Jacqueline Stephen

Phase 2 Randomised Controlled Trial and Feasibility Study of Future Care Planning in Patients with Advanced Heart Disease

Future Care Planning (FCP) rarely occurs in patients with heart disease until close to death by which time the potential benefits are lost. We assessed the feasibility, acceptability and tested a design of a randomised trial evaluating the impact of FCP in patients and carers. 50 patients hospitalised with acute heart failure or acute coronary syndrome and with predicted 12 month mortality risk of >20% were randomly allocated to FCP or usual care for 12 weeks upon discharge and then crossed-over for the next 12 weeks. Quality of life, symptoms and anxiety/distress were assessed by questionnaire. Hospitalisation and mortality events were documented for 6 months post-discharge. FCP increased implementation and documentation of key decisions linked to end-of-life care. FCP did not increase anxiety/distress (Kessler score -E 16.7 (7.0) vs D 16.8 (7.3), p = 0.94). Quality of life was unchanged (EQ5D: E 0.54(0.29) vs D 0.56(0.24), p = 0.86) while unadjusted hospitalised nights was lower (E 8.6 (15.3) vs D 11.8 (17.1), p = 0.01). Qualitative interviews indicated that FCP was highly valued by patients, carers and family physicians. FCP is feasible in a randomised clinical trial in patients with acute high risk cardiac conditions. A Phase 3 trial is needed urgently.

Nottingham Prognostic Index Plus: Validation of a clinical decision making tool in breast cancer in an independent series

The Nottingham Prognostic Index Plus (NPI+) is a clinical decision making tool in breast cancer (BC) that aims to provide improved patient outcome stratification superior to the traditional NPI. This study aimed to validate the NPI+ in an independent series of BC. Eight hundred and eighty five primary early stage BC cases from Edinburgh were semi‐quantitatively assessed for 10 biomarkers [Estrogen Receptor (ER), Progesterone Receptor (PgR), cytokeratin (CK) 5/6, CK7/8, epidermal growth factor receptor (EGFR), HER2, HER3, HER4, p53, and Mucin 1] using immunohistochemistry and classified into biological classes by fuzzy logic‐derived algorithms previously developed in the Nottingham series. Subsequently, NPI+ Prognostic Groups (PGs) were assigned for each class using bespoke NPI‐like formulae, previously developed in each NPI+ biological class of the Nottingham series, utilising clinicopathological parameters: number of positive nodes, pathological tumour size, stage, tubule formation, nuclear pleomorphism and mitotic counts. Biological classes and PGs were compared between the Edinburgh and Nottingham series using Cramers V and their role in patient outcome prediction using Kaplan–Meier curves and tested using Log Rank. The NPI+ biomarker panel classified the Edinburgh series into seven biological classes similar to the Nottingham series (p > 0.01). The biological classes were significantly associated with patient outcome (p < 0.001). PGs were comparable in predicting patient outcome between series in Luminal A, Basal p53 altered, HER2+/ER+ tumours (p > 0.01). The good PGs were similarly validated in Luminal B, Basal p53 normal, HER2+/ER− tumours and the poor PG in the Luminal N class (p > 0.01). Due to small patient numbers assigned to the remaining PGs, Luminal N, Luminal B, Basal p53 normal and HER2+/ER− classes could not be validated. This study demonstrates the reproducibility of NPI+ and confirmed its prognostic value in an independent cohort of primary BC. Further validation in large randomised controlled trial material is warranted.

Time dependence of biomarkers: non-proportional effects of immunohistochemical panels predicting relapse risk in early breast cancer

Background:We investigated the impact of follow-up duration to determine whether two immunohistochemical prognostic panels, IHC4 and Mammostrat, provide information on the risk of early or late distant recurrence using the Edinburgh Breast Conservation Series and the Tamoxifen vs Exemestane Adjuvant Multinational (TEAM) trial.Methods:The multivariable fractional polynomial time (MFPT) algorithm was used to determine which variables had possible non-proportional effects. The performance of the scores was assessed at various lengths of follow-up and Cox regression modelling was performed over the intervals of 0–5 years and >5 years.Results:We observed a strong time dependence of both the IHC4 and Mammostrat scores, with their effects decreasing over time. In the first 5 years of follow-up only, the addition of both scores to clinical factors provided statistically significant information (P<0.05), with increases in R2 between 5 and 6% and increases in D-statistic between 0.16 and 0.21.Conclusions:Our analyses confirm that the IHC4 and Mammostrat scores are strong prognostic factors for time to distant recurrence but this is restricted to the first 5 years after diagnosis. This provides evidence for their combined use to predict early recurrence events in order to select those patients who may/will benefit from adjuvant chemotherapy.

Rationale, design and methodology of a trial evaluating three strategies designed to improve sedation quality in intensive care units (DESIST study)

Objectives To describe the rationale, design and methodology for a trial of three novel interventions developed to improve sedation-analgesia quality in adult intensive care units (ICUs). Participants and Setting 8 clusters, each a Scottish ICU. All mechanically ventilated sedated patients were potentially eligible for inclusion in data analysis. Design Cluster randomised design in 8 ICUs, with ICUs randomised after 45 weeks baseline data collection to implement one of four intervention combinations: a web-based educational programme (2 ICUs); education plus regular sedation quality feedback using process control charts (2 ICUs); education plus a novel sedation monitoring technology (2 ICUs); or all three interventions. ICUs measured sedation-analgesia quality, relevant drug use and clinical outcomes, during a 45-week preintervention and 45-week postintervention period separated by an 8-week implementation period. The intended sample size was >100 patients per site per study period. Main Outcome measures The primary outcome was the proportion of 12 h care periods with optimum sedation-analgesia, defined as the absence of agitation, unnecessary deep sedation, poor relaxation and poor ventilator synchronisation. Secondary outcomes were proportions of care periods with each of these four components of optimum sedation and rates of sedation-related adverse events. Sedative and analgesic drug use, and ICU and hospital outcomes were also measured. Analytic approach Multilevel generalised linear regression mixed models will explore the effects of each intervention taking clustering into account, and adjusting for age, gender and APACHE II score. Sedation-analgesia quality outcomes will be explored at ICU level and individual patient level. A process evaluation using mixed methods including quantitative description of intervention implementation, focus groups and direct observation will provide explanatory information regarding any effects observed. Conclusions The DESIST study uses a novel design to provide system-level evaluation of three contrasting complex interventions on sedation-analgesia quality. Recruitment is complete and analysis ongoing. Trial registration number NCT01634451.

Cognitive impairment in early onset epilepsy is associated with reduced left thalamic volume

OBJECTIVE The objective of this study was to investigate whether reduction of thalamic volumes in children with early onset epilepsy (CWEOE) is associated with cognitive impairment. METHODS This is a nested case-control study including a prospectively recruited cohort of 76 children with newly-diagnosed early onset epilepsy (onset <5years age) and 14 healthy controls presenting to hospitals within NHS Lothian and Fife. Quantitative volumetric analysis of subcortical structures was performed using volumetric T1-weighted magnetic resonance imaging (MRI) and correlated with the results of formal neurocognitive and clinical assessment. False discovery rate was used to correct for multiple comparisons as appropriate with q<0.05 used to define statistical significance. RESULTS Age, gender, and intracranial volume (ICV)-adjusted left thalamic volumes were significantly reduced in CWEOE with cognitive impairment compared to CWEOE without impairment (5295mm3 vs 6418mm3, q=0.008) or healthy controls (5295mm3 vs 6410mm3, q<0.001). The differences in left thalamic volume remained if gray matter or cortical/cerebellar volumes were used as covariates rather than ICV (q<0.05). The degree of volume reduction correlated with the severity of cognitive impairment (q=0.048). SIGNIFICANCE Reduced left thalamic volume may be a biomarker for cognitive impairment in CWEOE and could help inform the need for further formal cognitive evaluations and interventions.

Trends in epilepsy admissions in children 1981-2013: population-based observational study using the Scottish national hospital discharge database

Objective To examine trends in epilepsy admissions in children from 1981 to 2013. Design Repeated cross-sectional, population-based study. Setting Scotland. Patients We identified admissions among children between 1981 and 2013 inclusive. Epilepsy admissions were identified from the Scottish national hospital discharge database by using relevant diagnostic codes. Primary epilepsy admissions (PEAs) were those with epilepsy as the primary discharge diagnosis, or convulsions as the primary diagnosis but with epilepsy as secondary diagnosis. All other epilepsy admissions were secondary epilepsy admissions (SEAs). Main outcome measures Trends in annual epilepsy and non-epilepsy admission rates, as well as sociodemographic, clinical characteristics, length of stay and readmissions of epilepsy admissions. Results 57 031 epilepsy and 3 863 809 non-epilepsy admissions were available for analysis. Overall, epilepsy and non-epilepsy admissions increased, with a greater increase in epilepsy admissions (interaction Χ2 test statistic 252, p<0.00001). Elective epilepsy admissions, unlike elective non-epilepsy admissions, continually increased, but emergency epilepsy admissions increased until 2000 and showed only minor fluctuations thereafter. Increase in SEAs was more marked than PEAs (interaction Χ2 test statistic 627, p<0.0001). 48% of epilepsy admissions were to children’s hospitals. No substantial trends were apparent in age, gender or deprivation distribution of epilepsy admissions. There was a clear trend towards shorter length of stay. Conclusions Childhood epilepsy admissions are increasing, at a faster rate than non-epilepsy admissions, and have changed towards shorter, more elective admissions. Many will not be to children’s hospitals, and the primary reason will often not be because of epilepsy/convulsions. More, not less, epilepsy resources are needed.

Challenges in the design and analysis of a factorial-design cluster randomised trial

Optimising sedation quality in mechanically ventilated intensive care patients is important because excessive sedation is associated with increased hospital acquired infections, longer intensive care (ICU) and hospital stay, and possibly higher mortality. The Development and Evaluation of Strategies to Improve Sedation Quality in InTensive Care (DESIST) study aims to optimise sedation practice. Here we focus on the study design, statistical analysis plan, performing the analysis and issues that occurred. DESIST randomised eight ICUs in pairs to four different combinations of sedation-related quality improvement interventions. The primary outcome assessed optimum sedation within each 12 hour nursing shift (referred to as a DESIST care period). This resulted in a three-level hierarchical data structure: DESIST care periods within admissions, within ICU.

Abstract P5-09-01: Nottingham prognostic index plus (NPI+): Validation of the modern clinical decision making tool in breast cancer

Introduction Current management of breast cancer (BC) relies on risk stratification based on well-defined clinicopathologic factors. The Nottingham Prognostic Index Plus (NPI+) is based on the assessment of biological class combined with established clinicopathologic prognostic variables providing improved patient outcome stratification superior to the traditional NPI*. This study aimed to validate the NPI+ in an independent series of BC. Methods A Validation series of 469 primary early-stage BC cases treated in Edinburgh, UK were matched for size, stage and grade to cases from Nottingham, UK used to develop the NPI+ (Training series). Adjuvant therapy was similar in both series except that 143 Edinburgh cases received endocrine therapy whilst the matched Nottingham cases had no adjuvant therapy. However, there was no significant difference in 10 year BC specific survival (BCSS) between the Training and Validation series. Cases, prepared as TMAs, were immunohistochemically assessed for Cytokeratin (Ck)5/6, Ck18, EGFR, Estrogen Receptor (ER), Progesterone Receptor (PgR), HER2, HER3, HER4, Mucin 1 and p53 expression. NPI+ biological class based on the expression of the 10 biomarkers was determined. Subsequent NPI+ prognostic scores were assigned using individual algorithms for each biological class developed using the Training series incorporating clinicopathologic parameters: positive nodes (including nodal stage), tumour size, tumour grade (including mitotic index) and PgR. NPI+ biological classes, prognostic scores and prognostic groups were compared between the Validation and Training series and their role in prediction of patient outcome. A p-value of Results As anticipated, there was a comparable distribution of NPI+ biological classes between Training and Validation series: Luminal A, n=143 (31%) vs n=115 (25%); Luminal N, n=99 (21%) vs n=89 (19%); Luminal B, n=75 (16%) vs n=85 (18%); Basal p53 altered, n=54 (12%) vs n=72 (15%); Basal p53 normal, n=37 (8%) vs n=53 (11%); HER2+/ER+, n=31 (7%) vs 18 (4%); HER2+/ER-, n=30 (6%) vs n=37 (8%; X2=13.792, p=0.032). BCSS was analogous between the Validation and Training series in each of the NPI+ biological classes except Luminal B (p=0.042). Similar BCSS was observed in the NPI+ Biological classes of the Training versus Validation series when taking into consideration adjuvant treatment modalities. The mean NPI+ score was similar between the Validation and Training series (2.30 vs 1.89, Pearson’s Regression p=0.079). The NPI+ prognostic groups significantly predicted patient outcome in each molecular class (BCSS, p Conclusion This study validates the NPI+ in an independent series of primary BC confirming its’ reproducibility. The NPI+ provides improved individualised clinical decision making for breast cancer for both prediction of clinical outcome and relevant therapeutic options. Acknowledgements Funded by the MRC References *Rakha EA et al Br J Cancer. 2014 110:1688-97. Citation Format: Andrew R Green, Daniel Soria, Jacqueline Stephen, Desmond G Powe, Christopher C Nolan, Ian Kunkler, Jeremy Thomas, Gill Kerr, Wilma Jack, David Camreron, Tammy Piper, Graham R Ball, Jonathan M Garibaldi, Emad A Rakha, John MS Bartlett, Ian O Ellis. Nottingham prognostic index plus (NPI+): Validation of the modern clinical decision making tool in breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-09-01.

Abstract P4-11-10: Time dependence of biomarkers: Non-proportional effects of immunohistochemical panels predicting relapse risk in early breast cancer

Background: We investigate the impact of follow-up duration to determine whether two immunohistochemical prognostic panels, IHC 4 and Mammostrat, provide information on the risk of early or late distant recurrence using the Edinburgh Breast Conservation Series and the Tamoxifen versus Exemestane Adjuvant Multinational (TEAM) trial. Methods: The multivariable fractional polynomial time (MFPT) algorithm was used to determine which variables had possible non-proportional effects. The performance of the scores was assessed at various lengths of follow-up and Cox regression modelling performed over the intervals 0-5 years and > 5 years. Results: We observed a strong time-dependence of both the IHC4 and Mammostrat scores with their effects decreasing over time. In the first five years of follow-up only, the addition of both scores to clinical factors provided statistically significant information (p 2 between 5 and 6% and increases in D-statistic between 0.16 and 0.21. Conclusion: Our analyses confirm that the IHC4 and Mammostrat scores are strong prognostic factors for time to distant recurrence but this is restricted to the first 5 years after diagnosis. This provides evidence for their combined use to predict early recurrence events in order to select those patients who may/will have benefit from adjuvant chemotherapy. Citation Format: Jacqueline Stephen, Gordon Murray, David Cameron, Jeremy Thomas, Ian Kunkler, Wilma Jack, Gill Kerr, Tammy Piper, Cassandra Brookes, Daniel Rea, Cornelis van de Velde, Annette Hasenburg, Christos Markopoulos, Luc Dirix, Caroline Seynaeve, John Bartlett. Time dependence of biomarkers: Non-proportional effects of immunohistochemical panels predicting relapse risk in early breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-10.

Abstract P4-11-09: Comparison of immunohistochemical residual risk panels to predict risk in early breast cancers treated with endocrine therapy

Background: We compare two residual risk models combining immunohistochemical (IHC) biomarkers, IHC4 and Mammostrat, in the Edinburgh Breast Conservation Series (BCS) and in the Tamoxifen versus Exemestane Adjuvant Multinational (TEAM) trial. Materials and Methods: The primary cohorts comprised 831 and 2,513 estrogen receptor (ER)-positive patients who did not receive adjuvant chemotherapy from the Edinburgh BCS and TEAM cohorts respectively. We evaluated prognostic scores for distant recurrence-free survival (DRFS). Results: Low scores for both IHC4 and Mammostrat are associated with better DRFS. In multivariate Cox regression analyses the addition of both scores to clinical factors provided independent information on residual risk (p Conclusion: The results showed that the scores have different capabilities in predicting DRFS depending on the study and subgroup of patients. However, significant benefit in estimating residual recurrence risk after treatment was observed from a combined use of both marker panels. This provides support for investigating their combined use for risk stratification of ER-positive early breast cancer patients. Citation Format: Jacqueline Stephen, Gordon Murray, David Cameron, Jeremy Thomas, Ian Kunkler, Wilma Jack, Gill Kerr, Tammy Piper, Cassandra Brookes, Daniel Rea, Cornelis van de Velde, Annette Hasenburg, Christos Markopoulos, Luc Dirix, Caroline Seynaeve, John Bartlett. Comparison of immunohistochemical residual risk panels to predict risk in early breast cancers treated with endocrine therapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-09.