Bayesian clinical trial designs : Another option for trauma trials?

The UK-REBOA Trial is funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (project number 14/199/09). PP was supported by the MRC Network of Hubs for Trials Methodology Research (MR/L004933/1-R/N/P/B1).Peer reviewedPublisher PD

Cell-free DNA mutations as biomarkers in breast cancer patients receiving tamoxifen

The aim was to identify mutations in serum cell-free DNA (cfDNA) associated with disease progression on tamoxifen treatment in metastatic breast cancer (MBC). Sera available at start of therapy, during therapy and at disease progression were selected from 10 estrogen receptor (ER)-positive breast cancer patients. DNA from primary tumor and normal tissue and cfDNA from minute amounts of sera were analyzed by targeted next generation sequencing (NGS) of 45 genes (1,242 exons). At disease progression, stop-gain single nucleotide variants (SNVs) for CREBBP (1 patient) and SMAD4 (1 patient) and non-synonymous SNVs for AKAP9 (1 patient), PIK3CA (2 patients) and TP53 (2 patients) were found. Mutations in CREBBP and SMAD4 have only been occasionally reported in breast cancer. All mutations, except for AKAP9, were also present in the primary tumor but not detected in all blood specimens preceding progression. More sensitive detection by deeper re-sequencing and digital PCR confirmed the occurrence of circulating tumor DNA (ctDNA) and these biomarkers in blood specimens

Maximizing geographical efficiency : An analysis of the configuration of Colorado’s trauma system

ACKNOWLEDGEMENT The data used for this study were supplied by the Health Facilities and Emergency Medical Services Division of the Colorado Department of Public Health and Environment, which specifically disclaims responsibility for any analyses, interpretations, or conclusions it has not provided. The data used for this study were supplied by the Health Facilities and Emergency Medical Services Division of the Colorado Department of Public Health and Environment, which specifically disclaims responsibility for any analyses, interpretations, or conclusions it has not provided.Peer reviewedPostprin

Behavioural optimisation to address trial conduct challenges : case study in the UK-REBOA trial

Acknowledgements We thank the UK-REBOA site staf for dedicating their time to be interviewedPeer reviewedPublisher PD

Cell-free DNA mutations as biomarkers in breast cancer patients receiving tamoxifen

The aim was to identify mutations in serum cell-free DNA (cfDNA) associated with disease progression on tamoxifen treatment in metastatic breast cancer (MBC). Sera available at start of therapy, during therapy and at disease progression were selected from 10 estrogen receptor (ER)-positive breast cancer patients. DNA from primary tumor and normal tissue and cfDNA from minute amounts of sera were analyzed by targeted next generation sequencing (NGS) of 45 genes (1,242 exons). At disease progression, stop-gain single nucleotide variants (SNVs) for CREBBP (1 patient) and SMAD4 (1 patient) and non-synonymous SNVs for AKAP9 (1 patient), PIK3CA (2 patients) and TP53 (2 patients) were found. Mutations in CREBBP and SMAD4 have only been occasionally reported in breast cancer. All mutations, except for AKAP9, were also present in the primary tumor but not detected in all blood specimens preceding progression. More sensitive detection by deeper re-sequencing and digital PCR confirmed the occurrence of circulating tumor DNA (ctDNA) and these biomarkers in blood specimens

The Constancy of the Constants of Nature: Updates

The current observational and experimental bounds on the time variation of the constants of nature (the fine structure constant $\alpha$, the gravitational constant $G$ and the proton-electron mass ratio $\mu=m_p/m_e$) are reviewed.Comment: 27 pages, 2 figures, to be published in Prog.Theor.Phys, ref. adde

Somatic tumor mutations detected by targeted next generation sequencing in minute amounts of serum-derived cell-free DNA

The use of blood-circulating cell-free DNA (cfDNA) as 'liquid-biopsy' is explored worldwide, with hopes for its potential in providing prognostic or predictive information in cancer treatment. In exploring cfDNA, valuable repositories are biobanks containing material collected over time, however these retrospective cohorts have restrictive resources. In this study, we aimed to detect tumor-specific mutations in only minute amounts of serum-derived cfDNA by using a targeted next generation sequencing (NGS) approach. In a retrospective cohort of ten metastatic breast cancer patients, we profiled DNA from primary tumor tissue (frozen), tumor-adjacent normal tissue (formalin-fixed paraffin embedded), and three consecutive serum samples (frozen). Our presented workflow includes comparisons with matched normal DNA or in silico reference DNA to discriminate germline from somatic variants, validation of variants through the detection in at least two DNA samples of an individual, and the use of public databases on variants. By our workflow, we were able to detect a total of four variants traceable as circulating tumor DNA (ctDNA) in the sera of three of the ten patients

The effectiveness and cost-effectiveness of resuscitative endovascular balloon occlusion of the aorta (REBOA) for trauma patients with uncontrolled torso haemorrhage : study protocol for a randomised clinical trial (the UK-REBOA trial)

Acknowledgements The UK-REBOA trial grantholders include Jan O. Jansen, University of Aberdeen, UK, and University of Alabama at Birmingham, USA; Marion K. Campbell, University of Aberdeen, UK; Chris Moran, Nottingham University Hospital Trust, UK; Karim Brohi, Queen Mary University of London, UK; Fiona Lecky, University of Sheffield, UK; Robbie Lendrum, Bart’s Health NHS Trust, UK; Graeme MacLennan, University of Aberdeen, UK; Jonathan J. Morrison, University of Maryland, USA; Nigel Tai, Academic Department of Military Surgery and Trauma, Royal Centre for Defence Medicine, UK; Tim Harris, Bart’s Health NHS Trust, UK; John Norrie, University of Edinburgh, UK; Dwayne Boyers, University of Aberdeen, UK; Alan Paterson, University of Strathclyde, UK; and Nick Welch. Funding {4} This study/project is funded by the National Institute for Health Research (NIHR) HTA Programme (reference 14/199/09). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The funder has/had no role in the design of the study; the collection, analysis, and interpretation of data; or writing the manuscript. The Health Services Research Unit, Institute of Applied Health Sciences (University of Aberdeen), is core-funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates.Peer reviewedPublisher PD

Mutation Analysis of Pancreatic Juice and Plasma for the Detection of Pancreatic Cancer

Molecular profiling may enable earlier detection of pancreatic cancer (PC) in high-risk individuals undergoing surveillance and allow for personalization of treatment. We hypothesized that the detection rate of DNA mutations is higher in pancreatic juice (PJ) than in plasma due to its closer contact with the pancreatic ductal system, from which pancreatic cancer cells originate, and higher overall cell-free DNA (cfDNA) concentrations. In this study, we included patients with pathology-proven PC or intraductal papillary mucinous neoplasm (IPMN) with high-grade dysplasia (HGD) from two prospective clinical trials (KRASPanc and PACYFIC) for whom both PJ and plasma were available. We performed next-generation sequencing on PJ, plasma, and tissue samples and described the presence (and concordance) of mutations in these biomaterials. This study included 26 patients (25 PC and 1 IPMN with HGD), of which 7 were women (27%), with a median age of 71 years (IQR 12) and a median BMI of 23 kg/m2 (IQR 4). Ten patients with PC (40%) were (borderline) resectable at baseline. Tissue was available from six patients (resection n = 5, biopsy n = 1). A median volume of 2.9 mL plasma (IQR 1.0 mL) and 0.7 mL PJ (IQR 0.1 mL, p &lt; 0.001) was used for DNA isolation. PJ had a higher median cfDNA concentration (2.6 ng/μL (IQR 4.2)) than plasma (0.29 ng/μL (IQR 0.40)). A total of 41 unique somatic mutations were detected: 24 mutations in plasma (2 KRAS, 15 TP53, 2 SMAD4, 3 CDKN2A 1 CTNNB1, and 1 PIK3CA), 19 in PJ (3 KRAS, 15 TP53, and 1 SMAD4), and 8 in tissue (2 KRAS, 2 CDKN2A, and 4 TP53). The mutation detection rate (and the concordance with tissue) did not differ between plasma and PJ. In conclusion, while the concentration of cfDNA was indeed higher in PJ than in plasma, the mutation detection rate was not different. A few cancer-associated genetic variants were detected in both biomaterials. Further research is needed to increase the detection rate and assess the performance and suitability of plasma and PJ for PC (early) detection.</p