Concordance of pharmacogenetic polymorphisms in tumor and germ line DNA in adult patients with acute myeloid leukemia.

Archived tumor tissue is a useful resource for retrospective studies addressing relationships between genetic polymorphisms and treatment outcomes. However, genotypes determined in tumor and somatic tissues may differ due to cytogenetic and molecular changes associated with malignant transformation and progression. Discordance between germ line and tumor genotypes may be particularly relevant in leukemia because cytogenetic abnormalities are frequent. We compared genotypes determined in DNA extracted from paired pretreatment bone marrow and buccal samples from 80 adult patients with acute myeloid leukemia (AML). Paired AML and buccal DNA samples were genotyped for polymorphisms (21 single nucleotide polymorphisms and 2 gene deletions) on genes encoding proteins involved in drug metabolism (CYP3A4, CYP2C8, CDA, and GSTP1), oxidative stress mechanisms (CAT, MnSOD, GSTT1, GSTM1, GSTA1, and GPX1), drug transport (MDR1, MRP1, and BCRP), and DNA repair (MGMT, XPD, and XRCC1). Genotypes were determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, except GSTM1 and GSTT1, for which deletion genotypes were determined using multiplex PCR. Concordance of genotypes was tested by kappa statistics. kappa statistics for paired AML and buccal DNA samples ranged between 0.94 and 1.00, indicating excellent agreement. The GSTT1 and GSTM1 genotypes were in perfect concordance for the paired samples. Agreement was also excellent for genes at AML chromosome deletion and translocation breakpoints, including MDR1 at 7q21.1 and MRP1 at 16p13.1. Based on these data, genotypes derived from archived AML bone marrow samples were not likely to differ from those from genomic DNA, and archived bone marrow samples may be useful for the conduct of retrospective pharmacogenetic studies.     

Intakes of selected food groups and beverages and adult acute myeloid leukemia

Few studies have explored the association between diet and adult acute myeloid leukemia (AML). In a hospital-based case–control study among 111 cases and 439 controls, AML risk was negatively associated with milk intake among women (OR 0.25, 95% CI 0.08–0.73) and tea (OR 0.50, 95% CI 0.23–1.09), and positively associated among women with beer (OR 2.48, 95% CI 1.05–5.85), wine (OR 2.32, 95% CI 1.05–5.09), and beef (OR 4.78, 95% CI 1.35–16.94). Our findings support a role of diet in adult AML; however, further research is needed to explore gender differences in risk.     

Maximizing allele detection: Effects of analytical threshold and DNA levels on rates of allele and locus drop-out

Interpretation of DNA evidence depends upon the ability of the analyst to accurately compare the DNA profile obtained from an item of evidence and the DNA profile of a standard. This interpretation becomes progressively more difficult as the number of ‘drop-out’ and ‘drop-in’ events increase. Analytical thresholds (AT) are typically selected to ensure the false detection of noise is minimized. However, there exists a tradeoff between the erroneous labeling of noise as alleles and the false non-detection of alleles (i.e. drop-out). In this study, the effect ATs had on both types of error was characterized. Various ATs were tested, where three relied upon the analysis of baseline signals obtained from 31 negative samples. The fourth AT was determined by utilizing the relationship between RFU signal and DNA input. The other ATs were the commonly employed 50, 150 and 200 RFU thresholds. Receiver Operating Characteristic (ROC) plots showed that although high ATs completely negated the false labeling of noise, DNA analyzed with ATs derived using analysis of the baseline signal exhibited the lowest rates of drop-out and the lowest total error rates. In another experiment, the effect small changes in ATs had on drop-out was examined. This study showed that as the AT increased from ～10 to 60 RFU, the number of heterozygous loci exhibiting the loss of one allele increased. Between ATs of 60 and 150 RFU, the frequency of allelic drop-out remained constant at 0.27 (±0.02) and began to decrease when ATs of 150 RFU or greater were utilized. In contrast, the frequency of heterozygous loci exhibiting the loss of both alleles consistently increased with AT. In summary, for samples amplified with less than 0.5 ng of DNA, ATs derived from baseline analysis of negatives were shown to decrease the frequency of drop-out by a factor of 100 without significantly increasing rates of erroneous noise detection.     

The contribution of changes in diet,exercise, and stress management to changes in coronary risk in women and men in the Multisite Cardiac Lifestyle Intervention Program

BACKGROUND: The relative contribution of health behaviors to coronary risk factors in multicomponent secondary coronary heart disease (CHD) prevention programs is largely unknown. PURPOSE: Our purpose is to evaluate the additive and interactive effects of 3-month changes in health behaviors (dietary fat intake, exercise, and stress management) on 3-month changes in coronary risk and psychosocial factors among 869 nonsmoking CHD patients (34% female) enrolled in the health insurance-based Multisite Cardiac Lifestyle Intervention Program. METHODS: Analyses of variance for repeated measures were used to analyze health behaviors, coronary risk factors, and psychosocial factors at baseline and 3 months. Multiple regression analyses evaluated changes in dietary fat intake and hours per week of exercise and stress management as predictors of changes in coronary risk and psychosocial factors. RESULTS: Significant overall improvement in coronary risk was observed. Reductions in dietary fat intake predicted reductions in weight, total cholesterol, low-density lipoprotein cholesterol, and interacted with increased exercise to predict reductions in perceived stress. Increases in exercise predicted improvements in total cholesterol and exercise capacity (for women). Increased stress management was related to reductions in weight, total cholesterol/high-density lipoprotein cholesterol (for men), triglycerides, hemoglobin A1c (in patients with diabetes), and hostility. CONCLUSIONS: Improvements in dietary fat intake, exercise, and stress management were individually, additively and interactively related to coronary risk and psychosocial factors, suggesting that multicomponent programs focusing on diet, exercise, and stress management may benefit patients with CHD.     

Development of ACRODAT<Superscript>®</Superscript>, a new software medical device to assess disease activity in patients with acromegaly

Purpose

Despite availability of multimodal treatment options for acromegaly, achievement of long-term disease control is suboptimal in a significant number of patients. Furthermore, disease control as defined by biochemical normalization may not always show concordance with disease-related symptoms or patient’s perceived quality of life. We developed and validated a tool to measure disease activity in acromegaly to support decision-making in clinical practice.

Methods

An international expert panel (n?=?10) convened to define the most critical indicators of disease activity. Patient scenarios were constructed based on these chosen parameters. Subsequently, a panel of 21 renowned endocrinologists at pituitary centers (Europe and Canada) categorized each scenario as stable, mild, or significant disease activity in an online validation study.

Results

From expert opinion, five parameters emerged as the best overall indicators to evaluate disease activity: insulin-like growth factor I (IGF-I) level, tumor status, presence of comorbidities (cardiovascular disease, diabetes, sleep apnea), symptoms, and health-related quality of life. In the validation study, IGF-I and tumor status became the predominant parameters selected for classification of patients with moderate or severe disease activity. If IGF-I level was ≤1.2x upper limit of normal and tumor size not significantly increased, the remaining three parameters contributed to the decision in a compensatory manner.

Conclusion

The validation study underlined IGF-I and tumor status for routine clinical decision-making, whereas patient-oriented outcome measures received less medical attention. An Acromegaly Disease Activity Tool (ACRODAT) is in development that might assist clinicians towards a more holistic approach to patient management in acromegaly.