No abstract

Highlights d Representative sequencing (Rep-Seq) is a new method for tumor molecular profiling d Rep-Seq homogenizes residual tumor tissue not taken for standard pathology d Representative sampling of tumors generates accurate tumor mutation burden scores d Rep-Seq detects more mutations and accurately resolves clonal from subclonal variants

We reviewed the literature for the impact of service delivery initiatives (SDIs) on patients' waiting times within radiology departments. We searched MEDLINE, EMBASE, CINAHL, INSPEC and The Cochrane Library for relevant articles published between 1995 and February, 2013. The Cochrane EPOC risk of bias tool was used to assess the risk of bias on studies that met specified design criteria. Fifty-seven studies met the inclusion criteria. The types of SDI implemented included extended scope practice (ESP, three studies), quality management (12 studies), productivity-enhancing technologies (PETs, 29 studies), multiple interventions (11 studies), outsourcing and pay-for-performance (one study each). The uncontrolled pre-and post-intervention and the postintervention designs were used in 54 (95 %) of the studies. The reporting quality was poor: many of the studies did not test and/or report the statistical significance of their results. The studies were highly heterogeneous, therefore metaanalysis was inappropriate. The following type of SDIs showed promising results: extended scope practice; quality management methodologies including Six Sigma, Lean methodology, and continuous quality improvement; productivityenhancing technologies including speech recognition reporting, teleradiology and computerised physician order entry systems. We have suggested improved study design and the mapping of the definitions of patient waiting times in radiology to generic timelines as a starting point for moving towards a situation where it becomes less restrictive to compare and/or pool the results of future studies in a meta-analysis.

Sequencing of cell-free DNA (cfDNA) in cancer patients’ plasma offers a minimally-invasive solution to detect tumor cell genomic alterations to aid real-time clinical decision-making. The reliability of copy number detection decreases at lower cfDNA tumor fractions, limiting utility at earlier stages of the disease. To test a novel strategy for detection of allelic imbalance, we developed a prostate cancer bespoke assay, PCF_SELECT, that includes an innovative sequencing panel covering ∼25 000 high minor allele frequency SNPs and tailored analytical solutions to enable allele-informed evaluation. First, we assessed it on plasma samples from 50 advanced prostate cancer patients. We then confirmed improved detection of genomic alterations in samples with <10% tumor fractions when compared against an independent assay. Finally, we applied PCF_SELECT to serial plasma samples intensively collected from three patients previously characterized as harboring alterations involving DNA repair genes and consequently offered PARP inhibition. We identified more extensive pan-genome allelic imbalance than previously recognized in prostate cancer. We confirmed high sensitivity detection of BRCA2 allelic imbalance with decreasing tumor fractions resultant from treatment and identified complex ATM genomic states that may be incongruent with protein losses. Overall, we present a framework for sensitive detection of allele-specific copy number changes in cfDNA.

Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient evolutionary relationships of metastases that evade treatment, we perform genome-wide copy number profiling and bespoke approaches targeting the androgen receptor (AR) on 167 metastatic regions from 11 organs harvested post-mortem from 10 men who died from prostate cancer. We identify diverse and patient-unique alterations clustering around the AR in metastases from every patient with evidence of independent acquisition of related genomic changes within an individual and, in some patients, the co-existence of AR-neutral clones. Using the genomic boundaries of pan-autosome copy number changes, we confirm a common clone of origin across metastases and diagnostic biopsies, and identified in individual patients, clusters of metastases occupied by dominant clones with diverged autosomal copy number alterations. These autosome-defined clusters are characterized by cluster-specific AR gene architectures, and in two index cases are topologically more congruent than by chance (p-values 3.07 × 10−8 and 6.4 × 10−4). Integration with anatomical sites suggests patterns of spread and points of genomic divergence. Here, we show that copy number boundaries identify treatment-selected clones with putatively distinct lethal trajectories.