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From the Pacific Northwest Evidence-based Practice Center, Oregon Health & Science University, and the Providence Cancer Center, Providence Health & Services, Portland, Oregon.
Disclaimer: The findings and conclusions in this article are those of the authors, who are responsible for its content, and do not necessarily represent the views of AHRQ. No statement in this report should be construed as an official position of AHRQ or the U.S. Department of Health and Human Services.
Acknowledgment: Andrew Hamilton, MLS, MS, conducted literature searches, and Miranda Pappas, MA; Jennifer Mitchell, BA; and Amanda Brunton, BS, provided assistance (all are affiliated with the Oregon Health & Science University). Linda Humphrey MD, MPH (Portland Veterans Affairs Medical Center), and Peggy Nygren, MA, contributed to earlier versions of the evidence review.
Grant Support: By AHRQ (contract HHSA-290-2007-10057-1-EPC3).
Potential Conflicts of Interest: Dr. Nelson: Grant (money to institution): AHRQ. Support for travel to meetings (money to institution): AHRQ. Dr. Smith: Grant (money to institution): AHRQ. Ms. Griffin: None disclosed. Dr. Fu: Grant (money to institution): AHRQ. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-2536.
Requests for Single Reprints: Heidi D. Nelson, MD, MPH, Pacific Northwest Evidence-based Practice Center, Oregon Health & Science University, Mailcode BICC, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239-3098; e-mail, email@example.com.
Current Author Addresses: Drs. Nelson and Fu and Ms. Griffin: Pacific Northwest Evidence-based Practice Center, Oregon Health & Science University, Mailcode BICC, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239-3098.
Dr. Smith: Oregon Health & Science University, Mailcode L475, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239-3098.
Author Contributions: Conception and design: H.D. Nelson, M.E.B. Smith.
Analysis and interpretation of the data: H.D. Nelson, M.E.B. Smith, J.C. Griffin, R. Fu.
Drafting of the article: H.D. Nelson, M.E.B. Smith.
Critical revision of the article for important intellectual content: H.D. Nelson, M.E.B. Smith, J.C. Griffin, R. Fu.
Final approval of the article: H.D. Nelson, M.E.B. Smith, R. Fu.
Provision of study materials or patients: H.D. Nelson.
Statistical expertise: H.D. Nelson, R. Fu.
Obtaining of funding: H.D. Nelson.
Administrative, technical, or logistic support: H.D. Nelson, J.C. Griffin.
Collection and assembly of data: H.D. Nelson, M.E.B. Smith, J.C. Griffin, R. Fu.
Background: Medications to reduce risk for primary breast cancer are recommended for women at increased risk; however, use is low.
Purpose: To update evidence about the effectiveness and adverse effects of medications to reduce breast cancer risk, patient use of such medications, and methods for identifying women at increased risk for breast cancer.
Data Sources: MEDLINE and Cochrane databases (through 5 December 2012), Scopus, Web of Science, clinical trial registries, and reference lists.
Study Selection: English-language randomized trials of medication effectiveness and adverse effects, observational studies of adverse effects and patient use, and diagnostic accuracy studies of risk assessment.
Data Extraction: Investigators independently extracted data on participants, study design, analysis, follow-up, and results, and a second investigator confirmed key data. Investigators independently dual-rated study quality and applicability using established criteria.
Data Synthesis: Seven good- and fair-quality trials indicated that tamoxifen and raloxifene reduced incidence of invasive breast cancer by 7 to 9 cases in 1000 women over 5 years compared with placebo. New results from STAR (Study of Tamoxifen and Raloxifene) showed that tamoxifen reduced breast cancer incidence more than raloxifene by 5 cases in 1000 women. Neither reduced breast cancer–specific or all-cause mortality rates. Both reduced the incidence of fractures, but tamoxifen increased the incidence of thromboembolic events more than raloxifene by 4 cases in 1000 women. Tamoxifen increased the incidence of endometrial cancer and cataracts compared with placebo and raloxifene. Trials provided limited and heterogeneous data on medication adherence and persistence. Many women do not take tamoxifen because of associated harms. Thirteen risk-stratification models were modest predictors of breast cancer.
Limitation: Data on mortality and adherence measures and for women who are nonwhite, are premenopausal, or have comorbid conditions were lacking.
Conclusion: Medications reduced the incidence of invasive breast cancer and fractures and increased the incidence of thromboembolic events. Tamoxifen was more effective than raloxifene but also increased the incidence of endometrial cancer and cataracts. Use is limited by adverse effects and inaccurate methods to identify candidates.
Primary Funding Source: Agency for Healthcare Research and Quality.
In 2002, the U.S. Preventive Services Task Force (USPSTF) recommended that clinicians discuss the potential benefits and harms of tamoxifen and raloxifene for reducing risk for primary breast cancer with women at high risk for breast cancer and low risk for adverse effects (1–2). The USPSTF also recommended against routine use in women at low or average risk for breast cancer.
Clinical trials demonstrate the efficacy of several medications to reduce the risk for invasive breast cancer in women without preexisting cancer (3–8), but only tamoxifen citrate and raloxifene for 5 years of use are approved by the U.S. Food and Drug Administration (FDA) for this purpose (9). Raloxifene is approved for postmenopausal women only. In addition to beneficial effects, these medications may cause adverse health effects (7, 10–11). In 2002, the USPSTF indicated that the risk for breast cancer within 5 years could be estimated by completing the National Cancer Institute Breast Cancer Risk Assessment Tool (Gail model). How to select patients for these medications in clinical practice has not been clear, however, and use of medications to reduce risk for breast cancer is low in the United States (12).
This report is an update for the USPSTF that was derived from a comprehensive comparative effectiveness review of the efficacy, adverse effects, and subgroup variations of medications to reduce risk for primary breast cancer in women (13). It also examines issues related to clinical effectiveness, such as patient choice, concordance, adherence, and persistence of use; and reviews methods to identify women at increased risk for breast cancer that are clinically applicable to determining candidacy for risk-reducing medications.
We followed a standard protocol for this review consistent with the Agency for Healthcare Research and Quality (AHRQ) Effective Health Care Program (14). Key questions were developed through the Effective Health Care Program and modified for the USPSTF. Investigators created an analytic framework incorporating the key questions and outlining the patient population, interventions, and outcomes (Figure 1). The target population includes women without preexisting invasive or noninvasive breast cancer who are not known carriers of breast cancer susceptibility mutations. Interventions include FDA-approved medications to reduce risk for primary breast cancer. Health outcomes include signs, symptoms, conditions, or events as opposed to intermediate outcomes, such as laboratory test results. A technical report (15) details the methods and includes search strategies and additional evidence tables.
Analytic framework.
DCIS = ductal carcinoma in situ.
We searched MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews from inception through 5 December 2012 for relevant English-language studies, systematic reviews, and meta-analyses (15). We manually reviewed reference lists of articles, citations in Web of Science and Scopus, and clinical trial registries. We requested scientific information packets from manufacturers of medications. (The only packet provided was for raloxifene.)
We developed selection criteria for studies based on the patient populations, interventions, outcome measures, and types of evidence. After an initial review of citations and abstracts, we retrieved full-text articles of potentially relevant material and conducted a second review to determine inclusion. A second reviewer confirmed results of the initial reviewer, and discrepancies were resolved by team consensus. Results of the search and selection process are provided in the Appendix Figure.
Summary of evidence search and selection.
* Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews.
† Identified from reference lists, hand searching, and suggestions by experts.
‡ Studies that provided data and contributed to the body of evidence were considered "included."
§ Some studies are included in more than 1 key question.
Inclusion criteria for studies of benefits, harms, and subgroup outcomes (key questions 1 through 3) have been fully described in previous publications (13, 15). For benefits, we included only double-blind, placebo-controlled or head-to-head, randomized, controlled trials (RCTs) of tamoxifen and raloxifene to reduce risk for breast cancer that enrolled women without preexisting breast cancer. We included trials that were designed and powered to demonstrate invasive breast cancer incidence as a primary or secondary outcome. For harms, we included RCTs and observational studies of tamoxifen and raloxifene in women without breast cancer that had a nonuser comparison group or direct comparisons between tamoxifen and raloxifene. We considered all adverse outcomes at all reported follow-up times to capture potential short- and long-term adverse effects.
We included RCTs, observational studies, and descriptive studies of decisions to use risk-reducing medications, concordance, adherence, and persistence of use (key question 4). Concordance occurs when a health care provider and patient reach a shared agreement about therapeutic goals after the patient is informed of the condition and options for treatment and becomes involved in the treatment decision (16). Adherence is the extent to which a patient acts in accordance with the prescribed interval and dose of a medication (17). Persistence is the duration of time from initiation to discontinuation of therapy (17).
We included studies of risk-stratification models that could be used in primary care settings to identify women at higher-than-average risk for breast cancer (key question 5). Only studies reporting discriminatory accuracy were included. Discriminatory accuracy is a measure of how well the model can correctly classify persons at higher risk from those at lower risk and is measured by the model's concordance statistic or c-statistic. The c-statistic is determined by the area under the receiver-operating characteristic curve, a plot of sensitivity (true-positive rate) versus 1 – specificity (false-positive rate). Perfect discrimination is a c-statistic of 1.0, whereas a c-statistic of 0.5 would result from chance alone. An acceptable level of discrimination is between 0.70 and 0.79, excellent is between 0.80 and 0.89, and outstanding is 0.90 or greater (18). We also abstracted model calibration, a measure of how well predicted probabilities agree with actual observed risk in a population. In a perfect prediction model, the predicted risk in a population would equal the observed number of cases, such that the percentage expected divided by the percentage observed equals 1.0. We excluded studies of individual risk factors or laboratory tests as well as models designed primarily to evaluate risk for deleterious BRCA mutations.
Our search strategies also included systematic reviews that addressed our key questions and had similar scope, inclusion criteria, and analytic methods for meta-analysis. Other types of analyses and statistical models were not included (19).
An investigator abstracted details of the patient population, study design, analysis, follow-up, and results. A second investigator confirmed key data elements. Using predefined criteria (20), 2 investigators independently rated the quality of studies (good, fair, or poor) and resolved discrepancies by consensus. Investigators assessed applicability of trials using the population, intervention, comparator, outcomes, timing of outcomes measurement, and setting (PICOTS) format (14).
We updated the results of our previous meta-analysis of benefits and harms of tamoxifen and raloxifene for 2 outcomes (mortality and endometrial cancer for raloxifene) with new data using methods described in previous publications (13). As a group, investigators used methods developed by the USPSTF to assess the overall quality of the body of evidence for each key question (good, fair, or poor) on the basis of the number, quality, and size of studies; consistency of results between studies; and directness of evidence (20).
This research was funded by AHRQ. Investigators worked with AHRQ staff and a technical expert panel to define the scope, analytic framework, and key questions; resolve issues arising during the project; and review the final report to ensure that it met basic methodological standards for systematic reviews. The draft report was reviewed by content experts, USPSTF members, AHRQ program officers, and collaborative partners. The funding source had no role in the selection, critical appraisal, or synthesis of evidence. The investigators were solely responsible for the content and the decision to submit the manuscript for publication.
Seven RCTs of tamoxifen or raloxifene in women without preexisting breast cancer provide breast cancer outcomes and data about mortality and fractures. These trials also provide estimates of harm, including thromboembolic events, cardiovascular disease events, uterine abnormalities, cataracts, and other adverse effects. Additional trials and an observational study describing harms of raloxifene were identified, but these studies were small, were methodologically limited, and did not contribute data to the meta-analysis.
Trials include a head-to-head comparison of tamoxifen and raloxifene, STAR (Study of Tamoxifen and Raloxifene) (21–22); 4 placebo-controlled trials of tamoxifen, including the IBIS-I (International Breast Cancer Intervention Study) (23–24), NSABP P-1 (National Surgical Adjuvant Breast and Bowel Project) (8, 11, 25–26), Royal Marsden Hospital trial (27–28), and the Italian Tamoxifen Prevention Study (29–32); and 2 placebo-controlled trials of raloxifene, MORE (Multiple Outcomes of Raloxifene Evaluation) with long-term follow-up in the CORE (Continuing Outcomes Relevant to Evista) study (10, 33–46) and the RUTH (Raloxifene Use for the Heart) trial (7, 47). An updated analysis of STAR with an 81-month median follow-up provided most of the new findings for this review (22).
The tamoxifen trials were designed to determine breast cancer incidence as the primary outcome (8, 11, 23–24, 27–32, 48). Inclusion criteria considered breast cancer risk in all but 1 trial (49). For raloxifene, breast cancer incidence was a primary outcome in RUTH and a secondary outcome in MORE. These trials were intended to evaluate the effect of raloxifene on reducing coronary heart disease events in RUTH (7) and preventing fractures in MORE (5, 40).
Trials varied by mean age at enrollment (47 to 50 years for the tamoxifen trials, 67 years for the raloxifene trials, and 59 years for STAR), estrogen use (23, 27, 29–32), and ascertainment of outcomes. For placebo-controlled trials of tamoxifen, median duration of treatment was approximately 4 years and follow-up was 7 to 13 years (8, 24). For raloxifene, results were reported after 3 and 4 years of treatment in the MORE trial (26–34, 36, 39), and results of CORE (a continuation study of MORE [44]) were reported for 4-year and combined 8-year outcomes (MORE and CORE) (37–38, 40). The median duration of treatment in RUTH was 5.1 years (41). In STAR, the mean duration of treatment was 3.8 years and median follow-up was 6.75 years (22).
All trials met criteria for fair or good quality and high applicability. The trials were multicenter, were relevant to primary care, and enrolled between 2471 (27) and 19 747 (48) women from clinics and communities predominantly in North America, Europe, and the United Kingdom.
In placebo-controlled trials, tamoxifen (risk ratio [RR], 0.70 [95% CI, 0.59 to 0.82]; 4 trials; 7 cases in 1000 women over 5 years) (8, 24, 28, 31) and raloxifene (RR, 0.44 [CI, 0.27 to 0.71]; 2 trials; 9 cases in 1000 women) (7, 44) reduced the incidence of invasive breast cancer (Appendix Table 1). In STAR, more women receiving raloxifene had breast cancer than those receiving tamoxifen (RR for raloxifene, 1.24 [CI, 1.05 to 1.47]; 5 cases in 1000 women over 5 years) (22). Tamoxifen (8, 24, 28, 31) and raloxifene (7, 44) reduced estrogen receptor–positive but not estrogen receptor–negative or noninvasive cancer in placebo-controlled trials and had similar effects in STAR (21–22, 48). Breast cancer–specific (8, 24, 28, 31, 50) and all-cause mortality rates (6–8, 24, 28, 31) were not reduced in placebo trials and were similar in STAR (22).
In placebo-controlled trials, raloxifene reduced incidence of vertebral fractures (RR, 0.61 [CI, 0.54 to 0.69]; 2 trials; 7 cases in 1000 women) (7, 37) and tamoxifen reduced incidence of nonvertebral fractures (RR, 0.66 [CI, 0.45 to 0.98]; 1 trial; 3 cases in 1000 women) (8). Tamoxifen and raloxifene had similar effects on incidence of vertebral fractures in STAR (48).
Thromboembolic event incidence was increased for tamoxifen (RR, 1.93 [CI, 1.41 to 2.64]; 4 trials; 4 cases in 1000 women) (11, 24, 28–29) and raloxifene (RR, 1.60 [CI, 1.15 to 2.23]; 2 trials; 7 cases in 1000 women) compared with placebo (7, 10), and raloxifene caused fewer events than tamoxifen in STAR (RR, 0.75 [CI, 0.60 to 0.93]; 4 cases in 1000 women) (22). Coronary heart disease event or stroke incidence was not increased in placebo-controlled trials (7–8, 24, 28, 31, 34) and did not differ in STAR (48), although women randomly assigned to raloxifene had a higher stroke mortality rate than that of those assigned to placebo in RUTH (RR, 1.49 [CI, 1.00 to 2.24]) (7).
Tamoxifen caused more cases of endometrial cancer (RR, 2.13 [CI, 1.36 to 3.32]; 3 trials; 4 cases in 1000 women) (11, 24, 28) and was related to more benign gynecologic conditions (24, 51); surgical procedures, including hysterectomy (24, 28, 51); and uterine bleeding (24, 51) than placebo. Raloxifene did not increase risk for endometrial cancer (7, 10, 52) or uterine bleeding (7, 35, 53–61). In STAR, raloxifene caused fewer cases of endometrial cancer (RR, 0.55 [CI, 0.36 to 0.83]; 5 cases in 1000 women), hyperplasia, and procedures than tamoxifen (22, 62). Women receiving tamoxifen had more cataract surgeries than those receiving placebo in NSABP P-1 (11). Raloxifene did not increase risk for cataracts or cataract surgery compared with placebo (7, 10) and caused fewer cataracts than tamoxifen in STAR (RR, 0.80 [CI, 0.72 to 0.95]; 15 cases in 1000 women) (22).
The most common side effects were vasomotor symptoms (11, 24, 28, 31) and vaginal discharge, itching, or dryness (11, 24, 28, 31) for tamoxifen and vasomotor symptoms (7, 35, 55–56, 58) and leg cramps (7, 35, 58) for raloxifene. In STAR, raloxifene users reported more musculoskeletal problems, dyspareunia, and weight gain, whereas tamoxifen users had more gynecologic problems, vasomotor symptoms, leg cramps, and bladder control symptoms (62–63).
In STAR, tamoxifen and raloxifene had similar effects on breast cancer outcomes regardless of age and family history of breast cancer (22). In NSABP P-1, cancer rates were highest and risk reduction greatest among women in the highest modified Gail model risk category (5-year risk >5%) and among women with previous atypical hyperplasia (8). Additional subgroup analyses of placebo-controlled trials indicated no differences for several factors (15, 43, 47). Thromboembolic events, strokes, and endometrial cancer were more common in older (>50 years) than younger women in NSABP P-1 (8). A recent meta-analysis of tamoxifen trials indicated that risks for endometrial cancer, deep venous thrombosis, and pulmonary embolism are low for women younger than 50 years (64).
Twelve studies described how women or physicians make decisions to use medications to reduce risk for primary breast cancer (Appendix Table 2) (65–76). In an interview-based, cross-sectional study after an educational session about indications and adverse effects of tamoxifen, women indicated that breast cancer (69%), pulmonary embolism (67%), endometrial cancer (63%), and deep venous thrombosis (58%) were "very important" in making their decisions about use (69). Only 18% expressed interest in actually using tamoxifen. Another survey of eligible women indicated concerns for adverse effects, including endometrial cancer and thromboembolic events, lack of information, and reluctance to discontinue menopausal hormone therapy as reasons for not choosing tamoxifen (70). Two other studies also described concerns about adverse effects (67, 71).
In 2 similar studies, women reviewed online decision aids that provided their personal 5-year breast cancer risk and information about risk reduction with tamoxifen (73) or tamoxifen and raloxifene (74). Immediately after viewing the decision aid, 29% of women in the tamoxifen study were likely to seek more information, 30% were likely to discuss it with their physicians, 19% did not believe that tamoxifen would reduce their risk for breast cancer, and 6% were likely to take it in the next year (73). Three months after viewing the decision aid, 1% of women had started taking tamoxifen, 6% had talked with their physicians, and 5% sought more information. Worry about side effects, belief that benefits were not worth the risks, and taking pills were cited as deterrents to use. Results were similar for the study considering both tamoxifen and raloxifene.
A study of women with elevated risk scores reported that 12% of women selected tamoxifen for breast cancer risk reduction, 77% declined, and 12% were undecided (68). Major adverse effects (61%) and small benefit from tamoxifen (32%) were the most common reasons for declining. However, 90% of women stated that they would take a medication with the same benefit as tamoxifen if it had no side effects, and one half would take a medication with the same side effects as tamoxifen if it could eliminate the chance of getting breast cancer.
In another study, 75% of women indicated that they would take a medication for an assumed 60% lifetime risk for breast cancer, although they overestimated their personal lifetime risk for breast cancer by 2- to 3-fold (75). Another survey indicated that 23% of responders interested in risk-reducing medications believed themselves to be at greater risk for breast cancer and were more worried about breast cancer than women who were not interested (P < 0.050) (66). A study about interest in using tamoxifen reported that more than 40% of women would be willing to take tamoxifen if they were determined to be at "high risk" (76). Asian women were more likely to take tamoxifen in this study (odds ratio, 3.0 [CI, 1.3 to 6.8]).
Of 350 physicians responding to a mailed survey, 27% had prescribed tamoxifen for breast cancer risk reduction within the previous 12 months (65). Prescribers were more likely than nonprescribers to have a family member with breast cancer (20% vs. 9%) and believed that the benefits of tamoxifen outweigh the risks (63% vs. 39%), colleagues are prescribing it (33% vs. 17%), it is easy to determine who is eligible (28% vs. 11%), and many female patients ask for information about it (15% vs. 5%). Physician prescribers and nonprescribers did not differ in their beliefs about whether the evidence for use of tamoxifen is controversial, it is too time-consuming to discuss in practice, and the risks for thromboembolic events and endometrial cancer are too great.
Three studies reported the concordance of physicians' recommendations and their patients' medication decisions (67, 71–72). Women evaluated for benign breast findings in a breast clinic were provided with estimates of their breast cancer risks and the option of using tamoxifen for risk reduction (71). They were then asked to discuss tamoxifen use with their family physicians. For 31% of the women, the family physician's advice was an important influence in their decision (71). In another study, women whose physicians recommended enrollment in NSABP P-1 were 13 times more likely to enroll than women whose physicians recommended against enrollment (P < 0.001) (72). Women eligible for STAR who received recommendations for risk-reducing medications from their physicians were more likely to select treatment than those not getting recommendations (67).
Seven primary prevention trials of tamoxifen and raloxifene (7–8, 10–11, 24–43, 45–48, 63, 77–78) and 6 additional trials of raloxifene (53, 57–58, 79–80) provided limited and heterogeneous data on adherence and persistence (Appendix Table 3). Adherence was reported in 2 placebo-controlled trials of tamoxifen (28, 81) and 4 placebo-controlled trials of raloxifene (7, 36, 60, 79). Of trials reporting adherence, at least 70% of participants used the planned treatment dose. In NSABP P-1, 41% of participants took 100% of study medication and 79% took at least 76% of study medication at 36 months (81). Forgetting was the primary reason for nonadherence for 62% of women at 36 months. In the Royal Marsden Hospital trial, adherence was 8% lower with tamoxifen versus placebo (P = 0.002) (28). In RUTH, adherence was similar between groups; approximately 70% took at least 70% of the study medication (7). Adherence was not reported separately in MORE; 92% of the study population took at least 80% of the assigned study medication (36).
Persistence was measured as duration of treatment in STAR (48), 1 placebo-controlled trial of tamoxifen (31), and 3 placebo-controlled trials of raloxifene (7, 58, 79), and as completion of the planned course of treatment by 2 placebo-controlled trials of tamoxifen (24, 31) and 6 placebo-controlled trials of raloxifene (7, 57–58, 60, 79–80). Completion rates were similar between groups in STAR (71.5% for raloxifene vs. 68.3% for tamoxifen) (48), the Italian Tamoxifen Prevention Study (59.8% for tamoxifen vs. 61.8% for placebo) (31), IBIS-I (72% overall) (24), and RUTH (80% for raloxifene vs. 79% for placebo) (7). Additional trials of raloxifene reported 60% to 91% of participants completing the planned duration of treatment (57–58, 60, 79–80).
Nineteen studies evaluating 13 risk-stratification models met inclusion criteria (Appendix Table 4) (82–102). Of these, 15 met criteria for good quality (82–85, 87–90, 92–96, 99–100). Four were rated as fair-quality because they inadequately described the population and follow-up (97), provided estimates for 1-year risks only (91), were not practical for primary care settings (86), or were based on small or narrowly defined populations (86, 98).
The Gail model, the first major breast cancer risk-stratification model to be used, was derived from multivariate logistic regression analysis of identified risk factors for breast cancer (82). In the original version of the model, breast cancer incidence rates and baseline hazard rates were determined for invasive cancer, ductal carcinoma in situ, and lobular carcinoma in situ from a cohort of white women in the BCDDP (Breast Cancer Detection and Demonstration Project). The model was subsequently modified by using U.S. national data for invasive cancer from SEER (Surveillance, Epidemiology and End Results) (83). From these data, the model was developed to allow the prediction of individualized absolute risk (probability) of developing invasive breast cancer in women having annual screening mammography over 5 years. This version is called the Gail-2 model or the Breast Cancer Risk Assessment Tool.
Subsequent risk-stratification models use a similar approach but vary in their use of reference standards and the variables they include (Appendix Table 5). The original Gail model included age, age at menarche, age of first birth, family history of breast cancer in first-degree relatives, number of previous breast biopsies, and history of atypical hyperplasia (82). Subsequent models include 1 or more of these variables in addition to other factors. These include race (87, 91–92, 103), previous false-positive mammogram or benign breast disease (91, 96), body mass index or height (86–87, 90–91, 93, 97, 99–100), estrogen and progestin use (86–87, 91, 93), history of breastfeeding (87), menopause status or age (91, 93, 97), smoking (87), alcohol use (86–87, 93), physical activity (86–87, 100), education (100), mammographic breast density (90–92), and diet (86).
Calibration was calculated for 7 of the 13 models (83, 85–88, 90–93, 97) (Appendix Table 5). For most models, the expected numbers of cases of breast cancer closely matched the observed numbers (expected–observed ratio, 0.90 to 1.10) (83, 85–88, 90–93, 97). Calibration varied in specialized populations (94–95), for estrogen receptor–negative breast cancer (83), and when outdated breast cancer incidence rates were used in the model (104).
Most studies of risk models reported modest discriminatory accuracy estimates (c-statistic, 0.55 to 0.65) (Appendix Table 5) (83–92, 94–96, 98–100). Only 1 study reported levels greater than 0.70 for both the Gail-2 (c-statistic, 0.74 [CI, 0.67 to 0.80]) and the Tyrer–Cuzick models (c-statistic, 0.76 [CI, 0.70 to 0.82]) (98). However, this study had limited applicability because it enrolled high-risk women and included only 54 cases of breast cancer. The Tyrer–Cuzick results were not replicated in a subsequent study (c-statistic, 0.54 [CI, 0.42 to 0.65]) (99). Overall, models that included breast density had the highest accuracy (c-statistic, 0.63 to 0.66) (90–92).
Some of the medication trials used individual risk scores for breast cancer as inclusion criteria (8, 11, 48). Three studies evaluated this approach to risk stratification by determining calibration or discriminatory accuracy based on risk quintiles (85, 87, 92), and 1 study determined these estimates based on a low (<1.67%) versus high (≥1.67%) 5-year risk threshold using the Gail model (92). The 1.67% threshold was used as inclusion criteria for NSABP P-1 and STAR, and is included in the FDA indication for the use of tamoxifen and raloxifene for risk reduction.
The BCSC (Breast Cancer Surveillance Consortium)–Tice model demonstrated high calibration (expected–observed ratio, 0.99 to 1.03) but modest discriminatory accuracy across risk quintiles (c-statistic, 0.61 to 0.64) (92). The Gail model showed high calibration in the higher risk quintiles despite a tendency to overpredict the number of invasive breast cancer cases, but inferior calibration in the lower quintiles with a tendency to underpredict (85, 87).
The Table summarizes the evidence for all key questions in our review. Placebo-controlled primary prevention trials indicate that tamoxifen and raloxifene reduce the incidence of invasive breast cancer by 7 to 9 cases per 1000 women over a 5-year treatment period primarily by reducing estrogen receptor–positive breast cancer. New results from STAR show that tamoxifen has a greater effect than raloxifene by reducing invasive breast cancer by 5 fewer cases per 1000 women. Noninvasive breast cancer incidence and breast cancer–specific and all-cause mortality rates were not statistically significantly reduced by either medication, although trials were not powered for mortality. Both medications reduced fractures.
Although trials indicated that women at all levels of breast cancer risk had a reduction in breast cancer incidence with tamoxifen, those at highest risk (based on risk scores or preexisting atypical hyperplasia) derived the most benefit (8). Benefits for higher-risk women were also demonstrated in a recent observational study of 2459 women with atypical breast lesions (atypical ductal and lobular hyperplasia; lobular carcinoma in situ) in a large health system (105). Women who received tamoxifen, raloxifene, or exemestane had a 10-year breast cancer risk of 7.5% compared with women without treatment, who had a risk of 21.3% (P < 0.001). Risk was reduced for all types of atypia.
Beneficial effects of risk-reducing medications are countered by more thromboembolic events for both medications, with tamoxifen causing 4 more events per 1000 women than raloxifene in STAR. Tamoxifen also increases incidence of endometrial cancer and related gynecologic outcomes and cataracts compared with placebo and raloxifene. Many women have less serious adverse effects that impact quality of life and adherence, such as vasomotor, genital, and musculoskeletal symptoms. In trials, older women had more adverse effects for some outcomes, such as endometrial cancer and thromboembolic events, than women younger than 50 years.
Small descriptive studies indicate that women make decisions to use tamoxifen to reduce breast cancer risk based on their concern for adverse effects as well as their risk for breast cancer. Many women overestimate their risk for breast cancer but weigh their physicians' recommendations highly when deciding whether to take tamoxifen. Similar data for raloxifene are lacking, and no studies about how women choose among several risk-reducing medications have been published. Comparisons of adherence and persistence rates across medications in trials are limited because not all trials reported them, measures varied, and trials were designed for different treatment purposes. From the few trials reporting data about discontinuation, rates for tamoxifen or raloxifene were generally higher than placebo, but differences were low (≤2% for adverse events and ≤4% for nonprotocol specified events).
Research on risk assessment relevant to identifying candidates for risk-reducing medications includes 13 risk-stratification models for use in clinical settings. Models considered several risk factors for breast cancer and predicted 1-year to lifetime risk estimates. Most risk models demonstrated high calibration but low to modest discriminatory accuracy in predicting the probability of breast cancer in a person. Most models performed only slightly better than age alone as a risk predictor (91, 94). Models that included breast density improved the predictive risk modestly (91), although breast density may be imprecise and unavailable in many clinical practices. Research evaluating the Gail model score that has been used as a risk threshold in trials and for the FDA indication for use (5-year risk ≥1.67%) found that it has low discriminatory accuracy in predicting the probability of breast cancer in a person. Most women aged 60 years or older without other risk factors would meet this threshold by age alone.
This review is limited by potential publication bias and biases of our literature review process, such as using only English-language reports. Trials of medications varied in their inclusion criteria, surveillance, and ascertainment of outcomes. Active surveillance ended with completion of therapy in most trials, and important long-term outcomes may have been underreported, particularly mortality. Continued follow-up of women enrolled in existing trials would provide needed data on long-term outcomes. Risks for some adverse outcomes and population subgroups were underestimated because of lack of statistical power. Data are lacking for nonwhite, premenopausal, or elderly women who have comorbid conditions or are taking additional medications for other indications. Studies of patient choice and use of medications are small, are descriptive, and may not apply to other populations. Measures of adherence and persistence in clinical trials may not be similar for patients in clinical practices.
Evidence gaps include determination of optimal doses, duration, and timing of use; persistence of effects after treatment; and outcomes in population subgroups. The ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) trial recently reported reduced recurrence of estrogen receptor–positive breast cancer and reduced breast cancer–specific and all-cause mortality rates in women with breast cancer after 10 versus 5 years of adjuvant therapy (106). Whether a longer course provides a more favorable benefit–harm tradeoff for risk reduction in women without breast cancer has yet to be determined.
Trials of other medications have also demonstrated reduction in breast cancer risk, including tibolone (5), lasofoxifene (3), and exemestane (4). Although they have not been FDA-approved for this purpose, they may expand clinical options. In the NCIC CTG MAP.3 (National Cancer Institute of Canada Clinical Trials Group Mammary Prevention.3) trial, exemestane reduced invasive breast cancer incidence by 65% after 3 years of therapy in postmenopausal women with increased risk for breast cancer, as determined by a Gail risk score greater than 1.66% or high-risk breast lesions (4). Hot flashes and arthritis were more common among women taking exemestane, but other adverse effects were not different from placebo.
Despite previous recommendations to identify women at increased risk for breast cancer and offer risk-reducing medications (2), use is low in the United States (65). It is not clear how to identify candidates for therapy. Although the trials indicate broad benefit, subgroup analysis and decision models (19) suggest that high-risk women, particularly those who had hysterectomies, may derive the most benefit with the least harms. Future research on clinical selection criteria reporting likelihood ratios of treatment thresholds would improve identification of candidates in practice settings and provide guidance for the appropriate use of risk-reducing medications.
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Despite a comprehensive review of randomized controlled trials and cohort studies regarding the benefits and harms of selective estrogen receptor modulators (SERMs) for breast cancer prevention, Dr Belson and colleagues (1) do not clearly answer the question of who will realistically benefit from SERMs.
As discussed in this review, tamoxifen is likely more effective than raloxifene in breast cancer prevention but more frequently associated with life-threatening complications such as endometrial cancer and thromboembolic events. Given long-lasting increased risk of endometrial cancer due to tamoxifen (2), use of tamoxifen may have to be limited to women who are at a very high risk of breast cancer or those who had hysterectomy for benign disease. Antitumor actions of raloxifene, a short-acting SERM, seem to depend on the duration of administration. In the initial analysis of the STAR trial, raloxifene was as effective as tamoxifen in reducing the risk of invasive breast cancer (relative risk 1.02, 95% CI 0.82-1.28) (3). in the updated analysis of STAR with extension of follow-up period from 47 months to 81 months after randomization (21 months after stopping SERM treatment), the risk of developing invasive breast cancer was significantly higher in the raloxifene group than in the tamoxifen group (relative risk 1.24, 95% CI 1.05-1.47) (2). Raloxifene is approved for the treatment of osteoporosis and prevention of vertebral fracture for an indefinite period of time because of its efficacy and safety (4). Since preventive agents for widespread use in an otherwise healthy population need to be virtually devoid of significant adverse effects, raloxifene, even if not superior to tamoxifen, may be more acceptable as a preventive drug (5).
In the light of reducing the burdens of both osteoporosis and breast cancer, all postmenopausal women with suspected osteoporosis might benefit form raloxifene, unless SERM is not contraindicated.
Tetsuji Fujita, MD
Department of SurgeryJikei University School of Medicine
Tokyo, Japan 105-8461
1. Nelson HD, Smith B, Griffin JC, Fu R. Use of medications to reduce risk for primary breast cancer: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2013; 158: 604-14.
2. Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, et al, National Surgical Adjuvant Breast and Bowel Project. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: preventing breast cancer. Cancer Prev Res (Phila). 2010;3:696-706.
3. Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial. JAMA 2006; 295: 2727-41.
4. Lippuner K, Buchard PA, De Geyter C, Imthurn B, Lamy O, Litschgi M, et al. Recommendations for raloxifene use in daily clinical practice in the Swiss setting. Eur Spine J 2012; 21: 2407-17.5. Gradishar WJ, Cella D. Selective estrogen receptor modulators and prevention of invasive breast cancer. JAMA 2006; 295: 2784-6.
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James Cameron collaborators Mike deGruy and Andrew Wight die in helicopter crash
LOS ANGELES (AP) — Mike deGruy, an award-winning cinematographer who spent three decades making documentary films about the ocean, was killed in a helicopter crash in eastern Australia. He was 60.
His employer, National Geographic, said Sunday that deGruy and Australian television writer-producer Andrew Wight died Saturday.
Their helicopter crashed soon after takeoff from an airstrip near Nowra, 97 miles north of Sydney, police said. Australia's ABC News reported that Wight was piloting the copter when it crashed.
DeGruy won multiple Emmy and British Academy of Film and Television Arts, or BAFTA, awards for cinematography.
An accomplished diver and submersible pilot, the Santa Barbara resident was the director of undersea photography for James Cameron's 2005 documentary "Last Mysteries of the Titanic."
"Mike and Andrew were like family to me," Cameron said in a joint statement with National Geographic. "They were my deep-sea brothers and both were true explorers who did extraordinary things and went places no human being has been."
After spending three years at the University of Hawaii in a Marine Biology Ph.D. program, DeGruy moved to the Marshall Islands, according to his website. He spent three years there, working as the manager of the Mid-Pacific Marine Lab, before transitioning to filmmaking.
DeGruy spent much of his early film career traveling the world, shooting for clients including the BBC, PBS and National Geographic, his website says. He later began producing and hosting the films.
David Bennett, president of Australia's South Coast Recreational Flying Club, said deGruy and Wight had set off to film a documentary when their helicopter crashed.
Wight, 52, of Melbourne, was the writer-producer of the 3D movie "Sanctum," which took in $100 million and was Australian cinema's biggest box office hit of 2010.
Copyright (2011) Associated Press. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.


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Pakistan struggles in race to develop armed drones
KARACHI, Pakistan -- Pakistan is secretly racing to develop its own armed drones -- frustrated with U.S. refusals to provide the aircraft -- but is struggling in initial tests with a lack of precision munitions and advanced targeting technology.
One of Islamabad's closest allies and Washington's biggest rivals, China, has offered to help by selling Pakistan armed drones it developed. But industry experts said there is still uncertainty about the capabilities of the Chinese aircraft.
The development of unmanned combat aircraft is especially sensitive in Pakistan because of the widespread unpopularity of the hundreds of U.S. drone strikes against Taliban and al-Qaida militants in the country's rugged tribal region bordering Afghanistan.
The Pakistani government denounces the CIA strikes as a violation of the country's sovereignty, though senior civilian and military leaders are known to have supported at least some of the attacks in the past. Pakistani officials also call the strikes unproductive, saying they kill many civilians and fuel anger that helps militants recruit additional fighters -- allegations denied by the U.S.
Pakistan has demanded the U.S. provide it with armed drones, claiming it could more effectively carry out attacks against militants. Washington has refused because of the sensitive nature of the technology and doubts that Pakistan would reliably target U.S. enemies.
The U.S. has held talks with Pakistan about providing unarmed surveillance drones, but Islamabad already has several types of these aircraft in operation, and the discussions have gone nowhere.


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As you are aware, it is mandatory for AOs to file Form No. 24G on monthly basis with in the prescribed time. Based on the particulars reported in Form No. 24G, Book Identification Number (BIN) is generated and intimated to the respective AOs by TIN Central System. AOs can download BIN from TIN Portal. AOs are required to intimate the BIN so generated to the concerned DDOs in respect of whom the sum deducted has been credited. Subsequently, the BIN is to be reported by the DDOs in the quarterly TDS/ TCS statements.
In case of delay in filing of Form No. 24G by the AOs, there would be delay in generation of BIN and subsequent intimation of the same by the PAOs to the concerned DDOs. This contributes towards delay in filing of quarterly TDS/ TCS statements resulting into levy of late filing fee u/s 234E of the I.T. Act (a sum of Two Hundred Rupees for every day during which the failure continues) on the deductors.Late filing of TDS statements also results into the TDS Credit not being available to the deductees (employees / vendors) for claiming the amount of tax already deducted from the payments made to them besides generating correct TDS Certificates for them.
From the records it is noticed that there was an inordinate delay (more than 3 weeks) on your part in filing of Form No. 24G for various months during current financial year i.e. 2013-14. As indicated above this has caused inconvenience to deductors and the taxpayers.
In view of the above, and the fact that the due date of filing of Form No. 24G for the month of December, 2013, which is 10th January, 2014, is approaching fast, you are advised to file Form No. 24G for the month of December, 2014 well within the due date so that the DDOs are also able to file there quarterly TDS/TCS Statements for third quarter of FY 2013- 14 with in the due time and avoid levy of fee u/s 234E of the I.T. Act.


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Just as our wine is an intricate blend, our team is a blend of unique individuals with a passion for creating wines of the highest quality and character.
Jay Turnipseed
WinemakerIt was a bottle of 1953 Chateau Margaux that kick-started Jay's interest in the wine industry. "I had about two sips and I thought, 'So THIS is what all the fuss is about.' Within days, I was figuring out how to get into wine."
Jay left the San Diego restaurant industry and enrolled in the Viticulture and Enology program at UC Davis in 2000. While in school, he focused on three research projects that included the effects of pruning, thinning and crop load on finished wine sensory characteristics. "These projects were integral in shaping the way I look at how wine is made," he explains. "I learned early on that what happens in the vineyard affects what happens in the glass."
After graduation in June 2002, Jay joined Gallo of Sonoma, first as an intern, then as Enologist. He joined Franciscan Estate in May 2004, and is thrilled to have an opportunity to work with MAGNIFICAT, a Bordeaux blend like the wine that changed his life.
"It's just a wonderful feeling to walk Franciscan Estate's Oakville vineyard and know that the quality is there to make unparalleled Bordeaux-style wines. I hope one day someone uncorks a bottle of MAGNIFICAT that I had a hand in and says, 'so THIS is what all the fuss is about...'"
WinemakerA native of California, Marla Carroll grew up in a small town in the mountains separating the Southern California High Desert and the rich agricultural lands of the Central Valley. It was here she grew up exploring the outdoors, hiking, camping, backpacking, and cultivating an appreciation for the outdoors, and laying the foundation for her deep interest in viticulture and the environmental factors that shape the expression of a vineyard.
With a strong understanding of nature and the science behind winemaking, Marla respects and appreciates the biological intricacies that go into each bottle. However, it is her passion for food and flavors that shape her approach to crafting wine at Franciscan Estate, paying close attention to the character and expression of each lot to create wines with complexity and nuance."I'm inspired by the endless layers of complexity that begin in the vineyard and lead to a bottle of wine. I love that it changes over time, yet is a snapshot of a particular vintage and harvest conditions." says Marla.
Marla received a degree in Biotechnology from the University of California at Davis with a concentration in Enology & Fermentation Science. While a few key courses introduced her to the world of wine, it wasn't until she took a position during harvest at the historic Charles Krug Winery in 2002 in the Napa Valley, that she truly understood her interest in winemaking. In 2004, Marla accepted a position with Franciscan Estate, spending seven years in a series of roles, including Enologist and Assistant Winemaker. After some time off with her family, Marla reunited with the Franciscan Estate team in 2013, where she continues to work closely with director of winemaking Janet Myers.Marla lives in Crockett, Calif. with her husband and their two daughters. She enjoys hiking, art and design, cooking from her garden, raising chickens, and seeking opportunities to serve in the community.


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What Kind of Carpet Should I GetKacy Faulconer
Oh, friend. Some weeks you cruise on through like a boss.
And some weeks your dryer breaks, your washer floods, your carpet soaks, and your floor boards swell.
Long story short: I'm getting new carpet. So. What should I get? Remember, I have 2 cats, a dog, and 4 kids who play in ponds, rivers, and beaver dams daily. Here's what I'm considering. Please weigh in if you have advice, regrets, or tips.
I am really liking the light-colored samples I'm bringing home. Home Depot has been great. They talked to me about Stainmaster carpet. I WANT. I watched this video about the Martha Stewert carpet. I did an experiment at home–poured brown soda on the carpet sample and blotted it up with a paper towel. It works. Do I dare get light carpet, even if it's stain resistant?
Next, I really like the loop carpet. This is my favorite. Supposedly it's really durable. Will I miss my plush cut pile? I'm having major commitment issues with carpet. I'm thinking about the loop carpet downstairs in the living room and on the stairs and a plusher cut pile in the bedrooms.
And finally, I'm wondering about quality. I want to get the best I can afford. There is a premium carpet within my budget that comes with a 25 year guarantee. Do I want that? Or should I spend less and plan on replacing my carpet sooner. Because styles change and I might get sick of it?
I really love all the options and varieties. But at some point I have to stop looking at samples and researching and just order the dang carpet. It's a big investment! In the mean time, however, we're living with exposed tacking strips–Not exactly kid friendly.
Read more of my writing at Kid Scoop.
Read more from me at Every Day I Write the Book.
Find me on Twitter and Facebook!
A big thanks to The Home Depot for sponsoring this campaign. Click here to see more of the discussion.


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I want to kick someone's butt!
I read about this last night and read more about it this morning.
Some woman in my town left her 5 kids, between the ages of 10 & 10 months in the car for 10-15 minutes with no adult supervision. The car was running.
When she came back to the car a 2 year old little girl had her head caught between the window and the door frame and she wasn't breathing.
The little girl is in critical condition at Children's Hospital.
Seriously... what the hell do people think when they leave their kids alone in a car? I am just so furious with this mother, who I've never met.
OMG! What makes people think to leave their kids unattended? It's just asking for something to happen. I have prayers and positive energy going to this little girl as I type. I hope she pulls through with no long term effects.
As for the mom......she knew better.
Last I read she was on life support and not able to breath on her own. The Crimes Against Children unit is investigating but no charges have been filed.
This is crazy, I have had six kids and I had never left my kids in the car alone.
Quoting amonkeymom:
Last I read she was on life support and not able to breath on her own. The Crimes Against Children unit is investigating but no charges have been filed.
This breaks my heart
What in the world? The 10 year old should have been old enough to help the child or prevent it from happening. In my state a 10 year old can supervise children for a short amount of time. That is horrid. I wouldn't leave my kids in the car simply because there are people who get get in the running car and take off with it and the kids still inside. Add to that a few other reasons. However when my son was 10, had I done so, I could have trusted him to supervise his siblings without incident.
Yikes! We have never left our kids alone in the car, in hot or cold weather. That's just plain craziness to me.


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Selling and shipping BP parts to Canada?
Tools and Technologies
> Selling and shipping BP parts to Canada?
October 4, 2012, 09:09 PM
I have a Pietta 1851 that is complete except no cylinder, a member in Nova Scotia Canada would like to buy it, anybody ever deal with something like this, I'm concerned about keeping this legal.
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Skinny 1950
October 4, 2012, 09:58 PM
In Canada reproduction handguns are restricted and the frame is the part that needs to be registered... this can only be done if the serial number is in the system already and transferred from one licensed owner to another. To import a restricted handgun (or frame) into Canada is an expensive and tedious ordeal and usually only undertaken when someone REALLY wants a gun that is not normally available in Canada.
October 4, 2012, 10:42 PM
Thanks I was afraid of that.
October 4, 2012, 10:44 PM
What part is registered on say, a Hawken rifle?
Skinny 1950
October 4, 2012, 11:32 PM
The long gun registry was recently struck down in Canada (Except in Quebec) so they don't need to be registered but you need a Possesion and Aquisition Licence (PAL) to buy one and own it. Flint lock rifles as well as wheel-lock and match-lock rifles are considered antiques even if the are of modern manufacture, cap lock rifles are non-restricted firearms if they are of modern manufacture but if they are made before 1898 they are considered antique and can be bought and sold with no restrictions except you must be at least 18 years old.
Flint-lock,wheel-lock and match-lock rifles can be imported into Canada no problem, modern cap lock rifles and cartridge rifles are not quite as difficult to import as handguns but still a steep curve to climb.
Guns that are considered Antiques on both sides of the border can move smoothly between Canada and the U.S as long as Duties are paid and everything is declared properly.
October 6, 2012, 12:05 AM
The way I understand it is that much of the paper work is due to the ITAR limitations on export and NOT getting into Canada. And since the US does not look at black powder C&B as being controlled firearms the only issue is with the provincial CFO up our way.
You'll want to check on this with your own Customs folks to ensure that they have no issue with sending a black powder frame out of country and you'll want to get the buyer to contact our own Canadian Firearms Program folks about what papers that your buyer will need.
Now if this were a more modern cartridge gun then Skinny would be 100% right that it's more trouble than it's worth. But for BP C&B guns it really should not be that hard.
October 6, 2012, 01:27 PM
Buyer did some checking also and we decided to nix the sale.
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I had a pair of adorable tights that no longer fit Kirsten and I just couldn't part with them. I decided to turn them into a stuffed snake for her. Now my sewing skills are so bad it's almost embarrassing, so if I can make this, anyone can. She loves her little snake – or 'worman' as she calls it – and has been taking it to bed with her every night. Here's how I made it:
What you'll need:
an old pair of tights
2 buttons
needle and thread
Here's how you make it:
Find an old, cute pair of tights:
Using your scissors, cut one of the legs off. Find 2 buttons (mine don't even match!) and sew them on the snake.
Cut a tongue out of your piece of felt and sew onto the snake. I pinched the end of the tights and sewed the tongue into the pinched part.
Here's what the tongue looks like – see how it's in the 'pinched' part:
Stuff your snake and tie the end shut. If you have sewing skills that are better than mine, you could even sew the end shut and make it look a little more professional. I don't care and neither does Kirsten, so I tied the end which was quick and easy.
Isn't she cute??
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Resolute - Republic Flagship Map
Click HERE or on the image above for a larger map of the Republic Flagship, Resolute.
Red Brick Location Descriptions
#3: Fast Build - Resolute Turbolasers - 500,000 studsMake your way to the Resolute's turbolaser battery room and look on the lower right side for a punching bag. Hit it five times to reveal this Red Brick which allows for much faster Lego-building.#5: Minikit Detector - Resolute Minikit Character Room - 750,000 studsTake an astromech droid to the Minikit Character room aboard the Resolute and roll down to the bottom-left corner, using the console there to open a tank with the brick inside. This Red Brick is invaluable in helping to find Minikits strewn about all of the levels in the game.#6: Super Speeders - Resolute Minikit Character Room - 40,000,000 studsTake Jar Jar and a Clone Trooper with a heavy weapon down to the Minikit room with the tanks for all the unlockable characters. Walk over to the top-right corner of the room and use Jar Jar to double-jump up to the walkway above. Demolish the crates there and rebuild the debris into a grappling point. Switch to your trooper and grapple up to the walkway, then head to the left and destroy the silver object to reveal the Red Brick. This brick makes it so all speeders shoot very powerful lasers capable of taking out regular, silver and golden buildings and objects.#7: Score X2 - Resolute Docking Bay - 500,000 studsFind this Red Brick in a crate in the upper left-hand corner of the Resolute's Docking Bay. Use a character with the grappling hook to pop open the crate and buy it. This brick will double all studs you accumulate and is stackable with other multiplier bricks.#8: Score X4 - Resolute Gold Brick Deck - 2,000,000 studsHead to the deck on the Resolute that houses your accumulated gold bricks in the upper right-hand corner. Walk over to the opposite side of the deck to find a trash compactor and three garbage cans. Use a Force-wielding character to place the cans in place in front of the compactor until the Red Brick pops out of the chute on the left. This brick quadruples the studs you collect and is stackable with other multiplier bricks.#9: Score X6 - Resolute Walkway Hub - 10,000,000 studsMake sure you have a Force-user and a character with a grappling hook, then head down the turbolift from the Resolute's bridge to the walkway hub below. Use the Force to plug in the power source just left of the turbolift, then use the grappling hook to ascend to the walkway above. The Red Brick, which sextuples the amount of studs you earn, is in a alcove to the left. As before, this brick stacks with other multiplier bricks.#11: Score X10 - Resolute Walkway Hub - 40,000,000 studsTake a Sith character and Robonino (because he has both a thermal detonator and charging ability) to the center of the Resolute's walkway hub. Destroy the crates next to the silver and blue box in the center of the walkway and rebuild them into a charging console. Use Robonino to throw a thermal detonator at the silver objects in the middle, then charge up the console. Finally, switch to your Sith character and use the Force to destroy the last blocks in the center, giving you access to the brick that decouples the amount of studs you find and can also stack with the other multiplier bricks.#12: Stud Magnet - Resolute Walkway Hub - 500,000Take a Jedi and rapid-fire Clone Trooper down to the Resolute's walkway hub, plugging the power cord in on the left side of the turbolift and grappling up to the upper walkway. Walk to the left and destroy the cylinder on the wall to the left of the alcove. Next, walk over to the right and extend the walkway there, then shoot the cylinder on the back wall. Drop down below and destroy the cylinder on the right side of the walkways, then turn around and destroy the one on the left side. Destroying all four will reveal the Red Brick to the right of the turbolift back up the bridge. This brick will make studs even more attracted to your character.#14: Character Studs - Resolute Brig - 100,000 studsIt takes some work to collect this brick. Firstly, make sure you've completed the Naboo and Christophisis Ground Assault levels for the Republic side so that all of the jail cells in the brig are occupied. Next, take Robonino and a Sith character to the bridge and open all but the third jail cell with your combination of dark-side, charging and bounty hunter abilities. Go switch out for a Separatist droid and use the console to open the third cell. With all of them open, knock the back wall out of the first four to reveal valves inside, then use the dark-side to turn them, opening the hatch in the final cell with the Red Brick. This brick will award you with studs for destroying enemies and other characters.#15: Super Saber Cut - Resolute Walkway Hub - 300,000 studsTake a character with a sniper rifle to the northern-most horizontal walkway on the Resolute's walkway hub, looking for three green targets that swivel down from the ceiling in the distance. Shoot all three to reveal this Red Brick, which makes cutting holes in walls with the lightsaber much faster.#17: Glow in the Dark - Resolute Medical Wing - 25,000 studsHead to the Medical Wing of the Resolute and smash the bed in the alcove on the wall just to the left of the character customization tanks to reveal the Glow in the Dark brick. This brick will make all of the lights in the game much brighter.#18: Red Brick Detector - Resolute Bridge - 125,000 studsLikely the first Red Brick you'll see, as it's on the bridge of the Resolute, you won't be able to obtain it until you have unlocked a small character. Once you have, head to the left side of the bridge and destroy the crate in the alcove there, then rebuild the pieces into a small vent. Switch to your small character and crawl down to collect it. The Red Brick Detector, as the name implies, will help you find the rest of the Red Bricks in the gameGO TO HUB WORLD: SEPARATIST FLAGSHIP - INVISIBLE HAND RED BRICK LOCATIONS MAPGO TO GROUND AND SPACE ASSAULT STRATEGIESGO TO CHEAT CODES, PASSWORDS, AND UNLOCKABLES
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text: Explore Dublin Grafton Street Trinity College The National Museum The National Gallery Merrion Square St Stephen's Green Temple Bar Dublin Castle and around O'Connell Street and around Parnell Square and around Old Jameson Distillery and Smithfield Collins Barracks West of the centre The northern suburbs South along the coast Share The growth in visitor numbers over the last decade or so has had a positive effect on the variety of accommodation available in Dublin, and there is plenty to choose from for all budgets, with the Northside and suburbs generally cheaper than the centre. Hotels in the city centre tend to be expensive, though many offer discounts midweek or outside the high season (especially via Web bookings), while B&Bs usually provide a very welcoming and comfortable alternative. If money is comparatively tight and you want to be near the action, hostels are the best option and almost all have private rooms. Booking in advance is always highly advisable, and essential around major festivals such as St Patrick's Day, in July and August, and on weekends all year round, especially when major concerts or sporting events are taking place. There is one campsite on Dublin's outskirts. Many of the city's top-range hotels are located around Temple Bar and St Stephen's Green, though the Northside also has some chic options. Dublin has a staggering number of B&Bs and you'll find economically priced options on the Northside's Gardiner Street or in the pleasant Southside suburbs of Ballsbridge, Donnybrook and Rathmines, which are all within easy reach of the centre. Numerous hostels offer both dormitory accommodation (€12–25 per person, depending on the season) and private rooms, usually sleeping between two and four people (€30–60 per person). Most rooms are en suite and the standard of private rooms is often as good as at B&Bs. Several Dublin hostels belong to the IHH though a few are members of the IHO. Many hostels offer free breakfast and provide internet access. Read More


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It was an expensive throw of the dice:
Back in 2006, the Pennsylvania State Employees Retirement System (SERS) and its board, headed by ex-state Rep. Nicholas Maiale (D., Phila.), gave more than $3 billion to six private investment firms so they could use it to buy high-priced hedge fund investments, in hopes of fat profits.
The goal was to beat the sluggish stock and bond markets and ease the system's deficit, which had been growing since Gov. Tom Ridge boosted pensions in 2001 but failed to pay for the increase.
One beneficiary of Pennsylvania's hedge fund strategy was a New York firm, Arden Asset Management. The state paid Arden $20 million to pick hedge funds from 2006-12.


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Top 100
Job hunting? Check out our reigning best places to work in D-FW
Photo: Tom Fox/Staff Photographer
Rank: #30 in Large companies
Business: Utilities - electricity and gas
Headquarters: Dallas
D-FW locations: 2
Employees (D-FW): 544
Past Rankings
2009: #35 in Midsize companies
2010: #24 in Midsize companies
2011: #28 in Midsize companies
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I am writing here because I have no one around me who really understands or can help me with my dilemma. Or maybe I just need to vent like a child.
I began eating a low carb, high protein, and low fat diet almost 1.5 years ago. After three months, I lost all my pregnancy weight, but my body just didn't feel right. Worse, the sugar and carb cravings were always there, and it concerned me that I would inhale a bunch of cupcakes any moment (which I did end up doing quite often). I still wanted to lose 10 pounds, so I began working out and eating well during the week. In the weekend, I indulged on sugary, carby treats.
Then I found Mark's website. It took a while to wrap my head around this fatty situation, but then finally bought into it. It has been around three months since I have been eating Primal. I also IF from time to time and eat when I am hungry. I feel SO much better. I have lost 10 pounds, and my body is in the best shape ever.
I have lost all my sugar and carb cravings, and I attribute that to my high fat consumption. Then why do I keep going back, from time to time, to my old unhealthy "treats?" For instance, two days ago, I wanted to have some ice-cream. Or I thought my mind wanted some ice-cream. I ate ice-cream. It didnt do anything for me. But I still ate it. I continued eating it, in the hope that it would do something for me. It didnt.
This seems so wrong. Why isnt this sugary, carby stuff giving me any "pleasure"? This sounds silly and weird and stupid, but I am so sad that I have lost that part of me. And in a confusing way, I am happy that that part of me does not exist anymore. Yet I feel that I will continue jeopardizing myself from time to time with this weird behavior. Ok, there are worse things out there in this world, but I mean, how can someone have no unhealthy, bad-for-you, indulgences??? More importantly, how can I be that someone? That seems quite impossible...given my life-time track record on ice-cream and dessert.
Am I the only one out there with this strange struggle/relationship with the old way of eating?


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Australia Burning
Fire Ecology, Policy and Management Issues
Illustrations, Index
280 pages
CSIRO Publishing
This book is no longer available in print.
The phenomenon of fire in the Australian landscape traverses many interests and disciplines. At a national level, there is an urgent need for the integration of both the natural and social sciences in the formulation of public policy.
With contributions from 30 leading experts, Australia Burning draws together these issues, under the themes:
The book examines some of the key questions that relate to the ecology, prediction and management of fire, urban planning, law, insurance, and community issues, including indigenous and non-indigenous concerns. It looks at what we need to know to inform public policy, given the present risks and uncertainty, and explores the avenues for closer integration between science, policy and the community.


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Two northern California police officers are in trouble after they allegedly used company equipment and time to search for women on internet dating sites. Police say Sergeant Stephen Ruiz and Detective Jacob Glashoff found women on websites like E-harmony and Match dot com. Then, they allegedly used government databases to perform background checks on the women they liked. Court documents go on to say Sgt. Ruiz and Detective Glashoff would perform the searches and have conversations about the dating sites in front of other officers. A separate law enforcement agency is in charge of the investigation of the two Fairfield police officers. If the allegations are found to be true, the officers could face felony criminal charges.
Cops accused of performing background checks on girls on dating websites
Government databases were allegedly used by officers to get information
POSTED: 10:41 PM PDT Aug 22, 2014
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Top Definition
Getting grounded from the family computer.
"That's it, you are under mouse arrest mister!" - Your mom after discovering your pornfolio
po Jason Септембар 8, 2004
Trending Now
Can you define these popular missing words?
Mouse arrest begins when your cordless mouse batteries die and ends when you get off your fat ass and get more batteries.
I was about to frag that n00b from behind all sneak-attack style but then I entered mouse arrest.
po Phil Август 29, 2007
The state of being stuck at your computer, to answer endless emails for example.
Sorry I missed lunch; work had me under mouse arrest.
po iamlazarus Август 14, 2007


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Maybe I can shed some light on the subject for you. In recent years, I've come to care a great deal about combating identity theft. As a father of two young daughters, I especially care about combating child identity theft — and I find child identity theft is too often something of an unknown danger to all too many parents.
You may never have even thought about the issue of child ID theft until you stumbled upon it, or something happened to you or someone you know that caused you to research it. Several years ago when I first joined Intersections and the Identity Guard® team, child identity theft was less pervasive than it is today. But, in the days and months that followed, what we have discovered has been a real eye-opener. We at Identity Guard found ourselves wanting to do something about it, and as I have learned more and more, I wanted to share what I have learned with you.
So, along with my colleague Steve Schwartz, I've just finished writing a book called Bankrupt at Birth. It's something Steve and I discussed on numerous conversations and we finally published it in order to help others understand child identity theft — its causes, what dangers you and your children face, and what you can and should do to protect them. My hope is that a large number of parents will get and read this book, and then share its insights, tips and strategies with their friends who will do the same.
Because of the fact we constantly deal with the prevention of identity theft, and especially child identity theft, my team and I have developed a special understanding of the problem, its consequences, and actions for its remediation. My goal now is to share this expertise on a continuing basis. So I have decided to write this blog to share with you what I am learning and what I am seeing in the world of identity theft, and to occasionally add my comments to all this.
I hope this will be beneficial and I believe it will give you new insights into a problem that we all face.


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Applying for Scholarships
How to Apply for Foundation Scholarships:
1. Log on to the STARS Scholarship Application website (https://sandburg.starsscholarshipsonline.com) and complete the student profile and questionnaire. The responses provided will help the process sort through the scholarships and show only those that apply to the criteria provided in the profile and questionnaire. Scholarship information is provided with each scholarship on the website, as well as on the Foundation Scholarships webpage.
New Students: Students who are new to the STARS application process (i.e. have never applied for scholarships on STARS), click the "Sign Up" button to create a user name and password.
Returning Students: Students who are returning to the STARS application process simply log in to the website with the username and password they previously created. If you have forgotten your username and/or password, please contact the Foundation Office at 309.341.5349.
Note: Paper applications are no longer accepted by the Foundation except when specified in scholarship requirements*. All students wishing to apply for scholarships must use the STARS Scholarship Application website and submit applications electronically.
Each scholarship requires a separate application, however the website saves the provided information in the student profile and questionnaire and automatically generates applications for the scholarships being applied for—making applying for multiple scholarships much more simple and straightforward.
The STARS Scholarship Application website will be open starting December 1st and will close March 1st. Applications submitted after March 1st will not be accepted.
All Foundation scholarships are awarded for the following academic year (i.e. if current academic year is 2013-2014, scholarships will be awarded for the 2014-2015 academic year). Awarded scholarships are contingent on the student enrolling and attending Carl Sandburg College in the following Fall/Spring semesters.
2. As of December 2011 copies of transcripts are not required to be attached to the student profile on the STARS Scholarship Application website.
Note: Carl Sandburg College requires transcripts to be provided when a student applies to the College for enrollment. If you have not submitted your transcripts to the registrar's office, please read below to learn which transcripts you will need to submit:
High School: If you have graduated from high school within the past five years, provide an official high school transcript to the registrar's office. (Transcripts must be obtained from the high school.) If you graduated five years ago or more, no high school transcript is required.
Transfer Student/Attended Other College: If you transferred to Sandburg from another college or university or you have attended another college prior to Sandburg, your college academic transcripts must be sent to the registrar's office.
High School Equivalency Certificate (HSEC):If you have completed a HSEC or received a high school diploma from an alternative program, proof of completion must be provided to the registrar's office.
3. Answer the brief essay questions required for all scholarships on the website. Students only need to answer these essays once as the process will attach them to each scholarship applied for. Responses should outline educational goals and why the scholarship is deserved. (If a student must meet specific criteria to be eligible for a scholarship, please include this information in the essay.)
4. Check to make sure that all required information has been submitted on the appropriate form for each scholarship being applied for. Students may save and exit the process at any time and return later to finish or update their information before March 1st.
5. All required information must be received on the STARS Scholarship Application website and/or in the Foundation Office on March 1, unless otherwise specified.
6. For questions or more information, please contact the Foundation Office at 309.341.5349 or by email.
*Scholarships that require a special application can be found on the Special Scholarship Application webpage. Special scholarship applications should be mailed or personally delivered to:
Carl Sandburg College Foundation
2400 Tom L. Wilson Blvd.
Galesburg, IL 61401


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Restoring W-Class trams
The Government has committed $8 million to restoring Melbourne's historic W-Class trams.
The Bendigo Trust is playing an important role in the ongoing maintenance of the W-Class tram fleet.
The first three W-Class trams that have been restored are currently taking passengers on the City Circle tram route.
Restoration of the fourth tram has commenced and is expected to be complete in the first quarter of 2016.
Trams are being restored to as close to their original appearance as possible, while meeting modern safety standards and having improved passenger comfort, performance and reliability.
This is a huge and complex project involving the extensive stripping down and rebuilding of a W-Class tram. The end result is effectively a brand new tram.
The complete refurbishment has included:
- new impact-resistant driver's cabin
- removal of high voltage wiring from the driver's cabin
- new electronics and wiring to allow for GPS surveillance and improved electrical performance
- a complete rebuild of the body to include better safety features
- painting and restoring the green and gold livery.
Project update
In March 2016, a fourth refurbished W-Class tram was completed at the Bendigo Tramways Depot and Workshop. The newly restored tram will operate on Melbourne's City Circle route.
For more information, see Restored W-Class tram enters service
View a video of the the fourth restored W-Class tram rolling out of Bendigo Tramways Depot and Workshop, below.
View a video of the third restored W-Class tram rolling out of Southbank depot, below.


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"Lands into Trust" -- Supreme Court to Hear Case
Apr 13, 2012
Native American Legislative Update - April 2012
For the last few years, a legislative priority for tribal governments, the administration and the congressional authorizing committees has been to clarify the authority of the Secretary of the Interior to assist tribes to acquire or expand their tribal homeland by placing land into trust with the federal government. Tribes place land into trust for economic development, infrastructure like housing and schools, and cultural and other purposes. We have reported on legislation called the "Carcieri fix," which is named after a 2009 Supreme Court decision in Carcieri v. Salazar, in which the Court held that only those tribes that were federally recognized at the time the Indian Reorganization Act was enacted in 1934 can have the Secretary of the Interior take land into trust for them. (The tribe that was the subject of the case had been recognized as an Indian tribe after 1934.)
On April 24, the Supreme Court will hear oral arguments in what will be the key Indian law case this term. The two cases that are being consolidated - Salazar v. Patchak and Match-She-Be-Nash-She-Wish Band of Pottawattami Indians v. Patchak - involve the Bureau of Indian Affairs taking land into trust for a Michigan Tribe, which built a casino on the property. A non-Indian individual who lives near the gambling facility challenged the acquisition, saying that the Tribe was not recognized as a tribe by the federal government in 1934. The high court will review the initial questions of whether Mr. Patchak has been injured in some way by the taking of these lands into trust and therefore might have a right to sue, and whether he can sue the United States government, which is generally immune from suit. If the court settles these two questions in Mr. Patchak's favor, it may go on to consider the merits of the case.


text: The 2008 Seahawks Season is over Posted by on Dec 29, 2008 00:13 ShareTweetby: Chris Sullivan Well guys, the misery is over. The 2008 season has drawn to a close, and with it, Mike Holmgren's 10 year career as the head coach of the Seattle Seahawks is done. The Jim Mora era begins in earnest tomorrow morning. The Seahawks gave it a pretty good try today, but lacked the fire necessary in the second half. The last quarter's play calling seemed like Holmgren was resigned to a loss in order to let Morris show his stuff a little more. But hey, I think Big Mike deserves the luxury to let us lose in his last game, if thats really the game he wants to call. Why not, right? UPDATED: Oakland won today as did Cincinatti, so it would appear that the Seahawks will be picking #4 overall. The draft order appears to be 1) Detroit 2) Kansas City 3) St Louis 4) Seattle 5) Cleveland. [Thanks to all who corrected me in the comments!] Okay, okay, enough prattling: Send this season out like it deserves… R-Rated Post begins F***ing NOW! ShareTweetSeahawks Tickets About View all posts by →


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The positive feedback you may be receiving from others for your accomplishments could make you feel validated today, for just knowing that others value what you do might feed into your sense of self-worth. While being acknowledged for your achievements is wonderful, you may wish to remind yourself that, as with anything in life, true validation comes only from within yourself. Perhaps you can ask yourself what you get from the praise you receive from others that you should be able to give to yourself. Instead of having others confirm your feelings about yourself today, you may want to look at everything you do as having a positive impact on the world. Seen in this way, you are always contributing to making others' lives better.
Success is born from our inner feelings of importance. When we recognize that all we do is worthwhile, the praise we get from others is an additional bonus to our work rather than the defining aspect of it. If we view ourselves from this perspective, we begin to see that our accomplishments are actually a by-product of living in an interconnected world and that the feedback we get from others is not necessary to our definition of who we are. Feeling good about ourselves will do more for us than looking outside of ourselves. Looking within for confirmation of your influence on others today will bring you closer to realizing that your triumphs are an ever-present part of this world.
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In this segment from The Motley Fool's everything-financials show, Where the Money Is, analysts David Hanson and Matt Koppenheffer play a round of "Fool in the Blank." In this game, a sentence is given, and each player must fill in the rest. The duo completes the following:
- Big banks are _____ about the Fed's decision.
- When first sizing up a bank, _____ good place to start.
- Concerned JPMorgan (NYSE: JPM ) investors should ______.
- I am ______ Janet Yellen is the front-runner.
Fool in your portfolio!
Have you missed out on the massive gains in bank stocks over the past few years? There's good news: It's not too late. Bargains of a lifetime are still available, but you need to know where to look. The Motley Fool's new report, "Finding the Next Bank Stock Home Run," will show you how and where to find these deals. It's completely free -- click here to get started.
Fool in the blank! Concerned JPMorgan $JPM investors should _______.— MotleyFoolFinancials (@TMFFinancials) September 19, 2013


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Browsing Dissertations by Author "Hautamäki, Juha"
Now showing items 1-1 of 1
Pattern-Based Tool Support for Frameworks: Towards Architecture-Oriented Software Development Environment Hautamäki, Juha (2005-02-04)Software engineering aims at techniques for producing better software products with less resources. A central concept for achieving this goal is a product line architecture. Frameworks are a popular object-oriented way to ...
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^ i feel uncomfortable with Err stalking and watching us whenever he wants.
thats awesome
if aramis is healthy all year id say Upton and him will give u better overall #'s in all 5 catagories.. avg is the only thing that would be close.. i would like to see him hit for a higher Avg and drive in more R's though.. kid is so young and so good but the supporting cast has to be better then last year so he has more opps at RBI's.
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Croatia fined €80k over racist chants
Soccer:Croatia was today fined €80,000 after their fans were found guilty of racially abusing Mario Balotelli during their European Championship game against Italy.
The punishment, which was also dished out for the setting off and throwing of fireworks, was the first for a racially-aggravated offence at a tournament which has been marred by the problem.
According to official observers, Italy striker Balotelli was subjected to monkey chants by between 300 and 500 Croatia fans during Thursday's 1-1 Group B draw in Poznan. There were also accusations of a banana being thrown onto the pitch at the Municipal Stadium.
UEFA said in a statement: "The Croatian Football Federation (HNS) has been fined 80,000 euros for the setting-off and throwing of fireworks, and the improper conduct of supporters (racist chants, racist symbols) at the Uefa Eeuro 2012 Group C match against Italy in Poznan on Thursday 14 June.
"An appeal can be lodged against this decision within three days of the dispatch of the reasoned decision."