid conditions, and obesity on cancer survival and adverse treatment effects. If upstream issues related to comorbidities, race, and ethnicity partly explain the purported link between obesity and cancer survival outcomes, these factors should be among those on which interventions are focused to reduce the burden of cancer.

Dose response to vitamin D supplementation in African Americans: results of a 4-arm, randomized, placebo-controlled trial

BACKGROUND Association studies have suggested that lower circulating 25-hydroxyvitamin D [25(OH)D] in African Americans may partially underlie higher rates of cardiovascular disease and cancer in this population. Nonetheless, the relation between vitamin D supplementation and 25(OH)D concentrations in African Americans remains undefined. OBJECTIVE Our primary objective was to determine the dose-response relation between vitamin D and plasma 25(OH)D. DESIGN A total of 328 African Americans in Boston, MA, were enrolled over 3 winters from 2007 to 2010 and randomly assigned to receive a placebo or 1000, 2000, or 4000 IU vitamin D₃/d for 3 mo. Subjects completed sociodemographic and dietary questionnaires, and plasma samples were drawn at baseline and 3 and 6 mo. RESULTS Median plasma 25(OH)D concentrations at baseline were 15.1, 16.2, 13.9, and 15.7 ng/mL for subjects randomly assigned to receive the placebo or 1000, 2000, or 4000 IU/d, respectively (P = 0.63). The median plasma 25(OH)D concentration at 3 mo differed significantly between supplementation arms at 13.7, 29.7, 34.8, and 45.9 ng/mL, respectively (P < 0.001). An estimated 1640 IU vitamin D₃/d was needed to raise the plasma 25(OH)D concentration to ≥ 20 ng/mL in ≥ 97.5% of participants, whereas a dose of 4000 IU/d was needed to achieve concentrations ≥ 33 ng/mL in ≥ 80% of subjects. No significant hypercalcemia was seen in a subset of participants. CONCLUSIONS Within African Americans, an estimated 1640 IU vitamin D₃/d was required to achieve concentrations of plasma 25(OH)D recommended by the Institute of Medicine, whereas 4000 IU/d was needed to reach concentrations predicted to reduce cancer and cardiovascular disease risk in prospective observational studies. These results may be helpful for informing future trials of disease prevention.

Impact of Vitamin D Supplementation on Inflammatory Markers in African Americans: Results of a Four-Arm, Randomized, Placebo-Controlled Trial

African Americans have a disproportionate burden of inflammation-associated chronic diseases such as cancer and lower circulating levels of 25-hydroxyvitamin D [25(OH)D]. The effect of vitamin D3 (cholecalciferol) supplementation on inflammatory markers is uncertain. We conducted a randomized, double-blind, placebo-controlled trial of supplemental oral vitamin D (placebo, 1,000, 2,000, or 4,000 IU/day of vitamin D3 orally for 3 months) in 328 African Americans (median age, 51 years) of public housing communities in Boston, MA, who were enrolled over three consecutive winter periods (2007–2010). Change from 0 to 3 months of plasma levels of 25(OH)D, high-sensitivity C-reactive protein (CRP), interleukin (IL)-6, IL-10, and soluble TNF-α receptor type 2 (sTNF-R2) in 292 (89%) participants were measured. Overall, no statistically significant changes in CRP, IL-6, IL-10, and sTNF-R2 were observed after the vitamin D supplementation period. Baseline CRP was significantly inversely associated with the baseline 25(OH)D level (P < 0.001) in unadjusted and adjusted models. An interaction between baseline 25(OH)D and vitamin D supplementation was observed for outcome change in log CRP (month 3–month 0; P for interaction = 0.04). Within an unselected population of African Americans, short-term exposure to vitamin D supplementation produced no change in circulating inflammatory markers. This study confirms the strong independent association of CRP with 25(OH)D status even after adjusting for body mass index. Future studies of longer supplemental vitamin D3 duration are necessary to examine the complex influence of vitamin D3 on CRP and other chronic inflammatory cytokines for possible reduction of cancer health disparities in African Americans. Cancer Prev Res; 7(2); 218–25. ©2013 AACR.

Perceived barriers to mammography among underserved women in a Breast Health Center Outreach Program

BACKGROUND To investigate perceived barriers to mammography among underserved women, we asked participants in the Siteman Cancer Center Mammography Outreach Registry-developed in 2006 to evaluate mobile mammographys effectiveness among the underserved-why they believed women did not get mammograms. METHODS The responses of approximately 9,000 registrants were analyzed using multivariable logistic regression. We report adjusted odds ratios (OR) and 95% confidence intervals (CI) significant at 2-tailed P values less than .05. RESULTS Fears of cost (40%), mammogram-related pain (13%), and bad news (13%) were the most commonly reported barriers. Having insurance was associated with not perceiving cost as a barrier (OR .44, 95% CI .40 to .49), but with perceiving fear of both mammogram-related pain (OR 1.39, 95% CI 1.21 to 1.60) and receiving bad news (OR 1.38, 95% CI 1.19 to 1.60) as barriers. CONCLUSION Despite free services, underserved women continue to report experiential and psychological obstacles to mammography, suggesting the need for more targeted education and outreach in this population.

Vitamin D and mammographic breast density: a systematic review

Studies suggest a protective relationship between Vitamin D and breast cancer risk. Several studies assessed the association of Vitamin D with mammographic breast density, a known and strong breast cancer risk factor. Understanding the potential role of Vitamin D in the modification of breast density might open new avenues in breast cancer prevention. This systematic review summarizes published studies that investigated the association between Vitamin D and mammographic breast density and offers suggestions for strategies to advance our scientific knowledge.

Obesity and Other Cancers

Purpose Evidence on overweight, obesity, and an increased risk of cancer continues to accumulate and was updated in the 2016 handbook on weight control from the International Agency for Research on Cancer (IARC). The underlying primary data, together with dose-response meta-analysis and, finally, pooled analysis of individual participant data, add insight into the relation between obesity and cancer risk and prognosis. We summarize the evidence for mortality from prostate cancer, hematologic malignancies, and kidney cancer. Methods We reviewed pooled analysis of rare end points across cohorts, regardless of primary results reported from the individual studies, further reducing risk of publication bias. Of these cancer sites, only kidney cancer was included in the IARC 2002 report, although mortality from prostate cancer and hematologic malignancies was noted in the American Cancer Society prospective cohort study in 2003. The 2016 update from the IARC added details for prostate and hematologic malignancies, classifying the evidence as sufficient to conclude that avoiding excess body fatness lowers the risk of multiple myeloma but found that the evidence for it lowering the risk of prostate cancer mortality or diffuse large B-cell lymphoma was limited. Results A higher body mass index is associated with an increased risk of advanced prostate cancer and prostate cancer mortality and is associated with worse survival in most subtypes of hematologic malignancies, in a dose-response fashion. Evidence for kidney cancer is built mostly on retrospective data, which supports an obesity paradox in patients with the clear cell variant; however, population-based cohort data indicate that a higher cohort-entry body mass index is associated with worse kidney cancer-specific survival. Conclusion Together, these data add support to the evidence for a growing cancer burden caused by adiposity in both early adult and later adult life, yet leave open the question of the means of weight management after diagnosis as a strategy to improve survival.

Successful subject recruitment for a prostate cancer behavioral intervention trial

Background Inadequate participant recruitment, which may lead to unrepresentative study samples that threaten a study’s validity, is often a major challenge in the conduct of research studies. Purpose The purpose of this article is to describe the development and implementation of a recruitment plan and evaluate the different recruitment strategies for a prostate cancer behavioral intervention trial. Methods Our recruitment plan was based on a framework (The Heiney—Adams Recruitment Model) that we developed, which combines relationship building and social marketing. We evaluated the success of our model using several different recruitment sources including: mailed letters, physician referral, and self-referral. Results Recruitment rates ranged from 67% for a support services department mailing to 100% for physician referral. While our original list of contacted patients was comprised of only 13% African American (AA) men, 22% of our recruited participants were AA. Limitations One of the strongest barriers to recruitment was strict patient eligibility. Another significant barrier was the lack of electronic records systems to allow for the identification of large numbers of potential participants. Conclusions In conclusion, our model incorporating social marketing and relationship building was quite successful in recruiting for a prostate cancer behavioral study, particularly AA participants. In developing strategies, future researchers should attend to issues of staffing, financial resources, physician support, and eligibility criteria in the light of study accrual. Clinical Trials 2010; 7: 411—417. http://ctj.sagepub.com

Assessing Cancer Prevention Studies—A Matter of Time

To reduce the incidence of neural tube defects, the US Food and Drug Administration (FDA) mandated folic acid fortification of flour and other grains beginning in 1998.1 Subsequent studies showed an overall increase in mean folic acid levels among US residents.2, 3. Within a few years of this mandate, a decrease in the incidence of neural tube defects was noted in newborn infants.4 However, longer-term benefits of FA fortification for disease prevention5 including multiple cancers6–8 remain to be documented. Animal studies suggest that modest supplementation can reduce carcinogenesis. On the other hand, high doses of FA may speed cell division and increase tumor progression in preneoplastic lesions.9, 10 Better understanding of time frame and dosage is key to balancing risk and benefits. In this issue of JAMA, Ebbing et al 11 present evidence of the association between FA treatment and cancer incidence and mortality, and all-cause mortality among persons in Norway, a country without FA food fortification. The study, a combined analysis of two randomized controlled trials (RCTs), evaluates an intervention with folic acid and B vitamins in high-risk cardiovascular disease patients as an adjunct to treatment to prevent recurrent cardiovascular disease or death after acute MI. The analysis addresses whether folic acid treatment in this group of patients is associated with a change in cancer incidence or mortality risk. Participants were randomized to one of four treatment groups containing a combination of FA 0.8mg, B12 0.4mg and vitamin B6 40mg. After a median of 39 months on trial and a further 38 months of voluntary follow-up, those receiving FA and B12 were at increased risk of cancer diagnosis, cancer mortality, and all-cause mortality. Understanding of time frame and dosage of FA administration will help to put these findings in context. There are three ways to address time frame: in the disease process, in exposure, and in study design. As for the disease process, most cancers can be prevented with changes in lifestyle. How long it takes to achieve benefit from a change in lifestyle is not well understood. Folic acid fortification and neural tube defects are one clear example of the disease process. Results are relatively immediate because pre-conception and in utero exposures to folic acid lead to reduced birth defects in a 9-month window.12 For cancer, on the other hand, a longer etiologic process means that causal and preventive exposures have a cumulative lifetime effect as cells progress from normal through accumulation of multiple genetic changes to final malignancy. Evidence for cancer shows that average folic acid intake of US adults is inversely related to incidence.6 In a prospective analysis in which prediagnostic levels of plasma folic acid were measured, there were significant inverse associations with colorectal cancer-specific and overall mortality before and after US food fortification,8 with 50% reductions in mortality risk. The preventive benefits of folic acid on tumor initiation will decrease cancer initiation rates in a population that would have otherwise been susceptible without FA.13 Mortality rates will be lower decades later. The current scientific evidence offers limited data on folic acid interacting with already present lesions in the short term. Plasma levels measured 2 or more years before diagnosis suggest no adverse effect on survival 6. Nor has the time frame been defined for inhibiting the development of new precursor lesions in the longer term. How such effects balance out at the population level will likely vary over time. To estimate these trade-offs at the population level requires knowledge of the proportion at each stage of progression from normal tissue to premalignant lesions to malignancy, which is currently unknowable. Duration of exposure is most precisely measured for tobacco use, drugs and vitamins. For example, data from 2 RCTs of aspirin and incident colorectal cancer show no significant benefit after 10 years. However, after a median of 23 years of follow-up a significant reduction in colorectal cancer was observed.14 Duration of prevention studies is quite variable, but RCTs most often are short-term due to the demands on participants to comply with an intervention. Observational studies on the other hand can accumulate exposure over the life course. The randomized trial design may be most helpful to evaluate specific prevention research questions when the benefit will be observed shortly after the implementation of an intervention. These interventions may be able to be more tightly controlled in a short term study, and often lead to looking for effects that fit the time frame. By analogy, when keys are missing, it is common to look for them under the lamppost where there is light rather than in the murky location where the keys were more likely dropped. Lack of adherence over time further hinders this design for long-term prevention studies. Long-term follow-up will often inform issues of duration of an intervention necessary to achieve a preventive benefit. For example, with the use of repeated measures, the duration and timing of exposure in the disease process can be measured more precisely. Clarifying the question being asked by different studies is essential for using the data to inform practice. In addition, the intervention dosage and mean plasma folic acid levels in the US population as a whole 2, 3, 8 are lower than the levels in the treatment group of the study by Ebbing et al 11 and other studies.15 Food fortification has led to an increased folic acid intake by an average of 100 µg/day and the proportion of adults reaching 400 µg/day is still below FDA targets.3 According to data from NHANES, less than 4% of the population age 65 and older consume 1 mg/day or more of folic acid with the largest percentage of the population consuming between 0.3 and 0.4 mg/day.3 The intervention in the current trial (800 µg/day) among patients after myocardial infarction occurred in a folic acid-poor Norwegian population. Extrapolating from this high dosage to the US population is complex. However, US fortification appears to have left the population well within safe limits. What do the results of the study by Ebbing et al 11 mean for population health and for clinicians ? The results indicate an excess of approximately 3.5 new cases of cancer per 1000 per year and 1 excess case of lung cancer per 1000 per year. The excess deaths correspond to 1.7 cancer deaths per 1000 per year. These numbers, if generalizable to the US, would be substantial at the overall level of total cancer incidence and mortality. Moreover, given the changes in blood levels of folic acid in the US, an increase in lung cancer incidence would be expected. However, rates for total cancer incidence decreased significantly from 2001 to 2005,16 and lung cancer incidence has also declined significantly in men over almost two decades and among women from the late 1990s.16 These national incidence rates do not support a substantial, population-wide adverse effect of the magnitude suggested in the study be Ebbing et al. Preventive interventions require long-term evaluation. While the report by Ebbing et al provides important short term data, the findings do not nullify the potential long-term benefits that folic acid fortification may have on population health. The time frame for benefit for some preventive interventions may span decades 17, although smoking cessation may be unique among lifestyle changes that produce a rapid reduction in cancer risk.18 Cancer prevention efforts do not start or end with folic acid. Cessation of cigarette smoking for all who currently smoke and prevention of smoking in youth and adolescents remains the highest priority for cancer prevention. For those who do not smoke, eating a healthy diet and exercising to avoid weight gain or maintain weight loss will translate to lower risk of cancer, diabetes, and other chronic conditions. These are population-wide changes that take time, and the benefits of such lifestyle changes can take years, even decades to realize.