Utility of patient-derived lymphoblastoid cell lines as an ex vivo capecitabine sensitivity prediction model for breast cancer patients.

Capecitabine is commonly used in treating breast cancer; however, therapeutic response varies among patients and there is no clinically validated model to predict individual outcomes. Here, we investigated whether drug sensitivity quantified in ex vivo patients' blood-derived cell lines can predict response to capecitabine in vivo. Lymphoblastoid cell lines (LCLs) were established from a cohort of metastatic breast cancer patients (n = 53) who were prospectively monitored during treatment with single agent capecitabine at 2000 mg/m2/day. LCLs were treated with increasing concentrations of 5'-DFUR, a major capecitabine metabolite, to assess patients' ex vivo sensitivity to this drug. Subsequently, ex vivo phenotype was compared to observed patient disease response and drug induced-toxicities. We acquired an independent cohort of breast cancer cell lines and LCLs derived from the same donors from ATCC, compared their sensitivity to 5'-DFUR. As seen in the patient population, we observed large inter-individual variability in response to 5'-DFUR treatment in patient-derived LCLs. Patients whose LCLs were more sensitive to 5'-DFUR had a significantly longer median progression free survival (9-month vs 6-month, log rank p-value = 0.017). In addition, this significant positive correlation for 5'-DFUR sensitivity was replicated in an independent cohort of 8 breast cancer cell lines and LCLs derived from the same donor. Our data suggests that at least a portion of the individual sensitivity to capecitabine is shared between germline tissue and tumor tissue. It also supports the utility of patient-derived LCLs as a predictive model for capecitabine treatment efficacy in breast cancer patients

Development of grid frameworks for clinical trials and epidemiological studies

E-Health initiatives such as electronic clinical trials and epidemiological studies require access to and usage of a range of both clinical and other data sets. Such data sets are typically only available over many heterogeneous domains where a plethora of often legacy based or in-house/bespoke IT solutions exist. Considerable efforts and investments are being made across the UK to upgrade the IT infrastructures across the National Health Service (NHS) such as the National Program for IT in the NHS (NPFIT) [1]. However, it is the case that currently independent and largely non-interoperable IT solutions exist across hospitals, trusts, disease registries and GP practices – this includes security as well as more general compute and data infrastructures. Grid technology allows issues of distribution and heterogeneity to be overcome, however the clinical trials domain places special demands on security and data which hitherto the Grid community have not satisfactorily addressed. These challenges are often common across many studies and trials hence the development of a re-usable framework for creation and subsequent management of such infrastructures is highly desirable. In this paper we present the challenges in developing such a framework and outline initial scenarios and prototypes developed within the MRC funded Virtual Organisations for Trials and Epidemiological Studies (VOTES) project [2]

Initial experiences in developing e-health solutions across Scotland

The MRC funded Virtual Organisations for Trials and Epidemiological Studies (VOTES) project is a collaborative effort between e-Science, clinical and ethical research centres across the UK including the universities of Oxford, Glasgow, Imperial, Nottingham and Leicester. The project started in September 2005 and is due to run for 3 years. The primary goal of VOTES is to develop a reusable Grid framework through which a multitude of clinical trials and epidemiological studies can be supported. The National e-Science Centre (NeSC) at the University of Glasgow are looking at developing the Scottish components of this framework. This paper presents the initial experiences in developing this framework and in accessing and using existing data sets, services and software across the NHS in Scotland

Economic burden of adverse drug reactions and potential for pharmacogenomic testing in Singaporean adults.

Adverse drug reactions (ADRs) contribute to hospitalization but data on its economic burden is scant. Pre-emptive pharmacogenetic (PGx) testing can potentially reduce ADRs and its associated costs. The objectives of this study were to quantify the economic burden of ADRs and to estimate the breakeven cost of pre-emptive PGx testing in Singapore. We collected itemized costs for 1000 random non-elective hospitalizations of adults admitted to a tertiary-care general hospital in Singapore. The presence of ADRs at admission and their clinical characteristics were reported previously. The economic burden of ADRs was assessed from two perspectives: (1) Total cost and (2) incremental costs. The breakeven cost of PGx testing was estimated by dividing avoidable hospitalization costs for ADRs due to selected drugs by the number of patients taking those drugs. The total cost of 81 admissions caused by ADRs was US$570,404. Costs were significantly higher for bleeding/elevated international normalized ratio (US$9906 vs. US$2251, p = 6.58 × 10-3) compared to other ADRs, and for drugs acting on the blood coagulation system (US$9884 vs. US$2229, p = 4.41 × 10-3) compared to other drug classes. There were higher incremental laboratory costs due to ADRs causing or being present at admission. The estimated breakeven cost of a pre-emptive PGx test for patients taking warfarin, clopidogrel, chemotherapeutic and neuropsychiatric drugs was US$114 per patient. These results suggest that future studies designed to directly measure the clinical and cost impact of a pre-emptive genotyping program will help inform clinical practice and health policy decisions

Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington's disease patients.

Quantification of disease-associated proteins in the cerebrospinal fluid (CSF) has been critical for the study and treatment of several neurodegenerative disorders; however, mutant huntingtin protein (mHTT), the cause of Huntington's disease (HD), is at very low levels in CSF and, to our knowledge, has never been measured previously

A cluster randomised controlled trial of a pharmacist-led collaborative intervention to improve statin prescribing and attainment of cholesterol targets in primary care

Background: Small trials with short term follow up suggest pharmacists’ interventions targeted at healthcare professionals can improve prescribing. In comparison with clinical guidance, contemporary statin prescribing is sub-optimal and achievement of cholesterol targets falls short of accepted standards, for patients with atherosclerotic vascular disease who are at highest absolute risk and who stand to obtain greatest benefit. We hypothesised that a pharmacist-led complex intervention delivered to doctors and nurses in primary care, would improve statin prescribing and achievement of cholesterol targets for incident and prevalent patients with vascular disease, beyond one year.<p></p> Methods: We allocated general practices to a 12-month Statin Outreach Support (SOS) intervention or usual care. SOS was delivered by one of 11 pharmacists who had received additional training. SOS comprised academic detailing and practical support to identify patients with vascular disease who were not prescribed a statin at optimal dose or did not have cholesterol at target, followed by individualised recommendations for changes to management. The primary outcome was the proportion of patients achieving cholesterol targets. Secondary outcomes were: the proportion of patients prescribed simvastatin 40 mg with target cholesterol achieved; cholesterol levels; prescribing of simvastatin 40 mg; prescribing of any statin and the proportion of patients with cholesterol tested. Outcomes were assessed after an average of 1.7 years (range 1.4–2.2 years), and practice level simvastatin 40 mg prescribing was assessed after 10 years.<p></p> Findings: We randomised 31 practices (72 General Practitioners (GPs), 40 nurses). Prior to randomisation a subset of eligible patients were identified to characterise practices; 40% had cholesterol levels below the target threshold. Improvements in data collection procedures allowed identification of all eligible patients (n = 7586) at follow up. Patients in practices allocated to SOS were significantly more likely to have cholesterol at target (69.5% vs 63.5%; OR 1.11, CI 1.00–1.23; p = 0.043) as a result of improved simvastatin prescribing. Subgroup analysis showed the primary outcome was achieved by prevalent but not incident patients. Statistically significant improvements occurred in all secondary outcomes for prevalent patients and all but one secondary outcome (the proportion of patients with cholesterol tested) for incident patients. SOS practices prescribed more simvastatin 40 mg than usual care practices, up to 10 years later.<p></p> Interpretation: Through a combination of educational and organisational support, a general practice based pharmacist led collaborative intervention can improve statin prescribing and achievement of cholesterol targets in a high-risk primary care based population

Factor VIIa administration in traumatic brain injury: an AAST-MITC propensity score analysis.

Background:Recombinant factor VIIa (rFVIIa) has been used off-label as an adjunct in the reversal of warfarin therapy and management of hemorrhage after trauma. Only a handful of these reports are rigorous studies, from which results regarding safety and effectiveness have been mixed. There remains no clear consensus as to the role of rFVIIa in traumatic brain injury (TBI). Methods:Eleven level 1 trauma centers provided clinical data and head CT scans of patients with a Glasgow Coma Scale (GCS) score of ≤13 and radiographic evidence of TBI. A propensity score (PS) to receive rFVIIa in those surviving ≥2 days was calculated for each patient based on patient demographics, comorbidities, physiology, Injury Severity Score, admission GCS score, and treatment center. Patients receiving rFVIIa within 24 hours of admission were matched to patients who did not receive rFVIIa for outcomes assessment. Subgroup analysis evaluated patients with primary head injury with PS matching. Results:There were 4284 patient observations; 129 received rFVIIa. Groups were comparable after matching. No differences in mortality or morbidity were found. Improvement in GCS score from admission to discharge was less among those receiving rFVIIa (5.5 vs. 2.4; P value 0.001); however, there was no difference in average GCS score at discharge. No significant differences in outcomes were identified in patients with isolated TBI receiving rFVIIa. Discussion:rFVIIa in early management of TBI is not associated with a decreased risk of mortality or morbidity, and may negatively impact recovery and functional status at discharge in the severely injured patient with polytrauma. Level of evidence:Level III. Study type:Therapeutic/care management

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types