Showing papers by "John F. Forbes published in 2017"

Participant-reported symptoms and their effect on long-term adherence in the international breast cancer intervention study I (IBIS I)

Abstract: PurposeTo assess the role of participant-reported symptoms on long-term adherence to preventive therapy in the United Kingdom sample of the International Breast Cancer Intervention Study (IBIS-I) IBIS-I was a randomized controlled trial that investigated the effectiveness of tamoxifen in reducing the risk of breast cancer among women at increased risk of the diseaseParticipants and MethodsWomen were randomly assigned to tamoxifen versus placebo (20 mg/day; n = 4,279) After 456 exclusions, 3,823 women were included in this analysis Adherence (< 45 years or ≥ 45 years) was calculated using data from six monthly clinical visits Analyses were adjusted for age, Tyrer-Cuzick risk, smoking, use of hormone replacement therapy, menopausal status, baseline menopausal symptoms, and treatmentResultsOverall, 697% of women were adherent for at least 45 years (tamoxifen: 652% v placebo: 740%; P < 001) Differences in adherence between treatment arms were observed from 12 months onward (all P < 01) and were

Symptoms and quality of life in patients with suspected angina undergoing CT coronary angiography: a randomised controlled trial.

Abstract: Background In patients with suspected angina pectoris, CT coronary angiography (CTCA) clarifies the diagnosis, directs appropriate investigations and therapies, and reduces clinical events. The effect on patient symptoms is currently unknown. Methods In a prospective open-label parallel group multicentre randomised controlled trial, 4146 patients with suspected angina due to coronary heart disease were randomised 1:1 to receive standard care or standard care plus CTCA. Symptoms and quality of life were assessed over 6 months using the Seattle Angina Questionnaire and Short Form 12. Results Baseline scores indicated mild physical limitation (74±0.4), moderate angina stability (44±0.4), modest angina frequency (68±0.4), excellent treatment satisfaction (92±0.2) and moderate impairment of quality of life (55±0.3). Compared with standard care alone, CTCA was associated with less marked improvements in physical limitation (difference −1.74 (95% CIs, −3.34 to −0.14), p=0.0329), angina frequency (difference −1.55 (−2.85 to −0.25), p=0.0198) and quality of life (difference −3.48 (−4.95 to −2.01), p Conclusions While improving diagnosis, treatment and outcome, CTCA is associated with a small attenuation of the improvements in symptoms and quality of life due to the detection of moderate non-obstructive coronary artery disease. Trial registration number: NCT01149590.

High-Sensitivity Cardiac Troponin I and the Diagnosis of Coronary Artery Disease in Patients With Suspected Angina Pectoris.

Abstract: Background: We determined whether high-sensitivity cardiac troponin I can improve the estimation of the pretest probability for obstructive coronary artery disease (CAD) in patients with suspected stable angina. Methods and Results: In a prespecified substudy of the SCOT-HEART trial (Scottish Computed Tomography of the Heart), plasma cardiac troponin was measured using a high-sensitivity single-molecule counting assay in 943 adults with suspected stable angina who had undergone coronary computed tomographic angiography. Rates of obstructive CAD were compared with the pretest probability determined by the CAD Consortium risk model with and without cardiac troponin concentrations. External validation was undertaken in an independent study population from Denmark comprising 487 patients with suspected stable angina. Higher cardiac troponin concentrations were associated with obstructive CAD with a 5-fold increase across quintiles (9%–48%; P P =0.004; χ 2 =16.8 [ P =0.032] to 14.3 [ P =0.074]). The updated model also improved classification of the American College of Cardiology/American Heart Association pretest probability risk categories (net reclassification improvement, 0.062; 95% confidence interval, 0.035–0.089). The revised model achieved similar improvements in discrimination and calibration when applied in the external validation cohort. Conclusions: High-sensitivity cardiac troponin I concentration is an independent predictor of obstructive CAD in patients with suspected stable angina. Use of this test may improve the selection of patients for further investigation and treatment. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01149590.

The FOCUS, AFFINITY and EFFECTS trials studying the effect(s) of fluoxetine in patients with a recent stroke: statistical and health economic analysis plan for the trials and for the individual patient data meta-analysis

Abstract: Small trials have suggested that fluoxetine may improve neurological recovery from stroke. FOCUS, AFFINITY and EFFECTS are a family of investigator-led, multicentre, parallel group, randomised, placebo-controlled trials which aim to determine whether the routine administration of fluoxetine (20 mg daily) for six months after an acute stroke improves patients’ functional outcome. The core protocol for the three trials has been published (Mead et al., Trials 20:369, 2015). The trials include patients aged 18 years and older with a clinical diagnosis of stroke and persisting focal neurological deficits at randomisation 2–15 days after stroke onset. Patients are randomised centrally via each trials’ web-based randomisation system using a common minimisation algorithm. Patients are allocated fluoxetine 20 mg once daily or matching placebo capsules for six months. The primary outcome measure is the modified Rankin scale (mRS) at six months. Secondary outcomes include: living circumstances; the Stroke Impact Scale; EuroQol (EQ5D-5 L); the vitality subscale of the 36-Item Short Form Health Survey (SF36); diagnosis of depression; adherence to medication; serious adverse events including death and recurrent stroke; and resource use at six and 12 months and the mRS at 12 months. Minor variations have been tailored to the national setting in the UK (FOCUS), Australia, New Zealand and Vietnam (AFFINITY) and Sweden (EFFECTS). Each trial is run and funded independently and will report its own results. A prospectively planned individual patient data meta-analysis of all three trials will provide the most precise estimate of the overall effect and establish whether any effects differ between trials or subgroups. This statistical analysis plan describes the core analyses for all three trials and that for the individual patient data meta-analysis. Recruitment and follow-up in the FOCUS trial is expected to be completed by the end of 2018. AFFINITY and EFFECTS are likely to complete follow-up in 2020. FOCUS: ISRCTN , ISRCTN83290762 . Registered on 23 May 2012. EudraCT, 2011-005616-29. Registered on 3 February 2012. AFFINITY: Australian New Zealand Clinical Trials Registry, ACTRN12611000774921 . Registered on 22 July 2011. EFFECTS: ISRCTN , ISRCTN13020412 . Registered on 19 December 2014. Clinicaltrials.gov, NCT02683213 . Registered on 2 February 2016. EudraCT, 2011-006130-16 . Registered on 8 August 2014.

Optimal linear–quadratic control of coupled parabolic–hyperbolic PDEs

Abstract: This paper focuses on the optimal control design for a system of coupled parabolic–hypebolic partial differential equations by using the infinite-dimensional state-space description and the corresponding operator Riccati equation. Some dynamical properties of the coupled system of interest are analysed to guarantee the existence and uniqueness of the solution of the linear–quadratic (LQ)-optimal control problem. A state LQ-feedback operator is computed by solving the operator Riccati equation, which is converted into a set of algebraic and differential Riccati equations, thanks to the eigenvalues and the eigenvectors of the parabolic operator. The results are applied to a non-isothermal packed-bed catalytic reactor. The LQ-optimal controller designed in the early portion of the paper is implemented for the original nonlinear model. Numerical simulations are performed to show the controller performances.

Abstract P1-09-06: Prognostic and predictive relevance of cell cycle progression (CCP) score in ductal carcinoma in situ: Results from the UK/ANZ DCIS trial

Abstract: Background: The prognostic abilities of most gene expression signatures in breast cancer are often due to detection of proliferative activity measured from expression of genes regulated as a function of cell cycle progression. Cell Cycle Progression (CCP) score is an important prognostic factor in prostate cancer, and has shown promising results for renal and lung cancer; its role in ductal carcinoma in situ (DCIS) has not been explored. We investigated the prognostic and predictive relevance of CCP Score in DCIS using material from UK/ANZ DCIS trial. Methods: Formalin-fixed paraffin embedded tissues were collected from patients enrolled in the UK/ANZ DCIS trial, a randomised 2X2 factorial design trial investigating role of tamoxifen, radiotherapy (RT) or both as adjuvant treatment in DCIS. mRNA expression of 25 S- and M-phase CCP genes was evaluated by reverse transcription followed by PCR on customized Taqman low-density arrays. CCP score is an un-weighted average of the expression values of CCP genes after normalisation with 14 housekeeping genes. CCP score was analysed as a continuous variable and also as an ordinal variable using tertile-based cut-offs. Exploratory analyses with subgroups defined by HER2 status by immunohistochemistry were performed. Results: CCP scores were evaluable in 521 (134 recurrence events) of 704 available samples (DCIS absent or insufficient RNA in 51, assay failure in 132). Increase in CCP score (median 1.15; IQR 0.71-1.74) was associated with increased risk of ipsilateral breast event (IBE) [Hazard ratio (HR) = 1.28; 95% Confidence Interval (95%CI) 1.08-1.51; p = 0.0049]. CCP score however was not an independent predictor in multivariate analyses [HR = 1.16; 95%CI 0.95-1.42; p = 0.14]. CCP scores were categorised as CCP low ( /= 0.87 to /= 1.52) by tertiles. The benefit of RT in reducing IBE was significant when CCP score was low [HR = 0.35; 95%CI 0.14-0.87; p = 0.024] or intermediate [HR = 0.23; 95%CI 0.09-0.59; p = 0.0023], however, those with high CCP score did not derive significant RT benefit [HR = 0.59; 95%CI 0.31-1.13; p = 0.11]. In exploratory subgroup analyses, HER2 negative DCIS with high CCP score (20.9% of all DCIS cases) did not derive RT benefit and the largest RT benefit was seen for DCIS that expressed HER2 and did not have a high CCP score (23.2% of all DCIS cases). Conclusions: CCP score is not independently associated with the risk of IBE but appears to be a predictor of RT benefit. Exploratory analyses suggest that combined with HER2 status, it may help in identifying a large DCIS subgroup where RT is highly indicated and another large subgroup where mastectomy may be merited. Citation Format: Thorat MA, Wagner S, Jones LJ, Levey PM, Bulka K, Hoff R, Sangale Z, Flake II DD, Bundred NJ, Fentiman IS, Forbes JF, Lanchbury JS, Cuzick J. Prognostic and predictive relevance of cell cycle progression (CCP) score in ductal carcinoma in situ: Results from the UK/ANZ DCIS trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-09-06.

Abstract P2-09-03: Long-term comparison of anastrozole versus tamoxifen: Results from LATTE/ATAC

Abstract: Background: Previous reports from the Anastrozole Tamoxifen Alone or in Combination (ATAC) trial have shown significantly prolonged disease-free survival, lower rates of recurrence and distant recurrence, and reduced contralateral breast cancer in patients treated with anastrozole compared to tamoxifen (Cuzick et al., Lancet, 2010). Here, we compare the long-term effects of anastrozole versus tamoxifen in patients randomised to either monotherapy arm in the ATAC trial. Methods: Postmenopausal women with hormone receptor positive breast cancer randomised to anastrozole or tamoxifen in the main ATAC trial were eligible for the LATTE observational study. The primary objective was to compare the long-term effects of tamoxifen and anastrozole on time to recurrence and death beyond 10 years after randomisation. Secondary objectives included time to distant recurrence, cancer-specific survival, new breast primaries, other cancers, fractures, and cardiac/cerebrovascular events. Cox proportional hazard methods were used to compute hazard ratios (95% CI) for recurrence from the time of last publication (10 years median follow-up). Results: 2452 women from 11 countries were entered into the LATTE study. 40 women withdrew consent and 759 women died or had a recurrence within 10 years, which left 1653 women for analysis (838 anastrozole vs. 815 tamoxifen). A total of 118 breast events (69 anastrozole (8.2%) vs. 49 tamoxifen (6.0%)) were reported. No significant difference between the two treatment arms were observed (HR=1.36 (0.94-1.97), P=0.098). 57 women had a distant recurrence (33 (3.9%) vs. 24 (2.9%)), 41 reported a loco-regional recurrence (23 (2.7%) vs. 18 (2.2%)), and 26 contra-lateral breast cancer were recorded (17 (2.0%) vs. 9 (1.1%)). None of the treatment comparisons were statistically significant. 305 deaths were recorded (147 (17.5%) vs. 158 (19.4%)), of which 31 were due to breast cancer. Significantly fewer gynaecological cancers were recorded with anastrozole (7 vs. 16; OR=0.42 (0.15-1.09), P=0.05), but overall the effect on other cancers was not significant (54 (6.4%) vs. 64 (7.9%). Fractures, cardiovascular, and cerebrovascular events were evenly distributed between the treatment arms. Conclusions: Although anastrozole was associated with significant fewer recurrences compared to tamoxifen in the first 10 years of follow-up, in this analysis, with limited number of patients, we could not find a significant difference between the two treatment arms. Citation Format: Cuzick J, Sestak I, Bianco A, Strobbe L, Bergh J, Hanusch C, Neven P, Dowsett M, Forbes JF, Buzdar A, Smith R, Howell A. Long-term comparison of anastrozole versus tamoxifen: Results from LATTE/ATAC [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-09-03.