Citations

Abstract Multiple myeloma (MM) is a cancer of the plasma cells in the bone marrow. Although rare, MM is a deadly form of cancer with a 5 year survival rate of only 37%. African Americans (AA) are twice as likely to be diagnosed with and die from MM as compared to European Americans (EA). Socioeconomic factors may contribute to this disparity, however, biological factors may also be an influence. We have identified somatic copy number alterations in MM as a part of the Multiple Myeloma Genomics Initiative by profiling 250 MM tumors using array-based comparative genomic hybridization (aCGH). Using this cohort, we identified 16 African American and 180 European American patients using a MMRC database that indicated the racial demographics of each patient. To determine if somatic alterations may play a role in the disparity in incidence and/or severity of MM in AA, we compared the frequency of specific chromosomal aberrations in genes and genomic regions found to be involved in progression and poor outcome. The number of events of occurring was calculated and a univariate analysis was conducted using the Fisher's exact test. P-values were used to determine statistical significance. Results revealed significant differences for chromosome 1 p alterations. Specifically, homozygous deletion at the p18 locus at 1 p occurred in 12.5% (2/16) of tumors from AA patients and 2.8% (5/180) of EA patient tumors (p = 0.045). Further stratification of tumors by hyperdiploid or non-hyperdiploid status revealed significant differences in p18 homozygous deletion. Homozygous deletion of p18 was found in 25% (2/8) of AA patients and only 1.2% (1/83) of EA patients with non-hyperdiploid tumors (p=3.2 × 10-4). A nominally significant difference among non-hyperdiploid patients was also present for overall 1 p deletion, which was observed in 2/8 (25%) of AA non-hyperdiploid tumors and 33/83 (40%) of EA with non-hyperdiploid tumors (p=0.05). No differences were observed for 1 p deletion or p18 homozygous deletion among hyperdiploid tumors between AA and EA patients. We then combined our AA dataset with an independent dataset of 8 AA MM patients generated at the Mayo Clinic, Scottsdale AZ and repeated the analysis. Interestingly, very little or no aberrations were found in the dataset from the Mayo Clinic, however, differences of p18 homozygous deletion and 16q deletion among AA and EA remained statistically significant. To determine the correlation between hemizygous and biallelic loss of p18 and poor prognosis we used the 70 gene signature (Shaughnessy, et al., 2007) as a surrogate to identify patients with poor prognosis within the Multiple Myeloma Genomics Initiative dataset. Genomic identification of significant targets in cancer (GISTIC) was used (Beroukhim et al., 2007) to identify regions of aberrant copy number that were over-represented among samples. A relationship between poor prognosis and biallelic loss was found to be statistically significant (p = 0002) while samples with hemizygous loss showed no relationship (p = 0.57). Although the size of the current AA cohort is small, these results suggest that homozygous deletions at the p18 locus may be more common among African American MM patients with non-hyperdiploid tumors which may help to explain the disparity in AA patients with MM. Array CGH is currently being conducted on an additional 40 tumors from AA MM patients for a more robust analysis. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):B64.

Abstract Purpose: The purpose of this study was to describe breast cancer risk factors and screening patterns in a sample of American Indian and Alaska Native (AI/AN) women from four tribes within the Bemidji Area of the Indian Health Service (Northern Plains region), and to ascertain the association between risk factors and adherence to mammographic screening guidelines. The IHS has noted that economic factors make increases in screening participation difficult. In this light, understanding the relationship between risk factors and screening adherence is an important first step in developing interventions to improve screening participation, especially for women at higher risk of breast cancer. Lending importance to the role of screening in reducing breast cancer deaths in Northern Plains AI/AN women are rates of later stage (regional or distant disease) diagnoses that are equal to the Non-Hispanic White (NHW) population (95.8 and 95.4/100,000 respectively). Later stage at diagnosis is associated with worse survival profiles. Procedures/Methods: Criteria for inclusion in this study were: ≥ 40 years of age, at least one mammogram on file, and no history of breast cancer. We reviewed the charts of 20% of eligible women in four tribes (1190 records). The study collected Gail Model risk factor data and also assigned BIRADS scores to at least one mammogram for each woman. For each Gail Model risk factor (age, age at menarche, age at first live birth, number of first degree relatives with a breast cancer history, breast biopsy, number of biopsies, history or atypical hyperplasia), women were assigned to higher or lower risk categories by comparison with calculated scores for women of the same age. Overall five-year and lifetime Gail Model risk scores also were calculated for each woman and compared with predicted risk for women of equivalent ages. For breast density, women were determined to be at lower risk if their BIRADS score was 1 or 2, and at higher risk if they were scored 3 or 4. To ascertain levels of screening adherence, we followed American Cancer Society (ACS) guidelines which recommend an annual mammogram beginning at age 40. We used this standard because it is the recommendation given to women in the clinics where the study was conducted. All women who received screening exams within 1.2 years (14.4 months) were considered adherent. Summary of Findings: There was no significant difference between overall Gail Model 5-year risk scores of Bemidji Area AI/AN women and the predicted scores. Bemidji Area women have a significantly lower lifetime risk than what is predicted. For individual risk factors, high screening adherence was significantly associated only with chronological age (p = 0.04) and history of biopsy (p =0.02). There was no significant association between screening adherence and BIRADS density scores. Conclusions: Absence of a relationship between risk and adherence, which is low generally, suggests that women are not using their individual risk factors or their overall risk to guide their screening decisions. This suggests that personal and clinic-centered mediators should be identified to guide future interventions to increase the proportion of women who adhere to screening guidelines, especially women who are at greater risk. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):B106.

Abstract Introduction: Breast cancer is a major cause of cancer mortality in American Indian and Alaska Native (AIAN) women. However regional differences are striking with lowers rates in Arizona and highest in Alaska with almost a three-fold difference in incidence and mortality between the two states. These differences may be due in part to varying levels of biologic tumor aggressiveness. To evaluate this, we compared a panel of biomarkers on consecutively diagnosed AIAN breast cancer cases from AZ (N=53) and AK (N=42). Methods: Retrospective analysis of tissue blocks measured expression levels for the following panel of biomarkers: ER and PR (ordinally coded as positive vs. negative); her2, BCL-2, and EGFR (coded 0.1.2. and 3+) and P53, MIB-1 and cyclin D (continuous percent of cells stained). Distributions of biomarker values were compared across state of residence using t-tests for continuous and ordinally scaled markers and chi-square tests of significance for binary markers. Age adjusted analyses were also carried out using linear and logistic regression models as appropriate to account for possible differences in age at diagnosis across states. Chart reviews recorded demographics and treatment characteristics. Results: The following demographics were observed with 95 cases of AIAN women with breast cancer analyzed. Average age at diagnosis was similar in the two states (mean, 58.4 for AZ vs. 56.1 for AK, t-test p value=0.45). 74% presented with a palpable mass. 32% had lumpectomy and axillary node dissection. 28% were premenopausal. 8% had a first-degree relative with breast cancer. 46% received adjuvant chemotherapy. 54% received adjuvant hormonal therapy. Cases from AK had higher levels of p53 staining (40.3 vs. 18.5, p=0.004) and lower levels of both EGFR (mean ordinal scaling 0.15 vs. 0.53, p=0.02) and Her2 (mean ordinal scaling 0.81 vs. 1.32, p=0.02) tan those from AZ. No differences in distribution were observed for MIB-1, Cyclin D, BCL-2, ER or PR. When examined together, the triple negative combination of ER/PR/Her2 also did not differ across states (12% for AK vs.13%forAZ, p=0.85). Conclusions: Our findings indicate that regional differences in biomarker expression levels of P53, EGFR and Her2 may exist in AIAN women. Further research is needed to confirm our results and determine to what extent these differences may explain the observed differences in mortality. Genetic testing for BRCA1,2 or other genetic associations with breast cancer have not been done in these populations and may also be useful to examine the reasons for differences in incidence and mortality. In addition, AIAN women are more likely to present with palpable masses representing higher risk stages of breast cancer. Outreach activities in this population continue to be highly important to change mortality. Supported in part by NCI U01 114609 Spirit of Eagles Community Network Program Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):A55.

Abstract Background: African Americans are underrepresented in cancer research trials. We propose that a collaborative effort with African American churches that brings cancer education events and a translational research project to the community with a mobile research unit will facilitate cancer awareness education and increase participation in translational research protocols among African Americans. Methods: From February 2010 through April 2010, Mayo Clinic partnered with predominantly African American Jacksonville churches, with the Volunteers in Medicine Clinic for the working uninsured, and with the local chapter of the Leukemia and Lymphoma Society, to provide 12 education programs focused on five behaviors that reduce cancer risk: proper nutrition, adequate fitness, tobacco cessation, breastfeeding, and limited alcohol consumption. Also offered during these programs was on site access to a translational cancer research pilot project evaluating the prevalence of t(14,18) and monoclonal proteins in African Americans and other racial/ethnic minorities. Translational research participation was facilitated by a mobile research unit (MRU), a converted RV that has sample collection, processing, and storage capabilities. Participants were surveyed on health knowledge and their willingness to participate in research. Results: A total of 236 of 318 participants (74%) returned written questionnaires provided during the education events. Forty-three percent resided in a health zone of Jacksonville that has worse health outcomes compared with any other sections of the city. Eighty-three percent responded that they had some type of health insurance and 88% had a primary care provider. Sixty-seven percent had never received any information on multiple myeloma, and 57% had never received information about clinical research studies. Sixty percent responded that they would participate in research studies and 61 % indicated that they would participate if the research focused on health issues that impacted African Americans. A total of 175 of 318 participants (55%) were enrolled in the translational research feasibility study. Seventy-two percent of the research study participants were female and 77% were African American, 19% Caucasians, and 4% Hispanic or of other racial/ethnic group. Ninety-three percent agreed to have their samples used for research of other health conditions and 85% agreed to have their samples shared with other research institutions. Conclusions: A high rate of participation in a blood collection translational research project was observed among this predominantly African American population. Most participants expressed a positive attitude towards research participation. Partnerships with African American churches in projects that provide community education and bring research to church venues with a mobile research unit are effective in improving health literacy related to a targeted topic, and in increasing translational research participation among African Americans. Funded by Mayo Clinic Comprehensive Cancer Center (NCI grant number P50-CA01508), Mayo Clinic CTSA (NCRR/NIH Grant Number 1 UL1 RR024150) and Active SPORE CA 90297052. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):A38.

Human epidermal growth factor receptor 2 (HER2) is an important prognostic and predictive factor in breast cancer. HER2 is overexpressed in approximately 15%–20% of invasive breast carcinomas and is associated with earlier recurrence, shortened disease free survival, and poor prognosis. Trastuzumab (Herceptin) a “humanized” monoclonal antibody targets the extracellular domain of HER2 and is widely used in the management of HER2 positive breast cancers. Accurate assessment of HER2 is thus critical in the management of breast cancer. The aim of this paper is to present a comprehensive review of HER2 with reference to its discovery and biology, clinical significance, prognostic value, targeted therapy, current and new testing modalities, and the interpretation guidelines and pitfalls.

Dexmedetomidine, is a α 2 adrenergic agonist approved by the Food and Drug administration for sedation and analgesia. A highly potent α 2 adrenergic agonist, it has quick onset of action, with peak effects within 1 hour of administration. It is metabolized in the liver and eliminated in the urine as a glucuronide. Dexmedetomidine is a substrate and inhibitor of cytochrome oxidase 2D6, but clinical evidence of significant drug interactions is lacking. Clinical trials suggest efficacy for the treatment of delirium in the intensive care unit setting with efficacy comparable to haloperidol and benzodiazepines. Dexmedetomidine also has an opioid-sparing action and can act to enhance analgesia. The purpose of this article is to review the pharmacodynamics and pharmacology of dexmedetomidine, and examine its potential use in the palliative care population, especially with regard to the management of delirium.

Coronary artery disease is a leading cause of death. Hypertension (HT) increases the incidence of cardiac events, but its effect on cardiac adaptation to coexisting coronary artery stenosis (CAS) is unclear. We hypothesized that concurrent HT modulates microvascular function in chronic CAS and aggravates microvascular remodeling and myocardial injury. Four groups of pigs ( n = 6 each) were studied: normal, CAS, HT, and CAS+HT. CAS and HT were induced by placing local irritant coils in the left circumflex coronary artery and renal artery, respectively. Six weeks later multidetector computerized tomography (CT) was used to assess systolic and diastolic function, microvascular permeability, myocardial perfusion, and responses to adenosine in the “area at risk.” Microvascular architecture, inflammation, and fibrosis were then explored in cardiac tissue. Basal myocardial perfusion was similarly decreased in CAS and CAS+HT, but its response to adenosine was significantly more attenuated in CAS. Microvascular permeability in CAS+HT was greater than in CAS and was accompanied by amplified myocardial inflammation, fibrosis, and microvascular remodeling, as well as cardiac systolic and diastolic dysfunction. On the other hand, compared with normal, micro-CT-derived microvascular (20–200 μm) transmural density decreased in CAS but not in HT or CAS+HT. We conclude that the coexistence of early renovascular HT exacerbated myocardial fibrosis and vascular remodeling distal to CAS. These changes were not mediated by loss of myocardial microvessels, which were relatively preserved, but possibly by exacerbated myocardial inflammation and fibrosis. HT modulates cardiac adaptive responses to CAS and bears cardiac functional consequences.