The National Cancer Institute of Canada Clinical Trials Group MAP.3 Trial: An International Breast Cancer Prevention Trial

Several large phase iii trials have demonstrated that tamoxifen—and more recently, raloxifene—can effectively reduce the incidence of invasive breast cancer by 50%. However, these selective estrogen receptor modulators can also be associated with several rare, but serious, adverse events. Recently, the third-generation aromatase inhibitors (AIS) have demonstrated excellent efficacy in adjuvant breast cancer trials, and they show particular promise in the breast cancer prevention setting. The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) has developed a randomized phase iii study to determine the efficacy of an ai (exemestane) to reduce the incidence of invasive breast cancer in postmenopausal women at an increased risk for developing breast cancer. The ncic ctg map.3 (ExCel) trial is a double-blind placebo-controlled multicentre, multinational trial. Based on the known preclinical and clinical profile of the ais, a greater reduction in breast cancer incidence with fewer side effects is hypothesized with this class of agents than with tamoxifen or raloxifene

Effects of Liarozole Fumarate (R85246) in Combination with Tamoxifen on N-methyl-N-nitrosourea (MNU)-induced Mammary Carcinoma and Uterus in the Rat Model

Background: Liarozole fumarate (liarozole – R85246) is a novel compound with characteristics of both aromatase inhibitor (AI) and a retinoic acid metabolism blocking agent (RAMBA). Our objective was to determine the effects of liarozole alone or in combination with tamoxifen on the N-methyl-N-nitrosourea (MNU)-induced rat mammary carcinoma model, as well as on the uterus in ovariectomized immature rats. Methods: (1) Tumor burden experiments: Animals bearing one or more tumors greater than 10 mm in diameter were treated for 56 consecutive days with 20 mg/kg or 80 mg/kg of liarozole by oral gavage, tamoxifen 100 μg/kg by subcutaneous injection, or a combination of liarozole and tamoxifen. At the end of the treatment period, total cumulative tumor volume as well as retinoic acid levels were measured. (2) Uterotrophic assay and proliferation experiments: 21-day-old ovariectomized (OVX) Sprague-Dawley rats were treated with 20 mg/kg or 80 mg/kg of liarozole by oral gavage, tamoxifen 1 mg/kg by subcutaneous injection, and combination of both for 4 consecutive days. At the end of the treatment period, uterine weight, epithelial lining cell height and indices of proliferation cell nuclear antigen (PCNA) were measured. Results: The tumor burden experiments in rats bearing estrogen receptor (ER) positive mammary tumours showed that liarozole has a marked anti-tumour effect. In combination with tamoxifen, liarozole had neither an additive nor an antagonistic effect. However, liarozole markedly reduced the uterotrophic effects induced by tamoxifen. Conclusion: Liarozole's antitumor effects on ER positive mammary tumors and its protective effect on the uterus merit further studies to confirm its clinical value in combination with tamoxifen in ER positive postmenopausal breast cancer. Liarozole and other retinomimetics might also be suitable chemoprevention drugs in combination with tamoxifen because of their favorable toxicity profile

Access to care issues adversely affect breast cancer patients in Mexico: oncologists’ perspective

Background: Despite recently implemented access to care programs, Mexican breast cancer (BC) mortality rates remain substantially above those in the US. We conducted a survey among Mexican Oncologists to determine whether practice patterns may be responsible for these differences. Methods: A web-based survey was sent to 851 oncologists across Mexico using the Vanderbilt University REDCap database. Analyses of outcomes are reported using exact and binomial confidence bounds and tests. Results: 138 participants (18.6% of those surveyed) from the National capital and 26 Mexican states, responded. Respondents reported that 58% of newly diagnosed BC patients present with stage III-IV disease; 63% undergo mastectomy, 52% axillary lymph node dissection (ALND) and 48% sentinel lymph node biopsy (SLNB). Chemotherapy is recommended for tumors > 1 cm (89%), positive nodes (86.5%), triple-negative (TN) (80%) and HER2 positive tumors (58%). Trastuzumab is prescribed in 54.3% and 77.5% for HER2 1 cm tumors, respectively. Tamoxifen is indicated for premenopausal hormone receptor (HR) positive tumors in 86.5% of cases and aromatase inhibitors (AI’s) for postmenopausal in 86%. 24% of physicians reported treatment limitations, due to delayed or incomplete pathology reports and delayed or limited access to medications. Conclusions: Even though access to care programs have been recently applied nationwide, women commonly present with advanced BC, leading to increased rates of mastectomy and ALND. Mexican physicians are dissatisfied with access to appropriate medical care. Our survey detects specific barriers that may impact BC outcomes in Mexico and warrant further investigation. Electronic supplementary material The online version of this article (doi:10.1186/1471-2407-14-658) contains supplementary material, which is available to authorized users

Competing risks of death in women treated with adjuvant aromatase inhibitors for early breast cancer on NCIC CTG MA.27

Baseline patient and tumor characteristics differentially affected type of death in the MA.17 placebo-controlled letrozole trial where cardiovascular death was not separately identified. The MA.27 trial allowed competing risks analysis of breast cancer (BC), cardiovascular, and other type (OT) of death. MA.27 was a phase III adjuvant breast cancer trial of exemestane versus anastrozole. Effects of baseline patient and tumor characteristics were tested for whether factors were associated with (1) all cause mortality and (2) cause-specific mortality. We also fit step-wise forward cause-specific-adjusted models. 7576 women (median age 64 years; 5417 (72 %) < 70 years and 2159 (28 %) ≥ 70 years) were enrolled and followed for median 4.1 years. The 432 deaths comprised 187 (43 %) BC, 66 (15 %) cardiovascular, and 179 (41 %) OT. Five baseline factors were differentially associated with type of death. Older patients had greater BC (p = 0.03), cardiovascular (p < 0.001), and other types (p < 0.001) of mortality. Patients with pre-existing cardiovascular history had worse cardiovascular mortality (p < 0.001); those with worse ECOG performance status had worse OT mortality (p < 0.001). Patients with T1 tumors (p < 0.001) and progesterone receptor positive had less BC mortality (p < 0.001). Fewer BC deaths occurred with node-negative disease (p < 0.001), estrogen receptor-positive tumors (p = 0.001), and without adjuvant chemotherapy (p = 0.005); worse cardiovascular mortality (p = 0.01), with trastuzumab; worse OT mortality, for non-whites (p = 0.03) and without adjuvant radiotherapy (p = 0.003). Overall, 57 % of deaths in MA.27 AI-treated patients were non-breast cancer related. Baseline patient and tumor characteristics differentially affected type of death with women 70 or older experiencing more non-breast cancer death

Molecular Tracers of the Central 12 pc of the Galactic Center

We have used the BIMA array to image the Galactic Center with a 19-pointing mosaic in HCN(1-0), HCO+(1-0), and H 42-alpha emission with 5 km/s velocity resolution and 13'' x 4'' angular resolution. The 5' field includes the circumnuclear ring (CND) and parts of the 20 and 50 km/s clouds. HCN(1-0) and HCO+ trace the CND and nearby giant molecular clouds while the H 42-alpha emission traces the ionized gas in Sgr A West. We find that the CND has a definite outer edge in HCN and HCO+ emission at ~45'' radius and appears to be composed of two or three distinct streams of molecular gas rotating around the nucleus. Outside the CND, HCN and HCO+ trace dense clumps of high-velocity gas in addition to optically thick emission from the 20 and 50 km/s clouds. A molecular ridge of compressed gas and dust, traced in NH3 emission and self-absorbed HCN and HCO+, wraps around the eastern edge of Sgr A East. Just inside this ridge are several arcs of gas which have been accelerated by the impact of Sgr A East with the 50 km/s cloud. HCN and HCO+ emission trace the extension of the northern arm of Sgr A West which appears to be an independent stream of neutral and ionized gas and dust originating outside the CND. Broad line widths and OH maser emission mark the intersection of the northern arm and the CND. Comparison to previous NH3 and 1.2mm dust observations shows that HCN and HCO+ preferentially trace the CND and are weaker tracers of the GMCs than NH3 and dust. We discuss possible scenarios for the emission mechanisms and environment at the Galactic center which could explain the differences in these images.Comment: 24 pages, including 17 figures; to appear in The Astrophysical Journa

Aromatase inhibitors, estrogens and musculoskeletal pain: estrogen-dependent T-cell leukemia 1A (TCL1A) gene-mediated regulation of cytokine expression

Introduction: Arthralgias and myalgias are major side effects associated with aromatase inhibitor (AI) therapy of breast cancer. In a recent genome-wide association study, we identified SNPs - including one that created an estrogen response element near the 3' end of the T-cell leukemia 1A (TCL1A) gene - that were associated with musculoskeletal pain in women on adjuvant AI therapy for breast cancer. We also showed estrogen-dependent, SNP-modulated variation in TCL1A expression and, in preliminary experiments, showed that TCL1A could induce IL-17RA expression. In the present study, we set out to determine whether these SNPs might influence cytokine expression and effect more widely, and, if so, to explore the mechanism of TCL1A-related AI-induced side effects. Methods: The functional genomic experiments performed included determinations of TCL1A, cytokine and cytokine receptor expression in response to estrogen treatment of U2OS cells and lymphoblastoid cell lines that had been stably transfected with estrogen receptor alpha. Changes in mRNA and protein expression after gene knockdown and overexpression were also determined, as was NF-κB transcriptional activity. Results: Estradiol (E2) increased TCL1A expression and, in a TCL1A SNP-dependent fashion, also altered the expression of IL-17, IL-17RA, IL-12, IL-12RB2 and IL-1R2. TCL1A expression was higher in E2-treated lymphoblastoid cell lines with variant SNP genotypes, and induction of the expression of cytokine and cytokine receptor genes was mediated by TCL1A. Finally, estrogen receptor alpha blockade with ICI-182,780 in the presence of E2 resulted in greatly increased NF-κB transcriptional activity, but only in cells that carried variant SNP genotypes. These results linked variant TCL1A SNP sequences that are associated with AI-dependent musculoskeletal pain with increased E2-dependent TCL1A expression and with downstream alterations in cytokine and cytokine receptor expression as well as NF-κB transcriptional activity. Conclusions: SNPs near the 3' terminus of TCL1A were associated with AI-dependent musculoskeletal pain. E2 induced SNP-dependent TCL1A expression, which in turn altered IL-17, IL-17RA, IL-12, IL-12RB2, and IL-1R2 expression as well as NF-κB transcriptional activity. These results provide a pharmacogenomic explanation for a clinically important adverse drug reaction as well as insights into a novel estrogen-dependent mechanism for the modulation of cytokine and cytokine receptor expression

Nitrogen in diamond

Nitrogen is ubiquitous in both natural and laboratory-grown diamond, but the number and nature of the nitrogen-containing defects can have a profound effect on the diamond material and its properties. An ever-growing fraction of the supply of diamond appearing on the world market is now lab-grown. Here, we survey recent progress in two complementary diamond synthesis methods—high pressure high temperature (HPHT) growth and chemical vapor deposition (CVD), how each is allowing ever more precise control of nitrogen incorporation in the resulting diamond, and how the diamond produced by either method can be further processed (e.g., by implantation or annealing) to achieve a particular outcome or property. The burgeoning availability of diamond samples grown under well-defined conditions has also enabled huge advances in the characterization and understanding of nitrogen-containing defects in diamond—alone and in association with vacancies, hydrogen, and transition metal atoms. Among these, the negatively charged nitrogen-vacancy (NV–) defect in diamond is attracting particular current interest in account of the many new and exciting opportunities it offers for, for example, quantum technologies, nanoscale magnetometry, and biosensing

From white elephant to Nobel Prize: Dennis Gabor’s wavefront reconstruction

Dennis Gabor devised a new concept for optical imaging in 1947 that went by a variety of names over the following decade: holoscopy, wavefront reconstruction, interference microscopy, diffraction microscopy and Gaboroscopy. A well-connected and creative research engineer, Gabor worked actively to publicize and exploit his concept, but the scheme failed to capture the interest of many researchers. Gabor’s theory was repeatedly deemed unintuitive and baffling; the technique was appraised by his contemporaries to be of dubious practicality and, at best, constrained to a narrow branch of science. By the late 1950s, Gabor’s subject had been assessed by its handful of practitioners to be a white elephant. Nevertheless, the concept was later rehabilitated by the research of Emmett Leith and Juris Upatnieks at the University of Michigan, and Yury Denisyuk at the Vavilov Institute in Leningrad. What had been judged a failure was recast as a success: evaluations of Gabor’s work were transformed during the 1960s, when it was represented as the foundation on which to construct the new and distinctly different subject of holography, a re-evaluation that gained the Nobel Prize for Physics for Gabor alone in 1971. This paper focuses on the difficulties experienced in constructing a meaningful subject, a practical application and a viable technical community from Gabor’s ideas during the decade 1947-1957

Randomized Trial of Letrozole Following Tamoxifen as Extended Adjuvant Therapy in Receptor-Positive Breast Cancer: Updated Findings from NCIC CTG MA.17

Background: Most recurrences in women with breast cancer receiving 5 years of adjuvant tamoxifen occur after 5 years. The MA.17 trial, which was designed to determine whether extended adjuvant therapy with the aromatase inhibitor letrozole after tamoxifen reduces the risk of such late recurrences, was stopped early after an interim analysis showed that letrozole improved disease-free survival. This report presents updated findings from the trial. Methods: Postmenopausal women completing 5 years of tamoxifen treatment were randomly assigned to a planned 5 years of letrozole (n = 2593) or placebo (n = 2594). The primary endpoint was disease-free survival (DFS); secondary endpoints included distant disease-free survival, overall survival, incidence of contralateral tumors, and toxic effects. Survival was examined using Kaplan-Meier analysis and log-rank tests. Planned subgroup analyses included those by axillary lymph node status. All statistical tests were two-sided. Results: After a median follow-up of 30 months (range = 1.5-61.4 months), women in the letrozole arm had statistically significantly better DFS and distant DFS than women in the placebo arm (DFS: hazard ratio [HR] for recurrence or contralateral breast cancer = 0.58, 95% confidence interval [CI] = 0.45 to 0.76; P<.001; distant DFS: HR = 0.60, 95% CI = 0.43 to 0.84; P = .002). Overall survival was the same in both arms (HR for death from any cause = 0.82, 95% CI = 0.57 to 1.19; P = .3). However, among lymph node-positive patients, overall survival was statistically significantly improved with letrozole (HR = 0.61, 95% CI = 0.38 to 0.98; P = .04). The incidence of contralateral breast cancer was lower in women receiving letrozole, but the difference was not statistically significant. Women receiving letrozole experienced more hormonally related side effects than those receiving placebo, but the incidences of bone fractures and cardiovascular events were the same. Conclusion: Letrozole after tamoxifen is well-tolerated and improves both disease-free and distant disease-free survival but not overall survival, except in node-positive patient