Citations

Abstract Purpose: The ultimate purpose of these studies and the proposed study is to use community-based interventions to increase overall use of mammographic services and to increase adherence with tribes' screening guidelines. Our immediate purposes by study: For Study 1, the purpose was to understand the risk and screening adherence profiles of women from four Bemidji Area tribes; for Study 2, the purpose was to ascertain whether non-adherent screeners and adherent screeners could be differentiated on any of six theoretical mediators of health behavior; in the proposed Study 3, the purpose is to use theoretical mediators that distinguish adherent and non-adherent screeners to design and test interventions to increase screening participation and adherence with tribes' screening guidelines. Experimental Procedures: All studies were designed to reflect principles of community-based participatory research. Study 1 was a chart review study that involved four tribes. Each tribe desired different levels of involvement that ranged from close control of all elements of the chart review to assigning the investigators to do the retrieval, review, and replacement of the medical records, and all elements of the analysis. All tribes managed the unique identifiers book which was a list of all women who were 40 years and older who had no prior history of breast cancer. Investigators retained only the unique identifiers and each individual's associated screening history and risk factors. Tribes received aggregated results from the study, but did not receive information on individual women's screening adherence or risk factors. Study 2, is guided by a community advisory committee that meets quarterly and involves one tribe. The study employs one tribal member and one tribal subcontractor, and has supported one student participant. The study team interviewed 55 women and used the results to develop a survey that is being administered to approximately 1400 women who are age 40 and older. Both the interviews and the survey are designed to examine the influence of six theoretical mediators (social norms, social networks, social support, health literacy, health beliefs, and theory of planned behavior) and demographic features on the behaviors of adherent and non-adherent mammographic screeners. Study 3 will involve four tribes and is designed to use the findings from Study 2 to develop and test interventions based on influential screening mediators. Each tribe has identified members who will serve on tribal research and advising units that will determine the specific interventions and receive training and mentoring to design and administer the interventions. The proposed interventions will be based on a case-control intervention design. Unpublished Data to Date: STUDY 1 showed that there were few significant differences (p = 0.05) based between adherent and non-adherent screeners based on risk factors. STUDY 2 interview results have shown some significant differences (p= 0.05) between adherent and non-adherent screeners related to self-efficacy (health beliefs model), perceived community support for annual mammograms (social norms), presence of 3rd degree relatives in social networks. There were no significant differences associated with health literacy, social support, and the theory of planned behavior. Conclusions: Findings in Study 2 show that potential differences between adherent and non-adherent screeners justify continuation to the survey phase. Should results of the survey demonstrate significant differences in the influential mediators of adherent compared to non-adherent screeners, follow-up with the intervention study (Study 3) will be an important next step. Citation Format: Wesley Petersen, Ann Nicometo, Robert Vierkant. Advancing toward interventions: Summary of two projects and a proposed intervention to improve mammography participation in Bemidji area native women. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr B91. doi:10.1158/1538-7755.DISP13-B91

Abstract Background: The health benefits associated with maintaining adequate circulating levels of vitamin D are well known. More recently, data have emerged supporting an inverse association between vitamin D levels and risk of several human cancers. Related to this, African Americans (AAs) are at increased risk of hypovitaminosis D due to elevated levels of melanin in the skin that reduce the conversion of cholesterol to vitamin D3 (cholecalciferol). Herein, we simultaneously assess levels of awareness regarding the health benefits of vitamin D and the prevalence of hypovitaminosis D in a metropolitan African American community. Methods: From January 2012 through August 2013, we partnered with African American churches and community organizations in the metropolitan Jacksonville, FL area to provide nine education programs focused on vitamin D and the evidence linking poor vitamin D levels with increased risk of chronic disease, including cancer. Participants were offered free vitamin D testing to estimate the prevalence of vitamin D insufficiency (<25 ng/mL) and deficiency (< 15 ng/mL) in this population. Moreover, participants also completed surveys prior to the events to assess their awareness of issues related to vitamin D, including the emerging link with cancer risk. Results: Out of 305 attendees, 285 agreed to provide blood samples for vitamin D screening. Of these, 262 (92%) self-identified as African American (75% female, 25% male). The median age of the AA participants was 59 years. Laboratory testing for 25(OH) vit D revealed 43% of the AA participants had normal levels of vitamin D (>25 ng/mL), 35% had insufficient levels (15-24 ng/mL) and 22% had deficient levels (< 15 ng/mL). Of interest, despite the high level of hypovitaminosis D (insufficient + deficient) in this population, participants reported high levels of awareness regarding vitamin D prior to the education program. For example, 82% of AA respondents correctly answered that the main source of vitamin D came from sunlight and 76% correctly answered that AAs are at risk of lower levels of vitamin D because of the amount of melanin in the skin. Moreover, 83% of AA respondents answered that maintaining proper vitamin D levels could potentially decrease risk for various chronic health conditions, including certain cancers. Finally, 75% of the AA participants reported never having had a vitamin D test discussed with them by their doctor. Conclusions: We report a high prevalence of hypovitaminosis D in a large AA community in Jacksonville, FL. Moreover, we report that despite this high prevalence, awareness of the health benefits of vitamin D are high, yet regular vitamin D testing levels appear to be very low. These data provide the foundation for developing targeted interventions to raise vitamin D levels in this community. Citation Format: Alexander Parker, Monica Albertie, Nancy Diehl, Matthew Drake. Evaluation of the prevalence of hypovitaminosis D and vitamin D awareness in African Americans living in a metropolitan southern community. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr B61. doi:10.1158/1538-7755.DISP13-B61

Abstract Background: Racial disparities in breast cancer (BC) outcomes are well-documented. As guidelines for BC screening change, it is particularly important that women have accurate knowledge of risk factors in order to meaningfully participate in screening decisions. We examined knowledge of risk factors for BC among a nationally representative sample of women for whom mammography screening is routinely recommended. Method: Non-Hispanic black (B), non-Hispanic white (W), Hispanic (H), and women of other/multiple races (O) were surveyed using a probability-based web panel weighted to match the known U.S. population of females aged 40-74 years. A total of 17 items were presented in English or Spanish; response options included: “does not put you at increased risk,” “puts you at a small increased risk,” and “puts you at a large increased risk.” For scoring, the latter two categories were combined to reflect “increased risk.” Items included 9 established risk factors: having mammographically dense breasts, first-degree relative diagnosed with BC, second-degree relative diagnosed with BC, drinking alcohol in excess, history of a breast biopsy, having a first child after age 30, use of hormone therapy for postmenopausal symptoms, BRCA gene mutation, late onset of menopause; 5 protective factors: menarche after age 15, having children, breastfeeding, having a diet rich in fruits and vegetables, exercising or being active; one factor with no clear association: being a smoker (correct response was no increased risk); and 2 distractors (beliefs for which there is no evidence, correct response was no increased risk): using antiperspirant/talc under your arms, experiencing injury/trauma to the breast. The survey cooperation rate was 65% (1,506 responders out of 2,311). Items were scored correct if the respondent's answer matched the actual risk profile (either does/does not put you at increased risk). Percent correct was calculated for each item overall and by race/ethnicity. All reported percentages and analyses are weighted to be nationally representative and compared for differences based on race/ethnicity using logistic regression models. P-values represent differences in percent correct between the racial/ethnic groups. Results: Knowledge of risk factors varied across items (range >90% to 20% correct). Percent correct was high overall for classifying a first-degree relative with BC as a risk factor and differed by race/ethnicity, with 86% B, 98% W, 92% H and 92% O recognizing this risk factor (p<0.001); similar percentages were observed for second-degree relatives (p=0.003). Lower knowledge overall was observed for risk factors including BRCA mutation (25% B, 44% W, 24% H, 38% O, p=0.002), later onset of menopause (41% B, 38% W, 42% H, 37% O, p=0.92), and having the first child after age 30 (39% B, 41% W, 38% H, 33% O, p=0.53). Having mammographically dense breasts is one of the strongest risk factors for BC, however knowledge of this was only moderate and did not differ by race/ethnicity (61% B, 54% W, 56% H, 52% O, p=0.64). Relative to risk factors, knowledge of protective factors was generally higher; only correct classification of fruits/vegetables as a protective factor differed by race/ethnicity (84% B, 93% W, 88% H, 89% O, p=0.03). Most women correctly responded that use of antiperspirant/talc does not increase risk of BC, however 60% of H women incorrectly classified injury/trauma to the breast as a risk factor, relative to 50% B, 41% W, and 40% O (p=0.02). Conclusions: Among U.S. women, there is wide variation in knowledge across several established BC risk factors and only moderate knowledge of breast density as an important risk factor. Differences in knowledge by race/ethnicity for several risk factors highlight the need for targeted education. Citation Format: Carmen Radecki Breitkopf, Deborah J. Rhodes, Sarah M. Jenkins, Jeanette Y. Ziegenfuss, Celine M. Vachon. Racial and ethnic differences in knowledge of risk factors for breast cancer: Findings from a recent national survey. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr B42. doi:10.1158/1538-7755.DISP13-B42

Abstract Although the association between benign breast disease (BBD) and risk of subsequent breast cancer is well-established, no previous studies have compared characteristics of breast cancers in women with a history of BBD to characteristics of cancers in the general population. In this study, we compared the characteristics of 109 breast cancers that developed in a population of African-American women with a history of benign breast disease (BBD population) to 10,601 breast cancers that developed in a general population of African-American women whose cancers were recorded by the Metropolitan Detroit Cancer Surveillance System (MDCSS population). The populations were compared on demographic characteristics such as age, marital status, and previous cancers, as well as clinical characteristics such as tumor hormone receptor status, grade, stage, behavior, size, and treatment. Overall and breast cancer-specific survival were also compared between populations. Women in the BBD population developed lower grade, earlier stage cancers that were more likely to be hormone receptor-positive and less likely to exhibit invasive behavior. Women in the BBD population were also significantly less likely to die from breast cancer after ten years of follow-up. These results suggest that although women with a history of BBD are at greater breast cancer risk, their breast cancers may be more likely to be detected early, leading to better breast cancer-specific survival. Citation Format: Susanna D. Mitro, Rouba Ali-Fehmi, Sudeshna Bandyopadhyay, Baraa Alosh, Bassam Albashiti, Quratulain Ahmed, Derek C. Radisky, Marlene H. Frost, Amy C. Degnim, Julie J. Ruterbusch, Michele L. Cote. Clinical characteristics of breast cancers in African American women with benign breast disease: A comparison to the Surveillance, Epidemiology and End Results Program. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr B39. doi:10.1158/1538-7755.DISP13-B39

AbstractThe population pharmacokinetic model reported here was developed using data from 2 phase 2 trials of irinotecan for treatment of malignant glioma to quantify the impact of concomitant therapy with enzyme‐inducing antiepileptic drugs (EIAEDs) on irinotecan pharmacokinetics. Patients received weekly irinotecan doses of 100 to 400 mg/m2, and plasma samples were collected and analyzed for irinotecan and its APC, SN‐38, and SN‐38G metabolites. Nonlinear mixed‐effects modeling was employed for population pharmacokinetic analysis. Concomitant therapy with phenytoin, phenobarbital, or carbamazepine increased the clearances of irinotecan, SN‐38, and SN‐38G but not APC. SN‐38 clearance was 2‐fold higher with concomitant EIAED use, resulting in 40% lower SN‐38 exposure. Evaluation of additional covariates revealed no clinically relevant effects of sex or concomitant corticosteroid use. The population pharmacokinetic model suggests that a 1.7‐fold increase in irinotecan dose may compensate for decreases in SN‐38 exposure in the presence of concomitant EIAEDs. Although slightly more conservative, this dose adjustment is consistent with those recommended based on increases in the maximally tolerated dose for malignant glioma patients receiving EIAEDs and may be an appropriate starting point for further investigation when extrapolating to other cancer types or alternative regimens.

ABSTRACTIntravenous immunoglobulin [IVIg], plasma exchange [PE], and corticosteroids are efficacious treatment in chronic inflammatory demyelinating polyneuropathy [CIDP]. IVIg is effective in multifocal motor neuropathy [MMN]. NIS, NIS‐weakness, sum scores of raw amplitudes of motor fiber (CMAPs) amplitudes, and Dyck/Rankin score provided reliable measures to detect and scale abnormality and reflect change; they are therefore ideal for office management of response‐based immunotherapy (R‐IRx) of CIDP. Using efficacious R‐IRx, a large early and late therapeutic response (≥ one‐fourth were in remission or had recovered) was demonstrated in CIDP. In MMN only an early improvement with late non‐significant worsening was observed. The difference in immunotherapy response supports a fundamental difference between CIDP (immune attack on Schwann cells and myelin) and MMN (attack on nodes of Ranvier and axons). Muscle Nerve 52: 488–497, 2015

Abstract Pancreatic cancer, one of the most lethal forms of human cancer, is largely resistant to many conventional chemotherapeutic agents. Although many therapeutic approaches focus on tumor growth, metastasis is a primary factor contributing to lethality. Therefore, novel therapies to target metastatic invasion could prevent tumor spread and recurrence resulting from local and distant metastasis. The protein Vav1 is aberrantly expressed in more than half of pancreatic cancers. Its expression promotes activation of Rac and Cdc42 and leads to enhanced invasion and migration, as well as increased tumor cell survival and proliferation, suggesting that Vav1 could be a potent therapeutic target for pancreatic cancer. The purine analogue azathioprine, well known for its function as an anti-inflammatory compound, was recently shown to function by inhibiting Vav1 signaling in immune cells. We therefore hypothesized that azathioprine could also inhibit Vav1 in pancreatic tumor cells to reduce its proinvasive functions. Indeed, we have found that treatment of cultured pancreatic tumor cells with azathioprine inhibited Vav1-dependent invasive cell migration and matrix degradation, through inhibition of Rac and Cdc42 signaling. Furthermore, azathioprine treatment decreased metastasis in both xenograft and genetic mouse models of pancreatic cancer. Strikingly, metastasis was dramatically reduced in Vav1-expressing tumors arising from p48Cre/+, KrasG12D/+, p53F/+ mice. These inhibitory effects were mediated through Vav1, as Vav1-negative cell lines and tumors were largely resistant to azathioprine treatment. These findings demonstrate that azathioprine and related compounds could be potent antimetastatic agents for Vav1-positive pancreatic tumors. Cancer Res; 75(14); 2907–15. ©2015 AACR.

Background— The incidence and cause of sudden cardiac death (SCD) in athletes is debated with hypertrophic cardiomyopathy often reported as the most common cause. Methods and Results— A database of all National Collegiate Athletic Association deaths (2003–2013) was developed. Additional information and autopsy reports were obtained when possible. Cause of death was adjudicated by an expert panel. There were 4 242 519 athlete-years (AY) and 514 total student athlete deaths. Accidents were the most common cause of death (257, 50%, 1:16 508 AY) followed by medical causes (147, 29%, 1:28 861 AY). The most common medical cause of death was SCD (79, 15%, 1:53 703 AY). Males were at higher risk than females 1:37 790 AY versus 1:121 593 AY (incidence rate ratio, 3.2; 95% confidence interval, 1.9–5.5; P <0.00001), and black athletes were at higher risk than white athletes 1:21491 AY versus 1:68 354 AY (incidence rate ratio, 3.2; 95% confidence interval, 1.9–5.2; P <0.00001). The incidence of SCD in Division 1 male basketball athletes was 1:5200 AY. The most common findings at autopsy were autopsy-negative sudden unexplained death in 16 (25%), and definitive evidence for hypertrophic cardiomyopathy was seen in 5 (8%). Media reports identified more deaths in higher divisions (87%, 61%, and 44%), whereas the percentages from the internal database did not vary (87%, 83%, and 89%). Insurance claims identified only 11% of SCDs. Conclusions— The rate of SCD in National Collegiate Athletic Association athletes is high, with males, black athletes, and basketball players at substantially higher risk. The most common finding at autopsy is autopsy-negative sudden unexplained death. Media reports are more likely to capture high-profile deaths, and insurance claims are not a reliable method for case identification.

A mouse model for ALS A G4C2 repeat expansion in C9ORF72 is known to be the major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). However, a lack of animal models recapitulating key disease features has hindered efforts to understand and prevent c9FTD/ALS-related neurodegeneration. Until now. Chew et al. describe a mouse model that mimics both neuropathological and clinical phenotypes of c9FTD/ALS. Science , this issue p. 1151

Abstract Background: Physical activity is associated with a lower incidence of colorectal cancer; however, the relationship of physical activity with colorectal cancer survival is not yet clear. We evaluated the association between prediagnostic physical activity and colorectal cancer survival, overall and accounting for tumor markers associated with colorectal cancer survival: BRAF and KRAS mutation status and microsatellite instability (MSI) status. Methods: Participants were 20- to 74-year-old colorectal cancer patients diagnosed between 1998 and 2007 from the population-based Seattle Colon Cancer Family Registry (S-CCFR). Self-reported physical activity in the years preceding colorectal cancer diagnosis was summarized as average metabolic equivalent task hours per week (MET-h/wk; n = 1,309). Somatic BRAF and KRAS mutations and MSI status were evaluated on a subset of patients (n = 1043). Cox regression was used to estimate HRs and 95% confidence intervals (CI) for overall and disease-specific survival after adjusting for relevant confounders. Stratified analyses were conducted across categories of BRAF, KRAS, and MSI, as well as tumor stage and site. Results: Higher prediagnostic recreational physical activity was associated with significantly more favorable overall survival (HR for highest vs. lowest category, 0.70; 95% CI, 0.52–0.96); associations were similar for colorectal cancer–specific survival. Results consistently indicated a favorable association with physical activity across strata defined by tumor characteristics. Conclusion: Individuals who were physically active before colorectal cancer diagnosis experienced better survival than those who were inactive or minimally active. Impact: Our results support existing physical activity recommendations for colorectal cancer patients and suggest that the beneficial effect of activity is not specific to a particular molecular phenotype of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(7); 1130–7. ©2015 AACR.