Citations

Abstract Background: Exemestane, a steroidal aromatase inhibitor, reduced the incidence of invasive breast cancers by 65% among 4560 post-menopausal randomized to exemestane or placebo for 5 years on MAP.3. Differences in quality of life (QOL) were judged to be minimal, but only summary information was reported. Purpose: To provide more detailed information about effects of exemestane on menopause-specific and health-related qualities of life. Method: Participation in quality of life assessment was an eligibility criterion. Menopause-specific and health-related qualities of life were assessed using the MENQOL (4 scales; physical, vasomotor, psychosocial, sexual) and SF-36 (8 scales; physical health, role function — physical, bodily pain, general health, vitality, social function, role function — emotional, mental health, and 2 summary scales) instruments, respectively at baseline, 6 months and then yearly after randomization. Compliance with QOL questionnaire completion at each follow-up visit ranged from 93–98%, and did not differ by group. Change scores for each MENQOL and SF-36 scale, calculated for each assessment time relative to baseline, were compared using the Wilcoxon Rank-Sum test. Summary scores were used to summarize the QOL scores observed at each time point for each SF-36 dimension and overall mental (MCS) and physical component summaries (PCS) and MENQOL domains. Clinically important worsening of MENQOL change scores was defined as an increase of ≥0.5/8 points. SF-36 change scores were considered worsened if scores decreased by ≥ 5 points from baseline. Results: Both groups were balanced on scores for MENQOL and SF-36 at baseline. Median follow-up was 35 months and the proportion of women who stopped study medication early for toxicity reasons was 15% in the exemestane arm and 11% in the placebo arm. There was a statistically significant difference in change scores for vasomotor symptoms among women on exemestane during the first 4 years (p-values <0.01), compared to placebo. However, no between-group differences in vasomotor change met the criterion for clinical importance. Women on exemestane had statistically poorer sexual functioning (mean change = −0.02, SD=1.37) compared to placebo (mean change = −0.12, SD=1.32) during the first 6 months on study (p-value = 0.03) but the differences were not statistically significant thereafter or clinically important at any time. Among the 8 SF-36 scales, only bodily pain was statistically different between exemestane and placebo for the first 24 months on study medication (p-value <0.01), but no between-group difference in change scores exceeded 5 points. Overall SF-36 PCS and MCS assessing changes in overall physical and mental health-related QOL did not differ significantly by group at any assessment. Conclusion: Our assessment that early differences in vasomotor symptoms and pain were probably not clinically important is supported by the observation of no between-group differences when overall physical and mental health-related QOL changes were compared. Exemestane does not appear to have a major negative impact on the quality of life among these women. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S6-1.

Abstract Background Exemestane significantly reduced invasive and preinvasive breast cancers in postmenopausal women at increased risk for breast cancer in the NCIC CTG MAP3 trial with no serious toxicities, including excess fractures or osteoporosis. Purpose: To provide additional information on the effect of exemestane on bone loss in women at high risk for breast cancer, within a subset of women participating on the NCIC CTG MAP.3B study. The primary hypothesis is that exemestane does not induce clinically significant bone loss in postmenopausal women at increased risk of developing breast cancer at 2 years. The primary objective of this companion study is to examine the effect of exemestane on lumbar spine and total hip BMD by DEXA at 2 years in women participating in the MAP3 trial. Methods: The MAP.3B bone sub-study registered women from the main MAP. 3 trial from May 2008 to March 2010. Eligible women had to have an acceptable quality BMD scan by DEXA taken within 12 months prior to randomization to MAP.3. A BMD T-score >-2.0 SD (i.e. better than 2 standard deviations below the average peak BMD of a young adult woman) was established as the study population cutoff. A questionnaire including information on height, falls, fractures, lifestyle information including physical activity, tobacco and alcohol use was completed at baseline, 12 months, 24 months and at last visit. Fasting serum for bone biomarkers was collected at 12 months and total hip and L1-L4 (postero-anterior) spine BMD were measured 2 years after randomization on the same Lunar or Hologic scanner. The primary objective was to determine differences in hip and spine BMD at 2 years. Secondary outcomes include number of skeletal fractures and development of osteoporosis 2 years after randomization and changes in bone biomarkers at 1 year after randomization. For the analysis of the primary endpoints, the upper limit of a one sided 95% confidence interval for the difference in mean percentage changes between placebo and exemestane will be calculated for the BMD by DEXA at each site. We will conclude that exemestane does not induce significant bone loss in postmenopausal women at increased risk of developing breast cancer at 2 years when the upper limit is less than 3% for both sites. Similar confidence interval approach will be used to analyze the secondary endpoints. Results: Between May 2008 and March 2010, 238 postmenopausal women were recruited. Median age was 61.8 years, and the majority of women were Caucasian (91%), with approximately 20% of the participants reporting a recent fall (within past 12 months) and another 13% reporting a recent fracture prior to randomization. We will report results from the primary as well as the secondary endpoints at the SABCS meeting. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-11-13.

3-Deazaadenosine (c3Ado) is a potent inhibitor ofS-adenosylhomocysteine hydrolase, which regulates cellular methyltransferase activity. In the present study, we sought to determine the effect of c3Ado on vascular smooth muscle cell (VSMC) function and neointima formation in vivo. c3Ado dose-dependently prevented the proliferation and migration of human coronary VSMCs in vitro. This was accompanied by an increased expression of the cyclin-dependent kinase inhibitors p21WAF1/Cip1, p27Kip1, a decreased expression of G1/S phase cyclins, and a lack of retinoblastoma protein hyperphosphorylation. In accordance with these findings, fluorescence-activated cell-sorting analysis of propidium iodide–stained cells indicated a cell cycle arrest in the G0/G1phase. Importantly, c3Ado did not affect the number of viable (trypan blue exclusion) or apoptotic cells (TUNEL). Mechanistically, c3Ado prevented FCS-induced Ras carboxyl methylation and membrane translocation and activity by inhibiting isoprenylcysteine carboxyl methyltransferase and reduced FCS-induced extracellular signal-regulated kinase (ERK)1/2 and Akt phosphorylation in a dose-dependent manner. Conversely, rescuing signal transduction by overexpression of a constitutive active Ras mutant abrogated c3Ado’s effect on proliferation. For in vivo studies, the femoral artery of C57BL/6 mice was dilated and mice were fed a diet containing 150 μg of c3Ado per day. c3Ado prevented dilation-induced Ras activation, as well as ERK1/2 and Akt phosphorylation in vivo. At day 21, VSMC proliferation (proliferating-cell nuclear antigen [PCNA]-positive cells), as well as the neointima/media ratio (0.7±0.2 versus 1.6±0.4;P<0.05) were significantly reduced, without any changes in the number of apoptotic cells. Our data indicate that c3Ado interferes with Ras methylation and function and thereby with mitogenic activation of ERK1/2 and Akt, preventing VSMC cell cycle entry and proliferation and neointima formation in vivo. Thus, therapeutic inhibition ofS-adenosylhomocysteine hydrolase by c3Ado may represent a save and effective novel approach to prevent vascular proliferative disease.

OBJECTIVE: The World Health Organization Atlas Project identified important deficiencies in world mental and neurological health resources. These deficiencies, especially evident in low and middle-income countries, can be overcome by improving research capacity. The objective of this study is to assess the status of mental and neurological research in Latin American countries and identify the main difficulties encountered in conducting research, publishing results, and shaping health policies, interventions, and programs. METHOD: Semi-structured interviews were conducted with 34 key informants from 13 Latin American countries. RESULTS: Participants reported that production of mental and neurological research in Latin American countries is low. Lack of financial and human resources, including lack of support from government agencies, were identified as the main factors contributing to the dearth of local research. The few research projects that do take place in Latin American countries are often funded at researchers' personal expense. Few policies, interventions, or programs are generated from research results. To address these deficiencies, participants called for training in research methodology, mechanisms for identifying funding opportunities, and greater recognition of their research products. CONCLUSIONS: Researchers and stakeholders recognize the need to mobilize local and international efforts aimed at strengthening research capacity and results implementation. This will lead to an overall optimization of mental and neurological research in the region.

Abstract Aberrant DNA methylation occurs early in oncogenesis, is stable, and can be assayed in tissues and body fluids. Therefore, genes with aberrant methylation can provide clues for understanding tumor pathways and are attractive candidates for detection of early neoplastic events. Identification of sequences that optimally discriminate cancer from other diseased and healthy tissues is needed to advance both approaches. Using well-characterized specimens, genome-wide methylation techniques were used to identify candidate markers specific for colorectal neoplasia. To further validate 30 of these candidates from genome-wide analysis and 13 literature-derived genes, including genes involved in cancer and others with unknown functions, a high-throughput methylation-specific oligonucleotide microarray was used. The arrays were probed with bisulfite-converted DNA from 89 colorectal adenocarcinomas, 55 colorectal polyps, 31 inflammatory bowel disease, 115 extracolonic cancers, and 67 healthy tissues. The 20 most discriminating markers were highly methylated in colorectal neoplasia (area under the receiver operating characteristic curve &gt; 0.8; P &lt; 0.0001). Normal epithelium and extracolonic cancers revealed significantly lower methylation. Real-time PCR assays developed for 11 markers were tested on an independent set of 149 samples from colorectal adenocarcinomas, other diseases, and healthy tissues. Microarray results could be reproduced for 10 of 11 marker assays, including eight of the most discriminating markers (area under the receiver operating characteristic curve &gt; 0.72; P &lt; 0.009). The markers with high specificity for colorectal cancer have potential as blood-based screening markers whereas markers that are specific for multiple cancers could potentially be used as prognostic indicators, as biomarkers for therapeutic response monitoring or other diagnostic applications, compelling further investigation into their use in clinical testing and overall roles in tumorigenesis. (Mol Cancer Res 2007;5(2):153–63)