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The purpose of this study was to determine professional evaluators’ perceptions of reflective practice (RP) and the extent and manner in which they engage in RP behaviors. Nineteen evaluators with 10 or more years of experience in the evaluation field were interviewed to explore our understanding and practice of RP in evaluation. Findings suggest that RP is a process of self and contextual awareness, involving thinking and questioning, and individual and group meaning-making, focused on facilitating growth in the form of learning and improvement. The roles of individual and collaborative reflection as well as reflection in- and on-action are also discussed. Findings support a call for the further refinement of our understanding of RP in evaluation practice. Evaluators seeking to be better reflective practitioners should be competent in skills such as facilitation and interpersonal skills, as well as budget needed time for RP in evaluation accordingly.

Objective The present study assessed agreement between resting cardiac output estimated by inert gas rebreathing (IGR) and thermodilution methods in patients with heart failure and those implanted with a left ventricular assist device (LVAD). Methods and Results Hemodynamic measurements were obtained in 42 patients, 22 with chronic heart failure and 20 with implanted continuous flow LVAD (34 males, aged 50 ± 11 years). Measurements were performed at rest using thermodilution and IGR methods. Cardiac output derived by thermodilution and IGR were not significantly different in LVAD (4.4 ± 0.9 L/min vs 4.7 ± 0.8 L/min, P = .27) or patients with heart failure (4.4 ± 1.4 L/min vs 4.5 ± 1.3 L/min, P = .75). There was a strong relationship between thermodilution and IGR cardiac index (r = 0.81, P = .001) and stroke volume index (r = 0.75, P = .001). Bland–Altman analysis showed acceptable limits of agreement for cardiac index derived by thermodilution and IGR, namely, the mean difference (lower and upper limits of agreement) for patients with heart failure –0.002 L/min/m2 (–0.65 to 0.66 L/min/m2), and –0.14 L/min/m2 (–0.78 to 0.49 L/min/m2) for patients with LVAD. Conclusions IGR is a valid method for estimating cardiac output and should be used in clinical practice to complement the evaluation and management of chronic heart failure and patients with an LVAD.

We sought to determine hemodynamic mechanisms of exercise intolerance in a group of patients with the HeartWare ventricular assist device (VAD) compared to a group of heart failure patients. Twenty VAD and 22 heart failure patients underwent symptom-limited active straight leg raising exercise during right heart catheterization with thermodilution (TD), and upright cycling cardiopulmonary stress testing with cardiac output measurement by inert gas rebreathing (IGR) method. The TD and IGR exercise cardiac indexes were higher in VAD compared with heart failure group (both P < 0.05), although there was only a borderline increase in peak exercise oxygen consumption (VO2) (P = 0.06). Baseline and exercise right heart catheterization pressures were not significantly different between the two groups. The only significant independent predictors of peak VO2 in the heart failure group were exercise heart rate and cardiac index (both P < 0.05). In contrast, for the VAD group only, resting pulmonary arterial wedge and pulmonary arterial mean pressures were independently related to peak VO2 (both P < 0.05). Thus, in heart failure, exercise cardiac index is an important limitation to exercise capacity, and VADs increase exercise cardiac index. However, in VAD patients, this only produces limited benefits as increased pulmonary and pulmonary wedge pressures limit increases in exercise capacity.

Although left ventricular assist device (LVAD) improves functional capacity, on average LVAD patients are unable to achieve the aerobic capacity of normal healthy subjects or mild heart failure patients. The aim of this study was to examine if markers of right ventricular (RV) function influence maximal exercise capacity. This was a single-center prospective study that enrolled 20 consecutive HeartWare ventricular assist device patients who were admitted at the Freeman Hospital (Newcastle upon Tyne, United Kingdom) for a heart transplant assessment from August 2017 to October 2018. Mean peak oxygen consumption (Peak VO2) was 14.0 ± 5.0 ml/kg/min, and mean peak age and gender-adjusted percent predicted oxygen consumption (%VO2) was 40.0% ± 11.5%. Patients were subdivided into two groups based on the median peak VO2, so each group consisted of 10 patients (50%). Right-sided and pulmonary pressures were consistently higher in the group with poorer exercise tolerance. Patients with poor exercise tolerance (peak VO2 below the median) had higher right atrial pressures at rest (10.6 ± 6.4 vs. 4.3 mmHg ± 3.2; p = 0.02) and the increase with passive leg raising was significantly greater than those with preserved exercise tolerance (peak VO2 above the median). Patients with poor functional capacity also had greater RV dimensions (4.4 cm ± 0.5 vs. 3.7 cm ± 0.5; p = 0.02) and a higher incidence of significant tricuspid regurgitation (moderate or severe tricuspid regurgitation in five patients in the poor exercise capacity group vs. none in the preserved exercise capacity group; p = 0.03). In conclusion, echocardiographic and hemodynamic markers of RV dysfunction discriminate between preserved and nonpreserved exercise capacity in HeartWare ventricular assist device patients.

Background Left ventricular assist devices (LVADs) mechanically unload the heart and coupled with neurohormonal therapy can promote reverse cardiac remodeling and myocardial recovery. Minimally invasive LVAD decommissioning with the device left in place has been reported to be safe over short-term follow-up. Whether device retention reduces long-term safety, or sustainability of recovery is unknown. Methods This is a dual-center retrospective analysis of patients who had achieved responder status (left ventricular ejection fraction, LVEF ≥40% and left ventricular internal diastolic diameter, LVIDd ≤6.0 cm) and underwent elective LVAD decommissioning for myocardial recovery from May 2010 to January 2020. All patients had outflow graft closure and driveline resection with the LVAD left in place. Emergent LVAD decommissioning for an infection or device thrombosis was excluded. Patients were followed with serial echocardiography for up to 3-years. The primary clinical outcome was survival free of heart failure hospitalization, LVAD reimplantation , or transplant. Results During the study period 515 patients received an LVAD and 29 (5.6%) achieved myocardial recovery, 12 patients underwent total device explantation or urgent device decommissioning, 17 patients underwent elective LVAD decommissioning, and were included in the analysis. Median age of patients at LVAD implantation was 42 years (interquartile range, IQR: 25-54 years), all had a nonischemic cardiomyopathy , and 5 (29%) were female. At LVAD implantation, median LVEF was 10% (IQR: 5%-15%), and LVIDd 6.6 cm (IQR: 5.8-7.1 cm). There were 11 hydrodynamically levitated centrifugal-flow (65%), and 6 axial-flow LVADs (35%). The median duration of LVAD support before decommissioning was 28.7 months (range 13.5-36.2 months). As compared to the turndown study parameters, 1-month post-decommissioning, median LVEF decreased from 55% to 48% ( p = 0.03), and LVIDd increased from 4.8 cm to 5.2 cm (p = 0.10). There was gradual remodeling until 6 months, after which there was no statistical difference on follow-up through 3-years (LVEF 42%, LVIDd 5.6 cm). Recurrent infections affected 41% of patients leading to 3 deaths and 1 complete device explant. Recurrent HF occurred in 1 patient who required a transplant. Probability of survival free of HF, LVAD, or transplant was 94% at 1-year, and 78% at 3-years. Conclusions LVAD decommissioning for myocardial recovery was associated with excellent long-term survival free from recurrent heart failure and preservation of ventricular size and function up to 3-years. Reducing the risk of recurrent infections, remains an important therapeutic goal for this management strategy.

The HeartWare left ventricular assist device has been in use for over 12 years. We sought to determine how outcomes at our centre have improved over time.Review of electronic hospital records at the Freeman Hospital, Newcastle upon Tyne, United Kingdom.A total of 255 first time adult implants were divided into 2 eras: Era 1: 2009-2015 (N = 154) and Era 2: 2016-2020 (N = 101). We prospectively aimed to avoid higher risk Intermacs Classifications in Era 2, which resulted in significant changes in Intermacs class to lower risk in Era 2 (P 0.001). There was a significant improvement in survival in Era 2, with 1 year survival increasing from 70 to 80% (P 0.05). This was particularly associated with lower 30 day mortality in Era 2 (1.7 ± 2.3 vs 15.5 ± 7%, P 0.005). This was associated with better right ventricular function in Era 2, and there was a trend to more temporary right ventricular assist devices used in Era 2 (28 ± 13 vs 12 ± 14%, P = 0.06). Deaths from intracranial haemorrhage, sepsis and right heart failure were unchanged between eras, though there was a trend towards less deaths in Era 2 from combined thromboses deaths (stroke and device thrombosis; 3.3 ± 5.4 vs 11.1 ± 7.4%, P = 0.07).Better patient selection in association with more use of temporary right ventricular assist support has resulted in a significant improvement in survival. Intracranial haemorrhage, sepsis and right heart failure remain significant problems.

Introduction and objectives: Pump thrombosis is a serious left ventricular assist device complication, though there are no guidelines regarding its treatment. The main aim of this study was to describe a strategy of intravenous anticoagulation as the initial treatment in these patients and then to compare intravenous heparin with bivalirudin. Methods: All consecutive patients who received a HeartWare left ventricular assist device from July 2009 to March 2019 were retrospectively analysed. Patients developing a pump thrombosis were selected, and treatment, outcomes and complications were recorded. Results: During this period of time (116 months), 220 patients underwent HeartWare left ventricular assist device implantation and 57 developed pump thrombosis, with an incidence rate of first pump thrombosis of 0.17 events per patient-year of support (incidence rate of all episodes of pump thrombosis: 0.30 events per patient-year of support). All the patients were initially treated medically, predominantly with either intravenous heparin (n = 26) or bivalirudin (n = 16). Patients treated with bivalirudin during the first pump thrombosis episode had less subsequent re-thrombosis episodes (18.7% vs 57.7%, p Conclusion: Left ventricular assist device thrombosis is a serious life-threatening complication; hence, we propose an initial conservative management of pump thrombosis with enhanced intravenous anticoagulation with either intravenous heparin or bivalirudin, with surgery reserved for refractory cases.

Introduction and purpose Pump thrombosis (PT) is a serious left ventricular assist device (LVAD) complication, though there are no guidelines regarding its treatment. We have adopted a strategy of intravenous anticoagulation as the initial treatment strategy in these patients. Methods All consecutive patients who received a HeartWare LVAD from July-2009 to January-2018 were retrospectively analyzed. Patients developing a PT were selected, and treatment, outcomes and complications were recorded. Results 197 patients underwent HVAD, and 49 developed PT. All the patients were initially treated medically, though during the first PT 26.5% of the patients needed surgery [VAD exchange (n=6), transplant (n=6), or decommissioning (n=1)]. The overall survival at 1 year was 63.3%. Patients were treated predominantly with either intravenous heparin or bivalirudin. There were no significant differences neither in complications nor in survival between the 2 treatments (Figure 1); however, patients treated with bivalirudin during the first PT episode had less subsequent re-thrombosis episodes (18.2% vs 57.7%, p Table 1. Comparison of baseline characteristics and outcomes between Heparin and Bivalirudin Heparin (n=26) Bivalirudin (n=11) p-value Male, gender n (%) 20 (76.9) 9 (81.8) 1.00 Age when implant (years) 48±11.8 49.8±11.4 0.67 AF n (%) 9 (34.6) 6 (54.5) 0.50 Diagnosis: Dilated cardiomyopathy n (%) 13 (50) 7 (63.6) Ischemic heart disease n (%) 12 (46.2) 3 (27.3) Congenital heart disease n (%) 1 (3.8) 1 (9) 0.50 Thrombolysis (+ alteplase) n (%) 19 (73.1) 4 (36.4) 0.08 Treatment duration (days) 11.5±7.2 15.3±6.5 0.15 % Time in range 36.3±7.1 59.7±4.2 0.009 Hospitalisation (days) 19.1±16.4 31.9±18.2 0.06 Complications: Ischemic Stroke n (%) 2 (7.7) 4 (36.4) 0.09 Intracraneal bleeding n (%) 2 (7.7) 0 (0) 0.88 Gastrointestinal bleeding n (%) 1 (3.8) 0 (0) 1.00 Serious bleeding n (%) 5 (19.2) 0 (0) 0.29 Any bleeding n (%) 7 (26.9) 2 (18.2) 0.88 LDH Baseline 271.7±79.3 221.6±41.3 0.10 Admision 727.8±448.2 517.5±171.3 0.21 Maximum 827.1±424.7 1217.6±1004 0.03 Discharge 334.9±135.9 308.6±111.8 0.70 Time to normalisation (days) 10.2±4.5 17.2±2.6 0.004 Outcomes: Transplant (total) n (%) 7 (26.9) 2 (18.2) 0.88 VAD Exchange (total) n (%) 8 (30.8) 4 (36.4) 1.00 Mortality at 2 years n (%) 15 (57.7) 5 (45.4) 0.831 Rethrombosis: Rethrombosis n (%) 15 (57.7) 2 (18.2) 0.03 Number of episodes of rethrombosis 0.15 +1 n=6 n=1 +2 n=4 n=1 +3 n=4 n=0 +4 n=1 n=0 Figure 1 Conclusion VAD thrombosis is a serious life threatening complication, though an initial strategy with enhanced intravenous anticoagulation is an acceptable strategy with either intravenous heparin or bivalirudin. Acknowledgement/Funding N. Bouzas-Cruz would like to thank the Spanish Society of Cardiology (Sociedad Española de Cardiología), for her research grant and fellowship.

Background Right heart failure (RHF) after left ventricular assist device (LVAD) implantation is a significant cause of morbidity and mortality. While multiple predictors of early RHF have been described, information on late RHF is scarce. The aim of this study was to identify predictors of late RHF in LVAD patients. Methods A retrospective analysis of all adult patients who underwent HeartWare-VAD implantation for ischemic heart disease or non-ischemic dilated cardiomyopathy in a single centre was performed. Late RHF was defined as RHF requiring hospitalization and medical treatment after 30 days of LVAD implantation. Results A total of 16 (10.3%) patients from 156 implantations developed late RHF. Patients developing late RHF were older at time of surgery, 56.7±6.9 vs 49.5±12.5 years; p Multivariate Cox proportional-hazards analysis for late right heart failure Variable Hazard ratio 95% confidence interval P-value Tricuspid regurgitation- moderate or severe 5.50 1.34–22.58 0.02 Mitral regurgitation (discharge)- moderate or severe 3.54 1.14–11.02 0.03 Age 1.07 1.01–1.14 0.03 Right ventricular basal diameter 1.14 0.43–3.03 0.79 Right ventricular fractional area change 0.98 0.87–1.10 0.79 Multivariate analysis showing predictors of late right heart failure according to a multivariate model. Late RHF according to TR severity Conclusions Pre-operative significant tricuspid regurgitation and mitral regurgitation after implantation predict the occurrence of late RHF. Prospective studies are needed to determine whether tricuspid valve interventions may reduce late RHF.

Introduction Left Ventricular Assist Devices (LVAD) improve survival and functional capacity in patients with advanced heart failure (HF). However, there are potential complications. Purpose We sought to determine parameters of exercise intolerance in a group of patients with the HeartWare LVAD (HVAD) compared to a group of HF patients. Methods This was a single-centre parallel prospective group-study. Briefly, echocardiograms, right heart catheterisation (RHC) and cardiopulmonary exercise tests were performed in forty-two patients admitted for a heart transplant assessment between August2017 and October2018.Of them 20 belonged to the HVAD group and 22 to the HF group. Results In our study, HVAD patients had a better exercise capacity than HF patients, although no significant differences were noted (14.0±5.0 ml/kg/min vs 11.3±3.9 ml/kg/min, p=0.06). To determine exercise tolerance, both HVAD and HF groups were subdivided into 2 groups based on the median peak exercise oxygen consumption (peakVO2) for that group. The table shows the comparison between preserved and non-preserved exercise tolerance in HF and HVADpatients. First of all, in the HVADgroup, all resting RHC pressures were significantly lower in the preserved exercise capacity group. However, in HFpatients there were no statistically significant differences between both subgroups in right-sided pressures, but Thermodilution exercise-induced change in cardiac output (ΔCO) and cardiac index (ΔCI) was significantly higher in the patients with preserved exercise tolerance. Secondly, in the HVADgroup the right ventricle was significantly larger in the reduced exercise tolerance subgroup. Moreover, patients with lower peak VO2 had more significant tricuspid regurgitation. Nevertheless, in HFpatients none of the echocardiographic parameters were related to the exercise capacity. HF HVAD > Median Peak V02 < Median Peak V02 p > Median Peak V02 < Median Peak V02 p Thermodilution CO, l/min: • Rest 4.3±1.0 4.4±1.8 0.82 4.8±0.8 4.2±1.2 0.21 • Exercise 5.6±1.7 4.8±1.8 0.36 7.1±3.2 4.8±0.8 0.05 • ΔCO 1.26±1.0 0.26±0.7 0.02 2.2±2.5 0.4±0.7 0.05 Right Atrium pressure, mmHg 7.0±4.5 6.8±4.10 0.92 4.3±3.2 10.6±6.40 0.02 Mean Pulmonary Artery pressure, mmHg 26.4±12.6 26.5±10.9 0.97 16.8±5.4 30.5±12.5 0.01 Tricuspid Regurgitation, n (%): • None 1 (9) 1 (9) 1 (12) 0 (0) • Mild 7 (64) 8 (73) 7 (88) 4 (44) • Moderate 2 (18) 0 (0) 0 (0) 4 (44) • Severe 1 (9) 2 (18) 0.36 0 (0) 1 (12) 0.03 Right Ventricle Basal Diastolic Diameter, cm 4.0±1.0 4.1±1.0 0.83 3.7±0.5 4.4±0.5 0.02 Conclusion Right-sided parameters in the echocardiogram and RHC pressures discriminate between preserved and non-preserved exercise capacity in HVADpatients, but not in HFpatients. In these last patients only ΔCO and ΔCI were statistically correlated with peak exercise oxygen consumption Acknowledgement/Funding N. Bouzas-Cruz would like to thank the Spanish Society of Cardiology (Sociedad Española de Cardiología), for her research grant and fellowship

Right-sided heart failure (RHF) after left ventricular assist device implantation is a significant cause of morbidity and mortality. Although multiple predictors of early RHF have been described, information on late RHF is scarce. The aim of this study was to identify predictors of late RHF in left ventricular assist device patients. A retrospective analysis of all adult patients who underwent HeartWare-ventricular assist device implantation as a bridge to transplantation in a single-centre was performed. Late RHF was defined as RHF requiring rehospitalization after 30 days of implantation. A total of 16 (10.3%) patients from 156 implantations developed late RHF. Median time to late RHF onset was 182.5 (interquartile range 105 to 618) days. Patients developing late RHF were older at surgery. A significantly higher rate of moderate or severe tricuspid regurgitation before implantation was found in patients presenting with late RHF (81.2% vs 33.5%; p0.001). Several echocardiographic parameters at discharge postimplant, such as significant mitral regurgitation, demonstrated a strong association with late RHF. A multivariate Cox regression analysis revealed that significant preoperative tricuspid regurgitation was the strongest predictor of late RHF (hazard ratio 5.50, 95% confidence interval [1.34 to 22.58]; p = 0.02). Significant mitral regurgitation postimplantation and older age also significantly predicted late RHF. In conclusion, preoperative significant tricuspid regurgitation and mitral regurgitation after implantation predict the occurrence of late RHF.

Left ventricular assist devices (LVADs) have become an established treatment for advanced heart failure, although with long-term support these patients are potentially exposed to serious complications. Our purpose was to assess the role of the neutrophil to lymphocyte ratio (NLR) in LVAD complications and to evaluate if higher values of NLR after 4-6 months on LVAD support (NLR 4_6m) are associated with worse prognosis. All consecutive patients who received a HeartWare LVAD (N = 188, age 50 ± 13 years), as bridge to transplant from December 2009 to January 2018 were included. Neutrophil to lymphocyte ratio was recorded pre-LVAD, post-LVAD, after 4-6 months on support and in case of a first adverse event to occur after the 4-6 months NLR was recorded. Median NLR values were pre-LVAD 4.26 (interquartile range [IQR], 3.1-6.9), at 1 day postoperative 11.6 (IQR, 8.3-16.6), and NLR 4_6m 4.4 (IQR, 3.0-6.4) (p < 0.001). Neutrophil to lymphocyte ratio increased significantly when patients had an infection, stroke, or pump thrombosis, as compared with the NLR 4_6m (all p < 0.05). Patients with NLR 4_6m ≥ median had higher rates of stroke and mortality. Survival time was shorter among patients with NLR 4_6m ≥ 4.4 (log-rank test p = 0.006). Neutrophil to lymphocyte ratio 4_6m was found to be predictive of increased mortality (area under the curve of 0.62, p = 0.007). After multivariate analysis, NLR 4_6m remained independently associated with increased mortality (hazard ratio [HR] 1.67; 95% confidence interval [CI], 1.03-2.7; p = 0.037). Neutrophil to lymphocyte ratio 4_6m values significantly increase in association with adverse events on LVAD support and are independently associated with mortality. This association suggests presence of inflammation adversely affects LVAD outcomes.

Purpose Although Left Ventricular Assist Device (LVAD) improves functional capacity, on average LVAD patients are unable to achieve the aerobic capacity of normal healthy subjects or mild heart failure patients. The aim of this study was to examine if markers of right ventricular (RV) function influence maximal exercise capacity. Methods This was a single-centre prospective study that enrolled 20 consecutive HeartWare ventricular assist device (HVAD) patients who were admitted at the Freeman Hospital (Newcastle upon Tyne, United Kingdom) for a heart transplant assessment from August 2017 to October 2018. Results Mean peak oxygen consumption (Peak VO2) was 14.0 ± 5.0 ml/kg/min, and mean peak age and gender-adjusted percent predicted oxygen consumption (%VO2) was 40.0 ± 11.5 %. Patients were subdivided into 2 groups based on the median peak VO2, so each group consisted of 10 patients (50%). Right-sided and pulmonary pressures were consistently higher in the group with poorer exercise tolerance. Patients with poor exercise tolerance (peak VO2 below the median) had higher right atrial pressures at rest (10.6mmHg ± 6.4 versus 4.3mmHg ± 3.2, p= 0.02) and the increase with passive leg raising was significantly greater than those with preserved exercise tolerance (peak VO2 above the median). Patients with poor functional capacity also had greater RV dimensions (4.4 cm ± 0.5 versus 3.7 cm ± 0.5, p= 0.02) and a higher incidence of significant tricuspid regurgitation (TR) (moderate or severe TR in 5 patients in the poor exercise capacity group versus none in the preserved exercise capacity group, p=0.03). Conclusion Echocardiographic and hemodynamic markers of RV dysfunction discriminate between preserved and non-preserved exercise capacity in HVAD patients.

Purpose To determine parameters of exercise intolerance in a group of patients with HeartWare Ventricular Assist Device(HVAD) compared to a group of heart failure(HF)patients Methods This was a single-centre parallel prospective group-study.Echocardiograms,right heart catheterisation(RHC) and cardiopulmonary exercise tests were performed in 42patients admitted for a heart transplant assessment between August2017 and October2018:20 belonged to the HVAD group and 22 to the HF group Results HVADpatients had a better exercise capacity than HFpatients, although no significant differences were noted(14.0±5.0ml/kg/min vs 11.3±3.9ml/kg/min, p=0.06).To determine exercise tolerance,both HVAD and HFgroups were subdivided into 2 groups based on the median peakVO2.The table shows the comparison between preserved and non-preserved exercise tolerance in HF and HVADpatients. In the HVAD group,all resting RHC pressures were significantly lower in the preserved exercise capacity group.However,in HFpatients there were no statistically significant differences between both subgroups in right-sided pressures,but Thermodilution exercise-induced change in cardiac output(ΔCO) and cardiac index(ΔCI) was significantly higher in the patients with preserved exercise tolerance.In the HVADgroup the right ventricle was significantly larger in the reduced exercise tolerance subgroup.Patients with lower peakVO2 had more significant tricuspid regurgitation.Nevertheless,in HFpatients none of the echocardiographic parameters were related to the exercise capacity Conclusion Right-sided parameters in the echocardiogram and RHC pressures discriminate between preserved and non-preserved exercise capacity in HVADpatients,but not in HFpatients.In these last patients only ΔCO and ΔCI were statistically correlated with peak exercise oxygen consumption.

Purpose A new app-based programme for INR reporting was introduced in our cohort of patients with the aim of improving compliance and patient satisfaction. A comparison between the app-based programme and our current conventional method of telephone reporting was undertaken. Methods From a cohort of 52 durable MCS patients, 17 patients were enrolled onto the INR app. The remainder of the cohort continued to report their INR by telephoning the VAD nurse specialist. All patients were given the opportunity to submit their INR between 8am-1pm on the day requested, either via the app or telephone. Patients who did not contact within this time, were then contacted by the nurse specialist to chase the INR result. Compliance over a 15-day period was reviewed. Results An average of 9 INR submissions were made via the app, per day; with a 96.5% compliance within the allocated time period. Comparatively, the traditional method of reporting by phone showed an average of 14 INR submissions per day, with only an 87% compliance in the telephone group. Of the 17 INR app users, 23.5% of that patient group had a history of poor compliance in reporting their INR. A patient satisfaction survey showed 93.75% of respondents stated that they preferred using the app. All patients who previously had issues with compliance preferred the app and all patients strongly agreed the app was easy to use and had saved them time. Conclusion Compliance in the app group was found to be higher compared to patients who reported their INR by phone. Introduction of the INR app has not only reduced nurse workload, but also saved the patients’ time. Patients have responded very positively to the introduction of the app, justifying further enrolment of the remaining patient cohort onto the app.

Purpose Long term VAD therapy is a highly complex treatment modality, posing significant challenges to patients, medical teams and allied health professionals. Traditionally lack of social support and social isolation for patients has raised concerns for hospital teams. We have reviewed our cohort of patients at a single centre to determine if lack of social support and isolation affects patients’ long term survival. Methods A total of 315 patients were reviewed, having undergone continuous flow VAD as a bridge to transplantation. 50 patients were identified as having a lack of social support at the time of implant and during their VAD journey. This was defined as patients who lived alone, with little or no carers. Survival data was reviewed at yearly intervals at year 1, 2 and 3. Data was censored if the VAD therapy was discontinued during this period at time of death, time of transplant or time of myocardial recovery at decommission. Results 86% of patients were still alive at year 1, with no transplants or decommissioning occurring in this period. (see table 1). Year 2 survival was 58% with 5 deaths, 3 transplants and 1 decommissioning and year 3 was 64% survival with 2 transplants occurring in that period. This was then compared to overall survival data at our own centre and the national average for VAD survival as detailed in the NHSBT report 2016. The results were favourable for the lack of social support in comparison to the national survival data, with 1 year survival higher in the lack of social support cohort at 86% compared with national % of survival ranging from 62-83% per centre. Year 2 survival at 58% compared to 56-73% respectively and year 3 survival at 64% compared with 48-65 %. Conclusion Our data shows that a lack of social support group should not prohibit the introduction of VAD therapy. Careful monitoring of all patients should be provided long term to enhance all patient survival

Purpose Right heart failure (RHF) after left ventricular assist device (LVAD) implantation is a significant cause of morbidity and mortality. Multiple factors have been identified in order to predict early RHF, though information is scarce regarding late RHF. The aim of this study was to analyse and identify predictors of late RHF in LVAD patients. Methods A retrospective analysis of adult patients who underwent HeartWare-VAD implantation from 2009 to 2017 in a single-centre was performed. Late RHF was defined as RHF after 30 days of implantation requiring hospital admission. Clinical data, echocardiographic and haemodynamic parameters before implantation, data regarding the early post-operative phase and echocardiographic parameters at discharge were analysed. Results A total of 22 (10.7%) patients from 206 implantations developed late RHF during follow-up. Time to first RHF admission was 202.5 (IQR 130-682) days. Patients presenting with late RHF had a higher incidence of pre-operative significant tricuspid regurgitation (p Conclusion Late RHF was more prevalent in patients with dilated cardiomyopathy or congenital heart disease, and is not predicted by early RHF. Significant tricuspid regurgitation at discharge post-implantation predicted the occurrence of late RHF. Prospective studies are needed to determine whether tricuspid valve interventions may reduce late RHF.

Purpose The incidence of MSSA bacteraemia continues to plague clinicians, with trends continually rising in the UK (Darzi, 2018). This is echoed in the MCS community. We aim to demonstrate how we have significantly reduced the incidence of this infection at our centre. Methods Following several root cause analyses exploring MSSA bacteraemia in our patient cohort, several practice developments were incorporated into our local and regional guidance, in conjunction with advice from our microbiologists. The changes included:Strategic: Root cause analysis for all VAD associated MSSA/MRSA bacteraemia, Review of health care acquired infections at Trust Serious Infection Review meetings. Operational: VAD MSSA policy Introduction of MSSA screening at intervals of pre operatively, weekly for all inpatients, and at all clinic visits. MSSA Eradication therapy. Robust aseptic non touch technique training for all clinicians and competency assessments. Universal anti-microbial washes. Antibiotic suppression for MSSA colonised patients. Driveline management: regular reviews, change of dressings, audits of appropriate dressing, timely surgical intervention. Results 160 patient records were reviewed retrospectively, with a total of 31 MSSA bacteremia being identified between 2011-2017. (Table 1) As seen in Table 1, a peak in MSSA bacteraemia was identified in 2012-2013 prior to the introduction of the practice developments. In subsequent years our rate of MSSA bacteraemia has fallen sharply. The total number of annual LVAD implants have stayed consistent around 30 per annum. Table 1 . Time period Number of MSSA bacteremia 2011 3 2012 11 2013 7 2014 4 2015 3 2016 2 2017 1 Conclusion With the introduction of our practice developments we have almost completely eliminated MSSA bacteremia in our LVAD community.

Jet production properties at s = 540 GeV have been measured in the UA2 detector at the CERN pp Collider. Results on the total transverse momentum of the jet system, on the parton density in the nucleon (structure function) and on the two-jet angular distributions are reported. The data are compared with QCD predictions and extrapolations from lower energy experiments. © 1984.

Aims and methodThe Royal College of Psychiatrists is considering how best to introduce a post-MRCPsych-examination assessment (‘exit examination’) in anticipation of external pressures to ensure patient safety through the use of such assessments. The Psychiatric Trainees' Committee conducted an online survey to gather the views of psychiatrists regarding the possible format and content of this examination in the hope that this information can be used to design a satisfactory assessment.ResultsOf the 2082 individuals who started the survey, 1735 completed all sections (83.3%). Participants included consultants and trainees from a range of subspecialties. There was general agreement that the content and structure of the exit examination should include assessment of clinical and communication skills.Clinical implicationsUK psychiatrists believe that an exit assessment should focus on clinical and communication skills. It should assess both generic and subspecialty-specific competencies and incorporate a mixture of assessment techniques.

We present a retrospective analysis on a cohort of low-grade, node-negative patients showing that human epidermal growth factor receptor 2 (HER2) status significantly affects the survival in this otherwise very good prognostic group. Our results provide support for the use of adjuvant trastuzumab in patients who are typically classified as having very good prognosis, not routinely offered standard chemotherapy, and who as such do not fit current UK prescribing guidelines for trastuzumab.

Tumor necrosis factor [alpha] converting enzyme (TACE) mediates shedding of human epidermal growth factor receptor-4 (HER4). Recent data suggest that released HER4 intracellular domain (4ICD) induces apoptosis in breast cancer. TACE expression, as measured by immunohistochemical analysis, was observed in 183 of 383 breast carcinomas, 39 of 217 ovarian carcinomas, and 16 of 24 and 17 of 24 hormone-sensitive and hormone-insensitive prostate carcinomas, respectively. HER4 expression was detected in breast carcinomas by using 2 antibodies recognizing an extracellular or intracellular epitope. TACE expression was predominantly seen in tumors with high levels of 4ICD and membranous HER4. Apoptotic activity was measured by the terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assay and cleaved caspase-3 staining in breast carcinomas. There was no significant association between cleaved caspase-3 or TUNEL positivity and 4ICD, whereas TUNEL positivity was seen predominantly in tumors with high levels of internalized HER4. The data presented herein show TACE expression in endocrine cancers and further support a role for TACE in breast cancer apoptosis.

Purpose: Amplified in breast cancer 1 (AIB1) is a member of the p160/steroid receptor coactivators family and is involved in estrogen-dependent gene transcription by reducing the antagonistic activity of tamoxifen-bound estrogen receptor-α (ER-α). The present study was carried out to test the hypothesis that AIB1 protein expression and/or gene amplification mediates tamoxifen resistance in breast cancer. Experimental Design: Immunohistochemistry using AIB1 antibody and fluorescence in situ hybridization using probes specific for AIB1 and chromosome 20 was done on 402 ER-α–positive tamoxifen-treated breast cancers. Results: AIB1 overexpression was not associated with relapse during treatment with tamoxifen. In contrast, high AIB1 expression in patients with human epidermal growth factor receptor (HER) 2– and HER3-overexpressing tumors or tumors expressing one or more of HER1, HER2, or HER3 (HER1-3 positive) was associated with an increased risk of relapse on tamoxifen [hazard ratio, 2.20; 95% confidence interval, 1.07-3.52 (P = 0.0416); hazard ratio, 2.42; 95% confidence interval, 1.32-4.43 (P = 0.0030), respectively]. AIB1 gene amplification was observed in 18 of 362 (5%) patients. High AIB1 gene copy number had no effect on overall or disease-free survival. Conclusions: Data presented here support a role for AIB1 expression on relapse during tamoxifen treatment in hormone-responsive HER-expressing clinical breast cancers and support clinical evidence, suggesting a cross-talk between ER-α and growth factor receptor pathways through changes in expression of specific coactivator proteins, such as AIB1. This study highlights the potential that tumor profiling, using multiple markers of treatment response, may improve patient selection for endocrine treatment, such as tamoxifen or aromatase inhibitors.

AIM: Immunohistochemical analysis of protein expression is central to most clinical translational studies and defines patient treatment or selection criteria for novel drugs. Interobserver variation is rarely analysed despite recognition that this is a key area of potential inaccuracy. Therefore our aim was to examine observer variation and suggest the revision of current standards. METHODS AND RESULTS: We analysed inter- and intra-observer variation, by interclass correlation coefficient (ICCC) and kappa statistics, in 8661 samples. Intra-observer assessment of nuclear, cytoplasmic and membrane staining for seven proteins in 1323 samples resulted in an ICCC of 0.94 and a kappa-value of 0.787. Interobserver reproducibility, assessed on 28 proteins by seven observer pairs in 8661 carcinomas, gave an ICCC of 0.90 and a kappa-value of 0.70. No significant effect of either antibody or cellular compartmentalization was observed. CONCLUSION: We have demonstrated that ICCC is a consistent method to assess observer variation when a continuous scoring system is used, compared with kappa statistics, which depends on a categorical system. Given the importance of accurate assessment of protein expression in diagnostic and experimental medicine, we suggest raising thresholds for observer variation: ICCC of 0.7 should be regarded as the minimum acceptable standard, ICCC of 0.8 as good and ICCC of > or = 0.9 as excellent.

Purpose: Resistance to tamoxifen is linked to overexpression of HER2, and aromatase inhibitors show particular benefit in progesterone receptor (PR)–negative patients. We previously reported reduced survival in patients overexpressing HER1, HER2, and HER3. We now show that both HER1-3 and PR status predicts for early relapse in estrogen receptor (ER)–positive tamoxifen-treated breast cancer patients. Experimental Design: Tissue microarray technology was used to analyze 402 ER-positive tamoxifen-treated patients. Immunohistochemistry using epidermal growth factor receptor, HER2, HER3, HER4, and PR antibodies was done. Kaplan-Meier life table and Cox Regression analysis (log-rank testing of differences in breast cancer–related relapse on tamoxifen) was done. Results: HER1-3 (but not HER4) overexpression predicted for early relapse on tamoxifen (P = 0.0060). PR-negative cases were also significantly more likely to relapse while on tamoxifen (P= 0.017). HER1-3-positive and/or PR-negative patients combined as a “high-risk” group were significantly more likely to relapse on tamoxifen in univariate (P < 0.0001) and Cox's multivariate analysis (P = 0.0069). However, this applied to early relapse on tamoxifen only, as any disease relapse after 3 years of tamoxifen was unrelated to PR/HER status. Conclusions: We show that HER1-3 and PR status can identify time-dependent de novo tamoxifen resistance with risk declining markedly after 3 years of tamoxifen treatment. These results parallel data from the ATAC and Intergroup Exemastane Study trials which suggest that whereas PR-negative patients derive greater benefit from initial aromatase inhibitor treatment, PR status has no effect on response when given as delayed treatment to those disease free on tamoxifen after 3 years.

Introduction Groote Schuur Hospital has a well-established low-dose rate (LDR) brachytherapy programme using I-125 seeds. Temporary implants in and around the eye, tongue, floor of mouth, palate or for keloid scars are custom-made for each individual. A pre-implant plan is done to determine seed positions and activities, while a post-implant plan is done to determine the actual dose distributions in the patient. Method and materials The pre-implant plans generally consist of a number of trains loaded with I-125 seeds in a geometry specified by the oncologist. Different activity seeds are used to create an optimal pre-implant dose distribution. Post-implant plans are currently worked out on orthogonal X-rays. The magnification factor is determined from specially placed brass rings and each seed has to be individually matched on each X-ray. This is a very time-consuming task, especially for implants with large seed numbers. Once the seeds have been identified, the correct activities have to be assigned to each seed. An investigation is under way to find a more efficient way of determining the seed co-ordinates from a post-implant CT scan. Results Initial investigations show that this is a feasible alternative in many cases for determining the seed co-ordinates. The 3D viewing option of the CT data also helps in assigning the seed activities. This may not be a suitable alternative for all implants, especially for some of the orbital implants that have a lead disk inserted under the eye lid for shielding purposes, and also to hold additional seeds. The lead disc, as well as the clamped ends of the seed trains, introduce artefacts on the CT scans, possibly obscuring individual seeds. Conclusion In cases where this post-planning option proves to be a suitable alternative, post-planning times are reduced significantly.

Src kinase, a non-receptor tyrosine kinase, is overexpressed and highly activated in a number of human cancers and appears to show a significant relationship with breast cancer progression. Recent in vitro studies have suggested that Src kinase may be involved in tamoxifen resistance.Immunohistochemistry was performed on 392 resected breast cancers using an antibody to c-Src. Expression was assessed using the weighted histoscore method.Forty-five percentage of breast tumours exhibited nuclear, 46% cytoplasmic and 7% membrane expression. Lymph node positivity correlated with cytoplasmic c-Src tumour expression levels (P0.001). Nuclear c-Src correlated negatively with cytoplasmic and membrane c-Src expression (P0.001, P = 0.005). High expression levels of cytoplasmic c-Src was associated with worse disease-specific survival (P = 0.026) after completing 5 years of tamoxifen therapy. However, high expression of c-Src at any cellular location did not show any association with de novo relapse on tamoxifen (c-Src nuc P = 0.906, c-Src cyto P = 0.735 and c-Src memb P = 0.791).No translational evidence was found in this study to support a role for Src kinase in developing de novo tamoxifen resistance. However, based on our findings on late clinical outcome, patients with high cytoplasmic c-Src may be selected for continuing endocrine therapy to prevent worsening prognosis.

We demonstrate here a new concept termed "oncogene tolerance" whereby human EGF receptor 2 (HER2) increases sphingosine kinase 1 (SK1) expression in estrogen receptor-positive (ER(+)) MCF-7 HER2 cells and SK1, in turn, limits HER2 expression in a negative-feedback manner. The HER2-dependent increase in SK1 expression also limits p21-activated protein kinase 1 (p65 PAK1) and extracellular signal regulated kinase 1/2 (ERK-1/2) signaling. Sphingosine 1-phosphate signaling via S1P(3) is also altered in MCF-7 HER2 cells. In this regard, S1P binding to S1P(3) induces a migratory phenotype via an SK1-dependent mechanism in ER(+) MCF-7 Neo cells, which lack HER2. This involves the S1P stimulated accumulation of phosphorylated ERK-1/2 and actin into membrane ruffles/lamellipodia and migration. In contrast, S1P failed to promote redistribution of phosphorylated ERK-1/2 and actin into membrane ruffles/lamellipodia or migration of MCF-7 HER2 cells. However, a migratory phenotype in these cells could be induced in response to S1P when SK1 expression had been knocked down with a specific siRNA or when recombinant PAK1 was ectopically overexpressed. Thus, the HER2-dependent increase in SK1 expression functions to desensitize the S1P-induced formation of a migratory phenotype. This is correlated with improved prognosis in patients who have a low HER1-3/SK1 expression ratio in their ER(+) breast cancer tumors compared to patients that have a high HER1-3/SK1 expression ratio.

The aim of the current study was to assess the expression levels of c-Src and phosphorylated Src kinase in human breast cancers and to establish if these are linked to oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status or patient survival. Tissue microarray technology was used to analyze 314 breast cancer specimens. Immunohistochemistry was performed using antibodies to c-Src, Y419Src, and Y215Src, and expression was assessed using the weighted histoscore method. High cytoplasmic c-Src kinase and high membrane phosphorylated activated Y419Src kinase was associated with decreased disease-specific survival. In contrast, phosphorylated activated nuclear and cytoplasmic Y215Src kinase expression levels were significantly associated with improved disease-specific survival. When the cohort was subdivided according to ER/PR/HER2 status, the ER-negative subgroup (105 patients) was associated with improved disease-specific survival and was found to be independent by multivariate analysis with a hazard ratio of 0.4 (interquartile range 0.2–0.8). High cytoplasmic c-Src expression was associated with decreased survival; high expression of activated c-Src (Y215) was associated with improved survival. This was potentiated in the ER/HER2-negative subgroup. Hence, administration of Src kinase inhibitors aiming to decrease phosphorylation should be approached with caution, especially in ER-negative patients. It is therefore essential to appropriately identify with the correct biomarkers which patients are most likely to respond to Src inhibitors.

Purpose: The expression and activation of the Ras/Raf-1/mitogen-activated protein kinase (MAPK) pathway plays an important role in the development and progression of cancer, and may influence response to treatments such as tamoxifen and chemotherapy. In this study we investigated whether the expression and activation of the key components of this pathway influenced clinical outcome, to test the hypothesis that activation of the MAPK pathway drives resistance to tamoxifen and chemotherapy in women with breast cancer.\ud \ud Experimental Design: Breast tumors from patients at the Glasgow Royal Infirmary and others treated within the BR9601 trial were analyzed for expression of the three Ras isoforms, total Raf-1, active and inactive forms of Raf-1 [pRaf(ser338) and pRaf(ser259), respectively], MAPK, and phospho-MAPK using an immunohistochemical approach. Analyses were done with respect to disease free-survival and overall survival.\ud \ud Results: Expression and activation of the Ras pathway was associated with loss of benefit from treatment with tamoxifen but not chemotherapy. Overexpression of pRaf(ser338) was associated with shortened disease-free and overall survival time in univariate analyses. Multivariate analysis suggested pRaf(ser338) was independent of known prognostic markers in predicting outcome following tamoxifen treatment (P=0.03).\ud \ud Conclusion: This study suggests that activation of the Ras pathway predicts for poor outcome on tamoxifen but not chemotherapy, and identifies pRaf(ser338) as a potential marker of resistance to estrogen receptor–targeted therapy. In addition, it suggests that expression of pRaf(ser338) could identify patients for whom tamoxifen alone is insufficient adjuvant systemic therapy, but for whom the addition of chemotherapy may be of benefit.

Elevated c-Src protein expression has been shown in breast cancer and in vitro evidence suggests a role in endocrine resistance. To investigate whether c-Src is involved in endocrine resistance, we examined the expression of both total and activated c-Src in human breast cancer specimens from a cohort of oestrogen receptor (ER)-positive tamoxifen-treated breast cancer patients. Tissue microarray technology was employed to analyse 262 tumour specimens taken before tamoxifen treatment. Immunohistochemistry using total c-Src and activated c-Src antibodies was performed. Kaplan–Meier survival curves were constructed and log-rank test were performed. High level of nuclear activated Src was significantly associated with improved overall survival (P=0.047) and lower recurrence rates on tamoxifen (P=0.02). Improved patient outcome was only seen with activated Src in the nucleus. Nuclear activated Src expression was significantly associated with node-negative disease and a lower NPI (PP=0.004). This shows that c-Src activity is increased in breast cancer and that activated Src within the nucleus of ER-positive tumours predicts an improved outcome. In ER/PgR-positive disease, activated Src kinase does not appear to be involved in de novo endocrine resistance. Further study is required in ER-negative breast cancer as this may represent a cohort in which it is associated with poor outcome.

HER2 status is routinely tested using immunohistochemistry or FISH following the licensing of a therapeutic agent targeting HER2. However, neither of these methods provides quantitative information relating to the 70-80% of patients with levels of expression lower than the assay detection thresholds. In this study, radioimmunohistochemistry was used to detect quantitative HER2 protein expression in 178 breast cancers. Survival analysis was performed, as were correlations with known prognostic variables and with overexpression of other HER family members. It is demonstrated that the populations expressing very high and very low levels of HER2 are each associated with increased risk of cancer-specific death on survival analysis (p = 0.0043). The group with low levels of HER2 was more likely to be of higher grade, EGFR-positive and ER/HER3/HER4-negative. HER2-positive cases were frequently ER-negative/HER3-positive, whilst cases with normal HER2 expression were often ER-positive/HER4-positive. The aggressive nature of the tumour group with low HER2 expression may be explained by actions of other HER family members, particularly EGFR, but whether these or other factors have a negative regulatory effect on HER2 expression remains to be determined.

Aims Activation of the PI3K/Akt signal transduction pathway has been linked to endocrine resistance in tamoxifen treated breast cancer patients. Activation of the PI3K/Akt pathway causes phosphorylation of Bad leading to modulation of cellular apoptosis. The present study was carried out to test the hypothesis that disruption of apoptosis in breast cancer, via Akt activation, is linked with hormone resistance. Methods Immunohistochemistry (IHC) was performed on 402 oestrogen receptor (ER) positive breast cancers using antibodies against Bad, pBad (ser 112), Bcl-2, Bcl-xl and Bax. Results Bad, pBad (ser 112), Bcl-2 and Bax expression was observed in the cellular cytoplasmic compartment only. Patients, whose tumours had high levels of Bad expression, had a significantly improved disease-free survival when compared to patients whose tumours had low levels of Bad expression (P = 0.049). Activation of the PI3K/Akt pathway by either heregulin or oestrogen had no effect on expression of Bad, Bcl-2, Bax or Bcl-xl. However, heregulin increased pBad (ser 112) expression. Discussion Data presented here shows that Bad expression is associated with relapse in tamoxifen-treated breast cancer patients, supporting our hypothesis that the apoptosis pathway is involved in tamoxifen resistance.

Introduction We have previously linked HER4 expression with increased survival in breast cancer. However, other reports have associated HER4 with adverse prognostic significance. One possible explanation for the conflicting reports may be that these results are antibody dependent. The HER4 protein is enzymatically cleaved, which may alter the function of its intracellular domain (ICD). We have therefore compared the staining patterns of antibodies against its intracellular and extracellular domains using tissue microarray technology. Methods Immunohistochemistry was performed and evaluated on tumours from 402 tamoxifen treated oestrogen receptor positive patients. The HFR1 antibody recognises the ICD of HER4 and thus recognises both the intact receptor and the cleaved ICD. The H4.77.16 clone recognises an extracellular domain of HER4 and thus detects the full length receptor only. Results Both antibodies demonstrated nuclear, cytoplasmic and membranous staining. Concordance between the membrane staining patterns was high (88.44%, kappa 0.426). The HFR1 antibody, however, demonstrated generally higher levels of cytoplasmic staining (concordance 74.77%, kappa 0.351). The antibodies demonstrated very different patterns of nuclear staining. Over 60% of patients stained with the H4.77.16 had no nuclear staining whereas the vast majority showed staining with the HFR1 antibody (concordance 40.12%, kappa 0.051). Neither antibody demonstrated relationships between membranous or cytoplasmic HER4 staining and survival, although associations were seen with known poor prognostic markers. Cases with H4.77.16-determined nuclear staining had significantly poorer survival outcomes. Conclusion The difference in antigen site may explain the different staining patterns we have seen with respect to location; with each antibody appearing to select for distinct compartments. Thus, HFR1 may select for cytoplasmic and nuclear HER4 ICD, whilst H4.77.16 selects for membranous HER4 and/or HER4 being recycled in cytoplasm or nucleus. This ability to distinguish between site and function of HER4 and its fragments is particularly important, with recent evidence highlighting the different functions of nuclear and mitochondrial HER4.

Oestrogen receptor (ERalpha) expression is a strong predictor of response to endocrine therapy. The PI3K/AKT/mTOR signal transduction pathway has been implicated in endocrine resistance in vitro. The present study was carried out to test the hypothesis that AKT activation mediates tamoxifen resistance in clinical breast cancer. Immunohistochemistry (IHC) using AKT1-3, pan-AKT, pAKT (Thr-308), pAKT (Ser-473), pER (Ser-167), and pHER2 antibodies was performed on 402 ERalpha-positive breast carcinomas from patients treated with tamoxifen. High pAKT (Ser-473) activity (p = 0.0406) and low AKT2 expression (p = 0.0115) alone, or in combination [high pAKT (Ser-473)/low AKT2; 'high-risk' patient group] (p = 0.0014), predicted decreased overall survival in tamoxifen-treated patients with ERalpha-positive breast cancers. There was no significant association between tumour levels of AKT expression or activity and disease-free survival (DFS); however, the 'high-risk' patient group was significantly more likely to relapse (p = 0.0491). During tamoxifen treatment, neither AKT2 nor pAKT predicted DFS. Finally, activation of AKT, via phosphorylation, was linked to activation of both HER2 and ERalpha in this patient cohort. The data presented here show that the PI3K/AKT/mTOR pathway is associated with relapse and death in ERalpha-positive breast cancer patients treated with tamoxifen, supporting in vitro evidence that AKT mediates tamoxifen resistance. Patients with a 'high-risk' expression profile were at increased risk of death (hazard ratio 3.22, p = 0.002) relative to 'low-risk' patients, highlighting the potential that tumour profiling, with multiple IHC markers predictive of therapeutic response, may improve patient selection for endocrine therapies, eg tamoxifen or aromatase inhibitor-based treatments.

Background We have shown previously that whereas overexpression of human epidermal growth factor receptor (HER)1, HER2 and HER3 is associated with poor prognosis in breast cancer, HER4 is associated with a good prognosis. Cell proliferation is a key component of aggressive cancers and is driven by growth factors. In this study, bromodeoxyuridine (BrdU)-derived proliferation indices are correlated with clinical outcome and HER1–4 status for further clarification of the differing roles for the HER family at a biological level. Methods Seventy-eight invasive breast cancers had BrdU labelling in vivo to determine the BrdU labelling index (BLI) and the potential tumour doubling time (Tpot). Long-term clinical follow-up was available for these patients. We used immunohistochemistry to establish the HER1–4 status in 55 patients from the BrdU cohort. Results We demonstrate a significant correlation between high BLI values and breast cancer-specific death (P = 0.0174). Low Tpot times were also significantly correlated with breast cancer-specific death (P = 0.0258). However, BLI did not independently predict survival in Cox's multiple regression analysis when combined with other prognostic factors such as size, grade and nodal status. Tumours found to be positive for HER1, HER2 or HER3 had significantly (P = 0.041) higher labelling indices, with HER1 also showing significantly higher indices when considered independently (P = 0.024). Conversely, HER4 positivity was significantly correlated (P = 0.013) with low BLI values, in line with previous data associating this receptor with good prognosis tumours. Conclusions These results support the hypothesis that HER1–3 are associated with driving tumour proliferation, whereas HER4 is involved in a non-proliferative or even protective role.

We report measurements of the behaviour of silicon diodes when exposed to integrated neutron doses of up to 5 x 10(13) neutrons/cm 2. The measurements have been made at diode temperatures between room temperature and -20-degrees-C. From measurements of the diode leakage current and depletion voltage, and consequent evaluations of the effective impurity concentration, the temperature dependence of these quantities is discussed in terms of the annealing behaviour of the diodes. Comments are made on the suitability of silicon as a detector medium for particle physics experiments at future accelerators.

We present a description of the RD2 design for a silicon tracking detector and discuss its function as an integrated component of an LHC experiment. An advantage of the design is that considerable flexibility is possible in the granularity and radial position of each plane; these parameters are determined by the physics requirements as well as by the radiation environment, engineering and electronics considerations. The simulated performance of the detector is discussed and our experimental investigations of irradiation effects are summarised. The development of an analogue pipe-line and related front-end electronics for the storage and processing of the signals is described. Our work indicates the suitability of silicon as a detector for LHC experiments.