Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Trends in the Use of Feeding Tubes in North Carolina Hospitals: 1989 to 2000

OBJECTIVE: National data describing the placement of feeding tubes demonstrated a rapid increase in use in the early and mid-1990s. In the past several years, substantial concerns have arisen regarding the appropriateness of the procedure in many chronically ill patients. The purpose of this study is to determine whether the use of feeding tubes has continued to increase through the 1990s despite these widely publicized concerns. DESIGN: Repeated measure cross-sectional study of the North Carolina Discharge Database. SETTING: Analyses of all nonfederal hospital inpatient admissions in North Carolina. MEASUREMENTS AND MAIN RESULTS: We examined the absolute numbers and rates of feeding tube placements from 1989 to 2000. The rate of feeding tube placement increased from 59/100,000 persons in 1989 to 94/100,000 persons in 2000, an overall 60% increase with slowing in the rate of increase in the late 1990s. However, when outpatient procedures were included, the increase in tube feeding continued throughout the 11-year period of observation. The increase was due to an increase in utilization within all hospitals over the time period. Utilization did not differ between profit and not for profit hospitals. The relative growth rate of inpatient feeding tube placement did not differ by age group but the absolute increase was greatest in those age 75 years and over. CONCLUSIONS: Our study demonstrates that the use of feeding tubes has continued to increase through the 1990s. This increase occurred despite ongoing controversy in the medical literature about feeding tube placement in chronically ill patients

Cerebral arterial fenestrations : a common phenomenon in unexplained subarachnoid haemorrhage

BACKGROUND Fenestrations of intracranial arteries are variants resulting from incomplete fusion of vessels during development with unknown clinical significance. They are best visualised with 3D rotational angiography (3DRA). OBJECTIVE In a prospective consecutive series of patients with suspected aneurysms, 3DRA was performed to identify not only the potential bleeding source but also to assess the frequency and location of any fenestrations of intracranial arteries. METHODS In 287 consecutive patients with possible intracranial aneurysms (accidental discovery or previous history of SAH), 3DRAs were prospectively performed, and the location of subarachnoid haemorrhage was assessed by CT. RESULTS Of 174 patients presenting with SAH, 153 had saccular aneurysms, and in 21 cases (12.1 %), no source of bleeding was found. In 20 of these 21 patients with "unexplained SAH" (95.2 %) an arterial fenestration was detected in the neighbourhood of the clot. The incidence of fenestration in the 153 aneurysmal SAH patients was 22.9 %, and it was 23.3 % in 266 patients with intracranial aneurysms (113 accidental and 153 ruptured). CONCLUSIONS Arterial fenestration was detected in 22.9 % of ruptured cerebral aneurysms, in contrast with 95.2 % in patients with unexplained SAH, the difference being statisctically significant (p < 0.01). Fenestration is a developmental defect, a structural wall weakness possibly making the vessel prone to rupture. Its incidence of nearly 100 % may suggest a connection with idiopathic SAH. The presented data indicate that arterial fenestrations are generally overlooked, and they can be considered as one of the candidates for the source of idiopathic SAH