Showing papers by "David Cameron published in 2010"
TL;DR: The simulation software for the ATLAS Experiment at the Large Hadron Collider is being used for large-scale production of events on the LHC Computing Grid, including supporting the detector description, interfacing the event generation, and combining the GEANT4 simulation of the response of the individual detectors.
Abstract: The simulation software for the ATLAS Experiment at the Large Hadron Collider is being used for large-scale production of events on the LHC Computing Grid. This simulation requires many components, from the generators that simulate particle collisions, through packages simulating the response of the various detectors and triggers. All of these components come together under the ATLAS simulation infrastructure. In this paper, that infrastructure is discussed, including that supporting the detector description, interfacing the event generation, and combining the GEANT4 simulation of the response of the individual detectors. Also described are the tools allowing the software validation, performance testing, and the validation of the simulated output against known physics processes.
1,514 citations
TL;DR: Increased understanding of the genetic abnormalities involved in the pathogenesis of TNBC, BLBC and BRCA1-associated tumors is opening up new therapeutic possibilities for these hard-to-treat breast cancers.
Abstract: This Review outlines the understanding and management of triple-negative breast cancer (TNBC). TNBC shares morphological and genetic abnormalities with basal-like breast cancer (BLBC), a subgroup of breast cancer defined by gene-expression profiling. However, TNBC and BLBC tumors are heterogeneous and overlap is incomplete. Breast cancers found in BRCA1 mutation carriers are also frequently triple negative and basal like. TNBC and BLBC occur most frequently in young women, especially African Americans, and tend to exhibit aggressive, metastatic behavior. These tumors respond to conventional chemotherapy but relapse more frequently than hormone receptor-positive, luminal subtypes and have a worse prognosis. New systemic therapies are urgently needed as most patients with TNBC and/or BLBC relapse with distant metastases, and hormonal therapies and HER2-targeted agents are ineffective in this group of tumors. Poly (ADP-ribose) polymerase inhibitors, angiogenesis inhibitors, EGFR-targeted agents, and src kinase and mTOR inhibitors are among the therapeutic agents being actively investigated in clinical trials in patients with TNBC and/or BRCA1-associated tumors. Increased understanding of the genetic abnormalities involved in the pathogenesis of TNBC, BLBC and BRCA1-associated tumors is opening up new therapeutic possibilities for these hard-to-treat breast cancers.
740 citations
TL;DR: In this article, the authors used the ATLAS detector to detect dijet asymmetry in the collisions of lead ions at the Large Hadron Collider and found that the transverse energies of dijets in opposite hemispheres become systematically more unbalanced with increasing event centrality, leading to a large number of events which contain highly asymmetric di jets.
Abstract: By using the ATLAS detector, observations have been made of a centrality-dependent dijet asymmetry in the collisions of lead ions at the Large Hadron Collider. In a sample of lead-lead events with a per-nucleon center of mass energy of 2.76 TeV, selected with a minimum bias trigger, jets are reconstructed in fine-grained, longitudinally segmented electromagnetic and hadronic calorimeters. The transverse energies of dijets in opposite hemispheres are observed to become systematically more unbalanced with increasing event centrality leading to a large number of events which contain highly asymmetric dijets. This is the first observation of an enhancement of events with such large dijet asymmetries, not observed in proton-proton collisions, which may point to an interpretation in terms of strong jet energy loss in a hot, dense medium.
630 citations
TL;DR: Final analyses of overall survival from a phase III trial of lapatinib and capecitabine in patients with human epidermal growth factor receptor 2–positive locally advanced or metastatic breast cancer that progressed following prior therapy including trastuzumab are presented.
Abstract: Objectives. A planned interim analysis of study EGF100151 prompted early termination of enrollment basedonalongertimetoprogressionwithlapatiniband capecitabine than with capecitabine alone in patients with human epidermal growth factor receptor (HER)-2previouslytreatedadvancedbreastcanceror metastatic breast cancer (MBC). Here, we report final analyses of overall survival. Patients and Methods. Women with HER-2 MBC who progressed after regimens that included, but were not limited to, anthracyclines, taxanes, and trastuzumab, were randomized to lapatinib (1,250 mg/day) plus capecitabine (2,000 mg/m 2 ) or capecitabine monotherapy (2,500 mg/m 2 ) on days 1–14 of a 21-day cycle. Results. At enrollment termination, 399 patients were randomized, and nine were being screened and were offered combination treatment. In total, 207 and 201 patients were enrolled to combination therapy and monotherapy, respectively. Thirty-six patients receiving monotherapycrossedovertocombinationtherapyfollowing enrollment termination. The median overall survival times were 75.0 weeks for the combination arm and 64.7 weeks for the monotherapy arm (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.71–1.08; p.210). A Cox regressionanalysisconsideringcrossoverasatime-dependent covariate suggested a 20% lower risk for death for patientstreatedwithcombinationtherapy(HR,0.80;95% CI, 0.64–0.99; p .043). The low incidence of serious adverseeventswasconsistentwithpreviouslyreportedrates. Conclusions. Although premature enrollment termination and subsequent crossover resulted in insufficient powertodetectdifferencesinoverallsurvival,exploratory analysesdemonstrateatrendtowardasurvivaladvantage with lapatinib plus capecitabine. These data continue to support the efficacy of lapatinib in patients with HER-2 MBC. The Oncologist 2010;15:924 –934
274 citations
TL;DR: The treatment of breast cancer in pregnancy should be executed by experienced specialists in a multidisciplinary setting and should adhere as closely as possible to standard protocols.
242 citations
TL;DR: An overview of the Tile Calorimeter performance as measured using random triggers, calibration data, data from cosmic ray muons and single beam data and the determination of the global energy scale was performed with an uncertainty of 4%.
Abstract: The Tile hadronic calorimeter of the ATLAS detector has undergone extensive testing in the experimental hall since its installation in late 2005. The readout, control and calibration systems have been fully operational since 2007 and the detector has successfully collected data from the LHC single beams in 2008 and first collisions in 2009. This paper gives an overview of the Tile Calorimeter performance as measured using random triggers, calibration data, data from cosmic ray muons and single beam data. The detector operation status, noise characteristics and performance of the calibration systems are presented, as well as the validation of the timing and energy calibration carried out with minimum ionising cosmic ray muons data. The calibration systems’ precision is well below the design value of 1%. The determination of the global energy scale was performed with an uncertainty of 4%.
203 citations
TL;DR: A retrospective evaluation of the AZURE trial data suggests a possible direct anti-tumour effect of ZOL in combination with CT, warranting formal evaluation in prospective studies.
Abstract: BACKGROUND: Pre-clinical studies have demonstrated synergistic anti-tumour effects of chemotherapy (CT) and zoledronic acid (ZOL). Within the AZURE trial, designed to determine whether the addition of ZOL to neoadjuvant therapy improves disease outcomes, a subgroup received neoadjuvant CT. We report a retrospective evaluation comparing pathological response in the primary tumour between treatment groups. METHODS: In total, 205 patients received neoadjuvant CT±ZOL (CT þZOL, n ¼102; CT, n ¼103). The primary end point was pathologically assessed residual invasive tumour size (RITS) at surgery. Secondary end points were pathological complete response (pCR) rate and axillary nodal involvement. Following review of surgical pathology reports (n ¼195), outcome differences between groups were assessed adjusting for potential response modifiers. RESULTS: Baseline characteristics and CT treatments were similar. In multivariate analysis, allowing for biological and clinical factors known to influence tumour response, the adjusted mean RITS in CT and CT þZOL groups were 27.4 and 15.5mm, respectively, giving a difference in means of 12mm (95% confidence interval: 3.5–20.4mm; P ¼0.006). The pCR rate was 6.9% in the CT group and 11.7% in the CT þZOL group (P ¼0.146). There was no difference in axillary nodal involvement (P ¼0.6315). CONCLUSION: These data suggest a possible direct anti-tumour effect of ZOL in combination with CT, warranting formal evaluation in prospective studies.
199 citations
TL;DR: The ATLAS Inner Detector as mentioned in this paper is a composite tracking system consisting of silicon pixels, silicon strips and straw tubes in a 2 T magnetic field, which was completed in 2008 and the detector took part in data-taking with single LHC beams and cosmic rays.
Abstract: The ATLAS Inner Detector is a composite tracking system consisting of silicon pixels, silicon strips and straw tubes in a 2 T magnetic field. Its installation was completed in August 2008 and the detector took part in data-taking with single LHC beams and cosmic rays. The initial detector operation, hardware commissioning and in-situ calibrations are described. Tracking performance has been measured with 7.6 million cosmic-ray events, collected using a tracking trigger and reconstructed with modular pattern-recognition and fitting software. The intrinsic hit efficiency and tracking trigger efficiencies are close to 100%. Lorentz angle measurements for both electrons and holes, specific energy-loss calibration and transition radiation turn-on measurements have been performed. Different alignment techniques have been used to reconstruct the detector geometry. After the initial alignment, a transverse impact parameter resolution of 22.1 +/- 0.9 mu m and a relative momentum resolution sigma (p) /p=(4.83 +/- 0.16)x10(-4) GeV(-1)xp (T) have been measured for high momentum tracks.
181 citations
TL;DR: The limited efficacy observed in this study, generally SD of relatively short duration, suggested little benefit of further investigation of single-agent pertuzumab in unselected patients with HER2-negative disease.
Abstract: Purpose Pertuzumab is a humanized monoclonal antibody inhibiting human epidermal growth factor receptor 2 (HER2) dimerization. The aim of this phase II trial was to assess the antitumor activity and safety profile of pertuzumab monotherapy in patients with HER2-negative metastatic breast cancer. The utility of biomarkers detected in paraffin-embedded tissue as predictors of response was also explored. Patients and Methods This was an international, multicenter, open-label, randomized phase II study. Patients (n = 79) with centrally confirmed HER2-negative metastatic breast cancer were randomly assigned to receive pertuzumab once every 3 weeks with a loading dose of 840 mg followed thereafter by either 420 mg (arm A) or 1,050 mg (arm B). Patients were stratified by country and prior taxane therapy. Results Of 79 patients who were randomly assigned, 78 were included in the intent-to-treat population. In arm A (n = 41), two patients had partial responses, and 18 patients (44%) experienced stable disease (SD)...
174 citations
TL;DR: The first measurements from proton-proton collisions recorded with the ATLAS detector at the LHC are presented in this paper, where the charged-particle multiplicity, its dependence on transverse momentum and pseudorapidity, and the relationship between mean transversal momentum and charge multiplicity are measured for events with at least one charged particle in the kinematic range.
159 citations
TL;DR: Lapatinib as a monotherapy or in combination with capecitabine seems to be equally effective in patients with p95HER2-positive and p95her2-negative HER2- positive breast tumors.
Abstract: Purpose: A subgroup of human epidermal growth factor receptor 2 (HER2)–overexpressing breast tumors coexpresses p95HER2, a truncated HER2 receptor that retains a highly functional HER2 kinase domain but lacks the extracellular domain and results in intrinsic trastuzumab resistance. We hypothesized that lapatinib, a HER2 tyrosine kinase inhibitor, would be active in these tumors. We have studied the correlation between p95HER2 expression and response to lapatinib, both in preclinical models and in the clinical setting. Experimental Design: Two different p95HER2 animal models were used for preclinical studies. Expression of p95HER2 was analyzed in HER2-overexpressing breast primary tumors from a first-line lapatinib monotherapy study (EGF20009) and a second-line lapatinib in combination with capecitabine study (EGF100151). p95HER2 expression was correlated with overall response rate (complete + partial response), clinical benefit rate (complete response + partial response + stable disease ≥24 wk), and progression-free survival using logistic regression and Cox proportional hazard models. Results: Lapatinib inhibited tumor growth and the HER2 downstream signaling of p95HER2-expressing tumors. A total of 68 and 156 tumors from studies EGF20009 and EGF100151 were evaluable, respectively, for p95HER2 detection. The percentage of p95HER2-positive patients was 20.5% in the EGF20009 study and 28.5% in the EGF100151 study. In both studies, there was no statistically significant difference in progression-free survival, clinical benefit rate, and overall response rate between p95HER2-positive and p95HER2-negative tumors. Conclusions: Lapatinib as a monotherapy or in combination with capecitabine seems to be equally effective in patients with p95HER2-positive and p95HER2-negative HER2-positive breast tumors. Clin Cancer Res; 16(9); 2688–95. ©2010 AACR.
TL;DR: A search for new heavy particles manifested as resonances in two-jet final states in 7 TeV proton-proton collisions by the LHC is presented, extending the reach of previous experiments.
Abstract: A search for new heavy particles manifested as resonances in two-jet final states is presented. The data were produced in 7 TeV proton-proton collisions by the LHC and correspond to an integrated luminosity of 315 nb(-1) collected by the ATLAS detector. No resonances were observed. Upper limits were set on the product of cross section and signal acceptance for excited-quark (q*) production as a function of q* mass. These exclude at the 95% C. L. the q* mass interval 0: 30< m(q)*< 1:26 TeV, extending the reach of previous experiments.
TL;DR: In this paper, the first measurements of the W and Z/gamma*-boson production cross sections in proton-proton collisions at 7 TeV are presented using data recorded by the ATLAS experiment at the LHC.
Abstract: First measurements of the W -> lnu and Z/gamma* -> ll (l = e, mu) production cross sections in proton-proton collisions at sqrt(s) = 7 TeV are presented using data recorded by the ATLAS experiment at the LHC. The results are based on 2250 W -> lnu and 179 Z/gamma* -> ll candidate events selected from a data set corresponding to an integrated luminosity of approximately 320 nb-1. The measured total W and Z/gamma*-boson production cross sections times the respective leptonic branching ratios for the combined electron and muon channels are $\stotW$ * BR(W -> lnu) = 9.96 +- 0.23(stat) +- 0.50(syst) +- 1.10(lumi) nb and $\stotZg$ * BR(Z/gamma* -> ll) = 0.82 +- 0.06(stat) +- 0.05(syst) +- 0.09(lumi) nb (within the invariant mass window 66 < m_ll < 116 GeV). The W/Z cross-section ratio is measured to be 11.7 +- 0.9(stat) +- 0.4(syst). In addition, measurements of the W+ and W- production cross sections and of the lepton charge asymmetry are reported. Theoretical predictions based on NNLO QCD calculations are found to agree with the measurements.
TL;DR: In women with early breast cancer receiving adjuvant chemotherapy, the most powerful predictor of benefit from anthracyclines is Ch17CEP duplication, and in view of the location of HER2/TOP2A on chromosome 17, Ch17 CEP duplication might explain the inconsistencies in previous studies of factors predicting benefit from AnthracyClines.
Abstract: Summary Background The NEAT/BR9601 trial showed benefit for addition of anthracyclines to cyclophosphamide, methotrexate, and fluorouracil (CMF) as adjuvant treatment for early breast cancer. We investigated prospectively predictive biomarkers of anthracycline benefit including HER2 and TOP2A . Methods 1941 tumours from 2391 women recruited to NEAT/BR9601 were analysed on tissue microarrays for HER2 and TOP2A amplification and deletion, HER1–3 and Ki67 expression, and duplication of chromosome 17 centromere enumeration probe (Ch17CEP). Log-rank analyses identified factors affecting relapse-free and overall survival, and regression models tested independent prognostic effect of markers, with adjustment for known prognostic factors (age, nodal status, oestrogen-receptor status, grade, and tumour size). The predictive value of markers was tested by treatment interactions for relapse-free and overall survival. Findings 1762 patients were analysed. 21% of tumours (n=367) were HER2 amplified, 10% were TOP2A amplified (n=169), 11% showed TOP2A deleted (n=191), 23% showed Ch17CEP duplication (n=406), and 61% had high (>13·0%) Ki67 (n=1136). In univariate analyses, only HER2 amplification and TOP2A deletion were significant prognostic factors for relapse-free (hazard ratio [HR] 1·59, 95% CI 1·32–1·92, p HER2, HER1–3 , or TOP2A . By contrast, in multivariate analyses, Ch17CEP duplication was associated with significant improvements in both relapse-free (HR 0·92, 95% CI 0·72–1·18 for tumours with normal Ch17CEP vs 0·52, 0·34–0·81 for tumours with abnormal Ch17CEP; p for interaction=0·004) and overall survival (0·94, 0·72–1·24 vs 0·57, 0·36–0·92; p for interaction=0·02) with anthracycline use. Interpretation In women with early breast cancer receiving adjuvant chemotherapy, the most powerful predictor of benefit from anthracyclines is Ch17CEP duplication. In view of the location of HER2/TOP2A on chromosome 17, Ch17CEP duplication might explain the inconsistencies in previous studies of factors predicting benefit from anthracyclines. Funding Cancer Research UK and the Scottish Breast Cancer Clinical Trials Group.
TL;DR: In this article, an overview of the ATLAS liquid argon calorimeter performance measured in situ with random triggers, calibration data, cosmic muons, and LHC beam splash events is presented.
Abstract: The ATLAS liquid argon calorimeter has been operating continuously since August 2006. At this time, only part of the calorimeter was readout, but since the beginning of 2008, all calorimeter cells have been connected to the ATLAS readout system in preparation for LHC collisions. This paper gives an overview of the liquid argon calorimeter performance measured in situ with random triggers, calibration data, cosmic muons, and LHC beam splash events. Results on the detector operation, timing performance, electronics noise, and gain stability are presented. High energy deposits from radiative cosmic muons and beam splash events allow to check the intrinsic constant term of the energy resolution. The uniformity of the electromagnetic barrel calorimeter response along eta (averaged over phi) is measured at the percent level using minimum ionizing cosmic muons. Finally, studies of electromagnetic showers from radiative muons have been used to cross-check the Monte Carlo simulation. The performance results obtained using the ATLAS readout, data acquisition, and reconstruction software indicate that the liquid argon calorimeter is well-prepared for collisions at the dawn of the LHC era.
TL;DR: This is the fifth independent study providing evidence that Mammostrat® can act as an independent prognostic tool for ER-positive, tamoxifen-treated breast cancer and revealed for the first time a possible association with outcome regardless of node status and ER-negative tumors.
Abstract: Introduction: Patients with early-stage breast cancer, treated with endocrine therapy, have approximately 90% 5-year disease-free survival. However, for patients at higher risk of relapse despite endocrine therapy, additional adjuvant therapy, such as chemotherapy, may be indicated. The challenge is to prospectively identify such patients. The Mammostrat® test uses five immunohistochemical markers to stratify patients on tamoxifen therapy into risk groups to inform treatment decisions. We tested the efficacy of this panel in a mixed population of cases treated in a single center with breast-conserving surgery and long-term follow-up. Methods: Tissue microarrays from a consecutive series (1981 to 1998) of 1,812 women managed by wide local excision and postoperative radiotherapy were collected following appropriate ethical review. Of 1,390 cases stained, 197 received no adjuvant hormonal or chemotherapy, 1,044 received tamoxifen only, and 149 received a combination of hormonal therapy and chemotherapy. Median age at diagnosis was 57, 71% were postmenopausal, 23.9% were node-positive and median tumor size was 1.5 cm. Samples were stained using triplicate 0.6 mm 2 tissue microarray cores, and positivity for p53, HTF9C, CEACAM5, NDRG1 and SLC7A5 was assessed. Each case was assigned a Mammostrat® risk score, and distant recurrence-free survival (DRFS), relapse-free survival (RFS) and overall survival (OS) were analyzed by marker positivity and risk score. Results: Increased Mammostrat® scores were significantly associated with reduced DRFS, RFS and OS in estrogen receptor (ER)-positive breast cancer (P < 0.00001). In multivariate analyses the risk score was independent of conventional risk factors for DRFS, RFS and OS (P < 0.05). In node-negative, tamoxifen-treated patients, 10-year recurrence rates were 7.6 ± 1.5% in the low-risk group versus 20.0 ± 4.4% in the high-risk group. Further, exploratory analyses revealed associations with outcome in both ER-negative and untreated patients. Conclusions: This is the fifth independent study providing evidence that Mammostrat® can act as an independent prognostic tool for ER-positive, tamoxifen-treated breast cancer. In addition, this study revealed for the first time a possible association with outcome regardless of node status and ER-negative tumors. When viewed in the context of previous results, these data provide further support for this antibody panel as an aid to patient management in early-stage breast cancer.
TL;DR: In this paper, the performance of the ATLAS detector in the first half a million minimum bias events of the LHC collision data was investigated at center-of-mass energies of 0.9 TeV and 2.36 TeV.
Abstract: More than half a million minimum-bias events of LHC collision data were collected by the ATLAS experiment in December 2009 at centre-of-mass energies of 0.9 TeV and 2.36 TeV. This paper reports on studies of the initial performance of the ATLAS detector from these data. Comparisons between data and Monte Carlo predictions are shown for distributions of several track- and calorimeter-based quantities. The good performance of the ATLAS detector in these first data gives confidence for successful running at higher energies.
TL;DR: Loss of both spine and hip BMD in pre-menopausal women during 6 months’ adjuvant systemic chemotherapy is demonstrated to be independent of changes in ovarian function, however, Ovarian function was related to BMD changes after chemotherapy ceased.
Abstract: Pre-menopausal women given adjuvant chemotherapy for breast cancer experience both premature ovarian failure and loss of bone mineral density (BMD), and this study was designed to see if these observations are causally linked. Chemotherapy was administered to 41 pre-menopausal women with early breast cancer enrolled prospectively in a study of ovarian function and BMD in such women given systemic therapy. After giving written informed consent, all patients underwent baseline and regular on-treatment measurements of BMD by dual-energy X-ray absorptiometry (DXA) scan, bone turnover and ovarian function by analysis of serum hormone levels and self-reported menstrual diaries. Baseline lumbar spine BMD in the 41 women given chemotherapy was higher than the normal population (Z score 0.28 ± 0.14 (mean ± SEM), P = 0.047), and fell significantly over the first 6 months from a mean of 1.05–1.01 g/m2, P < 0.0001, and similar but smaller changes were demonstrated in hip BMD. This fall was independent of age at diagnosis, type of chemotherapy, development of amenorrhoea or either baseline or on-treatment estradiol concentration. During the 6 months after completion of adjuvant chemotherapy, BMD fell further only in those women with low estradiol or experiencing amenorrhoea during the first 6 months, although all groups showed evidence of increased bone turnover. This study demonstrates loss of both spine and hip BMD in pre-menopausal women during 6 months’ adjuvant systemic chemotherapy to be independent of changes in ovarian function. Ovarian function was, however, related to BMD changes after chemotherapy ceased.
01 Oct 2010
TL;DR: The AZURE trial is an academic study designed to determine whether treatment with ZOL added to standard adjuvant therapy improves DFS and bone metastasis-free survival (BMFS) in a broader range of patients with stage II/III breast cancer.
Abstract: Background: The ABCSG XII trial demonstrated a 32% risk reduction in disease-free survival (DFS) events with Zoledronic acid (ZOL) use in a cohort of premenopausal women treated with endocrine therapy at 62 months median follow-up .[1,2] This strategy is increasingly being adopted in the wider breast cancer population. The AZURE trial is an academic study designed to determine whether treatment with ZOL added to standard adjuvant therapy improves DFS and bone metastasis-free survival (BMFS) in a broader range of patients with stage II/III breast cancer. Materials and methods: 3360 patients from 174 centres were randomized to receive (neo) adjuvant chemotherapy (CT) and/or endocrine therapy (ET) +/− ZOL 4mg iv every 3-4 weeks for 6 doses, then 3 monthly x 8 and 6 monthly x 5 to complete 5 years treatment. The primary DFS endpoint was to be determined after 940 DFS events, providing 80% power to detect a 17% reduction in hazard rates (HR) for DFS events. The rate of events on study has been slower than expected, resulting in an estimated final analysis in 2012. In light of the clinical interest in the results of AZURE, the DMEC has agreed to a second interim analysis after 705 events with boundaries set by an independent statistician, unaware of results at the first interim analysis, for both efficacy (HR ∼0.82, alpha spend 1%) and lack of clinical benefit (HR ∼0.935 with a 5% risk of declaring a false negative result). Contingent on DMEC advice, efficacy results that breach either boundary will be presented. A DMEC recommendation not to release the results at the second interim analysis may indicate that the point HR estimate lies between these boundaries. Results: Patient characteristics including stage, number of positive axillary nodes, CT type, ER status, menopausal status and statin use were well balanced. 3208 patients (96%) received (neo) adjuvant CT (93% anthracyclines, 23% taxanes). 152 patients received ET alone. As of June 9th 2010, with a median follow up of 49 (IQR 42-56) months, there have been 695 DFS events. The safety population comprised 3340 patients (ZOL 1665; control 1675). The addition of ZOL to standard treatment did not significantly impact on chemotherapy delivery. Serious adverse events (SAE) were similar in both treatment arms. To date 13 confirmed (0.83%; 95% CI 0.38%, 1.28%) and 12 possible (1.12%; 95% CI 0.39%, 1.85%) cases of osteonecrosis of the jaw (ONJ) in the ZOL arm have occurred. Discussion: AZURE is one of the largest phase III studies of adjuvant bisphosphonates, and the results from this study will help define the role of adjuvant ZOL in the management of early breast cancer. [1] Gnant M et al. NEJM 2009; 360(7):679-691 [2] Gnant M et al. ASCO 2010 Proceedings; abs #533. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S4-5.
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TL;DR: The cost effectiveness of adjuvant trastuzumab remains uncertain and dependent on assumptions regarding its clinical effect, but uncertainty around cost effectiveness could be reduced by further research into the duration of treatment effect, particularly in subgroups where this may be shorter.
Abstract: Background: Trastuzumab has significantly improved survival outcomes for women with HER2 positive early breast cancer. Trastuzumab was established as a costeffective adjuvant treatment in 2006. We present an updated cost-effectiveness analysis from the UK perspective which explores assumptions about the duration of benefit from treatment, pattern of metastatic recurrence and long-term cardiac toxicity. Methods: A cost-utility analysis was performed using a discrete-state timedependent semi-Markov model to calculate expected costs and benefits over the lifetime of an average cohort of women with HER2 positive early breast cancer treated with or without one year of adjuvant trastuzumab sequentially after chemotherapy. The perspective was the UK NHS. Probabilistic sensitivity analysis is used to characterise uncertainly around expected outcomes. Value of information analysis is used to identify areas of priority for further research. Results: The cost-effectiveness estimates are highly sensitive to the estimated duration of treatment benefit. Trastuzumab remains the cost-effective treatment strategy at a willingness-to-pay threshold of £30,000 per QALY provided the duration of benefit is more than 3.6 years from treatment initiation. An increasing proportion of brain metastases with trastuzumab produces small reductions in the costeffectiveness estimate. Long-term cardiac toxicity must rise to high levels to affect overall life-expectancy and cost-effectiveness. VoI analysis places highest value on research into the duration of treatment benefit. The relationship between progression free survival and overall survival and the costs of cancer recurrence are also important. Conclusion: The use of adjuvant trastuzumab remains cost-effective given current estimates of the duration of treatment effect. Uncertainty around cost-effectiveness could be reduced further by research into the duration of treatment effect, particularly in subgroups where this may be shorter. Long-term follow-up is warranted and methods to accurately measure duration of treatment effect and late toxicities should be developed for future adjuvant drug studies.
TL;DR: Both early/transient/proliferation response genes and continuous/late/estrogen-response genes are able to predict prognosis of primary breast tumours in a dynamic manner.
Abstract: Introduction: Tamoxifen is the most widely prescribed anti-estrogen treatment for patients with estrogen receptor (ER)-positive breast cancer. However, there is still a need for biomarkers that reliably predict endocrine sensitivity in breast cancers and these may well be expressed in a dynamic manner. Methods: In this study we assessed gene expression changes at multiple time points (days 1, 2, 4, 7, 14) after tamoxifen treatment in the ER-positive ZR-75-1 xenograft model that displays significant changes in apoptosis, proliferation and angiogenesis within 2 days of therapy. Results: Hierarchical clustering identified six time-related gene expression patterns, which separated into three groups: two with early/transient responses, two with continuous/late responses and two with variable response patterns. The early/transient response represented reductions in many genes that are involved in cell cycle and proliferation (e.g. BUB1B, CCNA2, CDKN3, MKI67, UBE2C), whereas the continuous/late changed genes represented the more classical estrogen response genes (e.g. TFF1, TFF3, IGFBP5). Genes and the proteins they encode were confirmed to have similar temporal patterns of expression in vitro and in vivo and correlated with reduction in tumour volume in primary breast cancer. The profiles of genes that were most differentially expressed on days 2, 4 and 7 following treatment were able to predict prognosis, whereas those most changed on days 1 and 14 were not, in four tamoxifen treated datasets representing a total of 404 patients. Conclusions: Both early/transient/proliferation response genes and continuous/late/estrogen-response genes are able to predict prognosis of primary breast tumours in a dynamic manner. Temporal expression of therapy-response genes is clearly an important factor in characterising the response to endocrine therapy in breast tumours which has significant implications for the timing of biopsies in neoadjuvant biomarker studies.
TL;DR: An intensive loading regimen of trastuzumab achieved higher-than-steady-state serum concentrations during cycle 1, was well tolerated, and had a good efficacy profile.
Abstract: PURPOSE Pharmacokinetics (PKs) and safety results from phase II/III trials suggest that, if high trastuzumab serum concentrations are reached early during treatment for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, patients will gain clinical benefit, and the synergistic effects of trastuzumab and chemotherapy will be maximized. This phase I/II study evaluated the PKs, efficacy, and safety of a novel, intensive loading regimen of trastuzumab in women with HER2-positive metastatic breast cancer (MBC). PATIENTS AND METHODS An intensive loading regimen of trastuzumab was given (6 mg/kg intravenously on days 1, 8, and 15 followed by 6 mg/kg every 3 weeks from day 22) to women age 18 years or older with HER2-positive MBC who may have received previous surgery, radiotherapy, and/or chemotherapy. Study medication was continued until disease progression or withdrawal occurred. Results All eligible women (N = 72) received at least one dose of trastuzumab. Median estimated trough concentration of trastuzumab at the end of 3 weeks of the intensive loading regimen (total of 18 mg/kg of trastuzumab administered) of cycle 1 was 119 mg/L, which is higher than steady-state trough concentrations with a conventional weekly or every-3-week regimen (64.9 or 47.3 mg/L, respectively). No new or unexpected adverse events or increased cardiotoxicity were reported during the study. In patients with measurable disease (n = 47), response rate was 23.4%. Median time to progression was 7.7 months (in all patients). CONCLUSION An intensive loading regimen of trastuzumab achieved higher-than-steady-state serum concentrations during cycle 1, was well tolerated, and had a good efficacy profile.
TL;DR: In this article, the ionization signals in the liquid argon of the ATLAS electromagnetic calorimeter are studied in detail using cosmic muons, and the drift time of the ionisation electrons is measured and used to assess the intrinsic uniformity of the CALorimeter gaps and estimate its impact on the constant term of the energy resolution.
Abstract: The ionization signals in the liquid argon of the ATLAS electromagnetic calorimeter are studied in detail using cosmic muons. In particular, the drift time of the ionization electrons is measured and used to assess the intrinsic uniformity of the calorimeter gaps and estimate its impact on the constant term of the energy resolution. The drift times of electrons in the cells of the second layer of the calorimeter are uniform at the level of 1.3% in the barrel and 2.8% in the endcaps. This leads to an estimated contribution to the constant term of (0.29(-0.04)(+0.05))% in the barrel and (0.54(-0.04)(+0.06))% in the endcaps. The same data are used to measure the drift velocity of ionization electrons in liquid argon, which is found to be 4.61 +/- 0.07 mm/mu s at 88.5 K and 1 kV/mm.
TL;DR: In this article, the use of atomic layer deposition (ALD) to produce the gas-sensitive tin dioxide film in a microhotplate gas sensor was reported, and the performance of the device was demonstrated using ethanol, acetone and acrylonitrile as model analytes.
Abstract: We report the use of atomic layer deposition (ALD) to produce the gas-sensitive tin dioxide film in a microhotplate gas sensor. The performance of the device was demonstrated using ethanol, acetone and acrylonitrile as model analytes. Fast response times and low drift rates of the output signal were measured, indicating a structurally stable tin dioxide film and reflecting the capabilities of ALD in gas sensor applications. Fabrication of the microhotplate using tungsten metallization and plasma deposited silicon dioxide dielectrics is also detailed.
TL;DR: Research into HER2 and TOP2A are discussed and evidence has emerged from presentations suggesting new candidate markers of response that warrant further investigation: Chr17CEP duplication and tissue inhibitor of metalloproteases 1.
Abstract: The search for a predictive marker of sensitivity to anthracycline-based chemotherapy has proven challenging. Despite human epidermal growth factor receptor 2 (HER2) being a strong prognostic marker in breast cancer, the only therapies with which there is a recognized functional link to the HER2 oncogene are those directly targeting the molecule itself. Despite this, HER2 has been extensively assessed as a predictive marker in a variety of chemotherapy regimens including anthracyclines. Analysis of anthracycline response in patients with HER2 amplification has given conflicting results. This led to the suggestion that HER2 amplification was acting as a surrogate for the gene encoding topoisomerase IIα (TOP2A), a direct cellular target of anthracyclines. Despite an attractive functional link between TOP2A and anthracyclines, published studies have failed to show strong evidence of an interaction between TOP2A genetic aberrations and anthracycline response. A number of other biomarkers have also been assessed for their role in predicting anthracycline response, including TP53 (tumour protein 53) and BRCA1 (breast cancer 1, early onset), together with an increasing emergence of gene expression profiling to produce predictive signatures of response. Moreover, recent evidence has emerged from presentations suggesting new candidate markers of response that warrant further investigation: Chr17CEP duplication and tissue inhibitor of metalloproteases 1. This review will discuss research into HER2 and TOP2A as predictive markers of anthracycline response and will focus on current research into other possible candidate predictive markers.
TL;DR: This study compared treatment and outcome information between the Medical Research Council Conventional versus Laparoscopic‐Assisted Surgery in Colorectal Cancer (CLASICC) trial and the National Cancer Data Repository (NCDR).
Abstract: Background:
Clinical trials are important but many factors limit their success, including the costs of long-term follow-up and participants often not being representative of the general population. The National Cancer Data Repository (NCDR) contains data about patients with cancer in England that may help overcome some of these problems. This study compared treatment and outcome information between the Medical Research Council Conventional versus Laparoscopic-Assisted Surgery in Colorectal Cancer (CLASICC) trial and the NCDR.
Methods:
Participants in the CLASICC trial were identified in the NCDR, and management and outcome data were compared. Data on all surgically treated English patients with colorectal cancer were extracted from the NCDR and compared with those of CLASICC participants.
Results:
Survival and treatment data for those in the CLASICC trial were available in the NCDR for 98·9 and 95·8 per cent of patients respectively. There was agreement in operation type for 86·1 per cent of patients but surgical approach coding was poor, with only 58·4 per cent of laparoscopic procedures coded in the NCDR. There was no significant difference in survival calculated from either data set. Surgical information was available in the NCDR for 19 of 20 trial participants with missing data. The trial population was younger (P < 0·001), of better socioeconomic status (P = 0·001) and with earlier disease (P < 0·001) than the general surgically treated colorectal cancer population. Rectal cancer survival was similar, but 5-year survival after treatment of colonic cancer was significantly better in the trial than in the national data: 57·1 (95 per cent confidence interval 51·5 to 62·3) versus 49·8 (49·3 to 50·2) per cent respectively.
Conclusion:
The National Cancer Data Repository demonstrates potential for informing clinical trials, but limitations prevent full intention-to-treat analyses. Copyright © 2010 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.
TL;DR: In this article, a correlation between the bulk plasma, interfacial adhesion of the coating to 316L stainless steel, surface characteristics and biomolecule interaction is presented in this work, and it was observed that the effect of nanoscale surface roughness (dose to 6 nm) was less significant, and that the surface chemistry played a significant role in governing the fibrinogen adsorption.
Abstract: The success of a biomaterial depends on the nature of interaction and the progressive reaction between the biological components and the surface of the biomaterial. In order to control the interaction between the biomaterial and biological component, it is necessary to understand the factors that influence the protein adsorption and cell proliferation. Surface chemistry plays a crucial role in the success of any blood contacting biomaterial. Plasma enhanced chemical vapour deposition (PECVD) is an interesting commonly used technique for tailoring surface characteristics while retaining bulk material properties. Two different films, namely polymer-like and silica-like coatings, with varying surface characteristics have been deposited from hexamethyldisiloxane, by PECVD, on 316L stainless steel. A correlation between the bulk plasma, interfacial adhesion of the coating to 316L steel, surface characteristics and biomolecule interaction is presented in this work The interfacial adhesion strength analysis demonstrated that silica-like coatings have higher adhesion strength to 316L stainless steel than polymer-like coatings, caused due to the formation of a strong Fe-O-Si and Cr-O-Si bonds. It was observed that the effect of nanoscale surface roughness (dose to 6 nm) was less significant, and that the surface chemistry played a significant role in governing the fibrinogen adsorption. Highest fibrinogen adsorption on plain steel was due to the electrostatic interaction of the metal oxide layer with the protein Hydrophobicity of the polymer like film resulted in a higher fibrinogen binding than the silica-like films.
TL;DR: The problems encountered by those responsible for drug reimbursement decisions as a consequence of the current drug development pathway are described, the potential for decision theoretic methods to help overcome these problems is introduced and potential obstacles in implementation are highlighted.
TL;DR: How the availability of new tracers, or new applications for existing PET/CT technologies, could deliver clinical benefit in cancer is considered, using breast cancer as a paradigm.
Abstract: The glucose analogue fluorodeoxyglucose (FDG) has demonstrated enhanced uptake in the majority of tumours as a result of increased uptake and fixation by phosphorylation. It is the most widely used radiotracer in positron emission tomography (PET), being used in >90% of scans, and is useful for diagnosis, staging and detection of residual/recurrent cancer. However, there are limits to the utility of FDG, particularly in certain tumour types. The development of new radiotracers to study molecular processes such as proliferation, apoptosis, angiogenesis and hypoxia will complement FDG by providing additional information on the cell biology of tumours. The aim of this paper is to consider how the availability of new tracers, or new applications for existing PET/CT technologies, could deliver clinical benefit in cancer, using breast cancer as a paradigm.