Christine L. Sardo Molmenti

A Phase Ib Study of the Effects of Black Raspberries on Rectal Polyps in Patients with Familial Adenomatous Polyposis

Familial adenomatous polyposis (FAP) is characterized by the early onset of colonic polyposis and a high risk for colorectal cancer. FAP is treated by colectomy followed by lifelong removal of rectal polyps. This study determined whether black raspberries (BRBs) might regress rectal polyps in patients with FAP. Fourteen patients with FAP were treated with BRBs daily for 9 months. Seven patients received BRB powder orally plus two BRB suppositories inserted into the rectum at bedtime. The other 7 received an oral placebo plus the suppositories. Rectal polyp counts and polyp sizes were obtained at time zero and after 9 months of BRB treatment. Polyps and adjacent normal tissue were collected at both time points. The burden (P = 0.036) but not number (P = 0.069) of rectal polyps was significantly decreased. No benefit was noted with the addition of oral BRBs. Three patients were nonresponders. BRBs significantly decreased cellular proliferation, DNA methylation methyl transferase 1 protein expression, and p16 promoter methylation, but not promoter methylation of the Wnt pathway antagonists, SFRP2 and WIF1, in rectal polyps (adenomas) from responders but not from nonresponders. The MBD-seq assay revealed more demethylated transcription start sites (TSS), including those for miRNAs, in BRB-treated adenomas from the responders. In conclusion, BRB suppositories seem sufficient for regressing rectal polyps in patients with FAP. Cancer Prev Res; 7(7); 666–74. ©2014 AACR.

Trends in Obesity Prevalence in Adults With a History of Cancer: Results From the US National Health Interview Survey, 1997 to 2014

PURPOSE Obesity after a diagnosis of specific cancers has been associated with worse prognosis. We examined the trend in obesity prevalence among cancer survivors in the United States in the past two decades and compared trends with those of adults without a history of cancer. PATIENTS AND METHODS This was a population-based nationally representative sample of 538,969 noninstitutionalized US adults 18 to 85 years old with and without a history of cancer who participated in annual cross-sectional National Health Interview Surveys from 1997 to 2014. Obesity was defined as body mass index ≥ 30 kg/m(2) for non-Asians and body mass index ≥ 27.5 kg/m(2) for Asians. RESULTS Among 32,447 cancer survivors identified, the most common cancer diagnoses were breast (n = 6,948), prostate (n = 3,984), and colorectal (n = 2,546). From 1997 to 2014, the prevalence of obesity increased from 22.4% to 31.7% in cancer survivors and from 20.9% to 29.5% in adults without a history of cancer (P for trend < .001, both groups). Over this period, the estimated rate of annual increase in obesity prevalence was higher in women and men with a history of cancer compared with those without a history of cancer (all P for interaction < .001). The estimated rate of annual increase in obesity prevalence was 3.1% in female and 3.7% in male colorectal cancer survivors, 3.0% in breast cancer survivors, and 2.1% in prostate cancer survivors (all P < .001). In subgroup analyses, populations with the highest rates of increasing obesity burden were colorectal cancer survivors, breast cancer survivors, and non-Hispanic blacks. CONCLUSION From 1997 to 2014, obesity increased more rapidly among adult cancer survivors compared with the general population. Colorectal and breast cancer survivors and non-Hispanic blacks were identified as being at the highest risk for obesity.

Concentrations of the Vitamin D Metabolite 1,25(OH)2D and Odds of Metabolic Syndrome and its Components

AIM Few epidemiological studies have investigated the association between circulating concentrations of the active vitamin D metabolite 1,25(OH)2D and metabolic syndrome. We sought to determine whether blood levels of 1,25(OH)2D are associated with metabolic syndrome and its individual components, including waist circumference, triglycerides, blood pressure, and glucose, and high-density lipoprotein. We also investigated these associations for the more abundant precursor vitamin D metabolite, 25(OH)D. METHODS Participants from two completed clinical trials of colorectal neoplasia with available metabolic syndrome data and blood samples for measurement of 1,25(OH)2D (n=1048) and 25(OH)D (n=2096) were included. Cross-sectional analyses of the association between concentrations of 1,25(OH)2D, 25(OH)D, metabolic syndrome, and its components were conducted. RESULTS A statistically significant inverse association was observed for circulating concentrations of 1,25(OH)2D and metabolic syndrome, with adjusted ORs (95% CIs) of 0.73 (0.52-1.04) and 0.52 (0.36-0.75) for the second and third tertiles of 1,25(OH)2D, respectively (p-trend <0.001). Significant inverse relationships were also observed between 1,25(OH)2D and high triglycerides (p-trend <0.001), and low high-density lipoprotein (p-trend <0.001). For 25(OH)D concentrations, significant inverse associations were found for metabolic syndrome (p-trend <0.01), high waist circumference (p-trend <0.04) and triglyceride levels (p-trend <0.01). Participants with 25(OH)D ≥30 ng/ml and in the highest tertile of 1,25(OH)2D demonstrated significantly lower odds of metabolic syndrome, with an OR (95% CI) of 0.38 (0.19-0.75) compared to those in the lowest category for both metabolites. CONCLUSION These results provide new evidence that the relatively rarely-studied active hormonal form of vitamin D, 1,25(OH)2D, is associated with metabolic syndrome and its components, and confirm prior findings for 25(OH)D. The finding that 1,25(OH)2D is related to high-density lipoprotein, while 25(OH)D is not, suggests that there may be an independent mechanism of action for 1,25(OH)2D in relation to metabolic dysregulation.

Physical activity, sedentary behavior, and vitamin D metabolites

Physical activity is associated with circulating 25-hydroxyvitamin D (25(OH)D). However, the influence of activity and/or sedentary behavior on the biologically active, seco-steroid hormone 1α,25-dihydroxyvitamin D (1,25(OH)2D) is unknown. We conducted a cross-sectional analysis among ursodeoxycholic acid (UDCA) randomized trial participants (n=876) to evaluate associations between physical activity, sedentary behavior, and circulating vitamin D metabolite concentrations. Continuous vitamin D metabolite measurements and clinical thresholds were evaluated using multiple linear and logistic regression models, mutually adjusted for either 1,25(OH)2D or 25(OH)D and additional confounding factors. A statistically significant linear association between 1,25(OH)2D and moderate-vigorous physical activity per week was strongest among women (β (95% CI): 3.10 (1.51-6.35)) versus men (β (95% CI): 1.35 (0.79-2.29)) in the highest tertile of activity compared to the lowest (p-interaction=0.003). Furthermore, 25(OH)D was 1.54ng/ml (95% CI 1.09-1.98) higher per hour increase in moderate-vigorous activity (p=0.001) and odds of sufficient 25(OH)D status was higher among physically active participants (p=0.001). Sedentary behavior was not significantly associated with either metabolite in linear regression models, nor was a statistically significant interaction by sex identified. The current study identified novel associations between physical activity and serum 1,25(OH)2D levels, adjusted for 25(OH)D concentrations. These results identify the biologically active form of vitamin D as a potential physiologic mechanism related to observed population-level associations between moderate-vigorous physical activity with bone health and chronic disease risk. However, future longitudinal studies are needed to further evaluate the role of physical activity and vitamin D metabolites in chronic disease prevention.

Phase II Feasibility Study of a Weight Loss Intervention in Female Breast and Colorectal Cancer Survivors (SWOG S1008).

This study aimed to test the feasibility of a 12‐month weight loss intervention using telephone‐based counseling plus community‐situated physical activity (PA) in female breast cancer (BC) and colorectal cancer (CRC) survivors.

Abstract 1888: Calcium, magnesium, and vitamin D metabolites in colorectal adenoma prevention

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA In addition to the synergistic interaction between calcium and vitamin D observed in many previous studies, a recent study found that magnesium may also modify the association between serum 25-hydroxyvitamin D (25D) and risk colorectal cancer mortality. However, the study was unable to include the biologically active form of vitamin D, 1α,25-dihydroxyvitamin (1,25D), a critical component of calcium homeostasis. Both 1,25D and its precursor metabolite 25D are associated with increased risk of colorectal neoplasia when circulating concentrations are low. Furthermore, no study has investigated whether magnesium may also modify the association between serum vitamin D and risk of colorectal adenoma recurrence. We therefore conducted logistic regression analysis to evaluate the relationship between circulating vitamin D metabolites concentrations and risk of colorectal adenoma recurrence stratified by intake tertiles of magnesium or calcium, among 878 participants from the ursodeoxycholic acid randomized trial for colorectal adenoma prevention. Tertiles were created for all continuous exposure variables and all models were mutually adjusted for either magnesium or calcium, respectively. Although circulating 25D levels were not significantly associated with risk, those with 1,25D levels within the middle tertile were at significantly reduced risk of adenoma recurrence (OR = 0.68, 95% CI: 0.48-0.95). In stratified analysis by tertile of magnesium or calcium intake, we found higher 1,25D concentrations were associated with reduced risks of adenoma recurrence only for those with mean magnesium intake around the Recommended Dietary Allowance (RDA; i.e. 319 mg/day), particularly for proximal colorectal adenoma recurrence, with an OR of 0.48 (95% CI: 2.25-0.89) for the highest tertile of 1,25D compared to the lowest (p for trend, 0.02). Also, we found circulating 1,25D concentrations significantly interacted with intake of calcium in relation to risk of proximal colorectal adenoma recurrence (p for interaction, 0.01); and the inverse association between 1,25D and risk may primarily appeared in those who had intake of calcium close to or above Dietary Reference Intake (DRI) level (i.e. 1000 mg/day). No statistically significant interactions were observed for circulating 25D concentrations. Few studies have evaluated the role of 1,25D in colorectal adenoma recurrence or interactions with intake of calcium, and this is the first to examine the interaction between 1,25D with intake of magnesium. These results support the importance of interactions between calcium and magnesium homeostasis with the vitamin D endocrine system in the development of colorectal neoplasia; however, continued work, particularly large-scale studies, is necessary to replicate the finding and understand the cellular mechanism driving these population-level associations as well as applications to colorectal neoplasia prevention. Citation Format: Elizabeth A. Hibler, Peter W. Jurutka, Qi Dai, Christine L. Sardo Molmenti, Elizabeth T. Jacobs. Calcium, magnesium, and vitamin D metabolites in colorectal adenoma prevention. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1888. doi:10.1158/1538-7445.AM2015-1888