Neutral tumor evolution?

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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

Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Impact of Perioperative Dexamethasone on Hospital Length of Stay and Glycemic Control in Patients With Type 2 Diabetes Undergoing Total Hip Arthroplasty

Purpose: This study aimed to evaluate effects of perioperative dexamethasone on hospital length of stay (LOS) and glycemic control for patients with type 2 diabetes mellitus undergoing total hip arthroplasty (THA). Methods: We performed retrospective case review of THA performed in adults (≥ 18 years old) with type 2 diabetes at Springfield Memorial Hospital (Springfield, IL) immediately before (2013), during (2014), and after (2015) publication of consensus guidelines for use of perioperative dexamethasone. Hospital LOS was the primary endpoint. Capillary blood glucose by hospital day, proportion of patients treated with insulin, and median insulin dose by hospital day were secondary endpoints. Results: A total of 209 patients were included: 109 not dosed with dexamethasone (“no dexamethasone”), and 100 treated with perioperative dexamethasone. The most common dose of dexamethasone was 4 mg (63% of patients). Mean (95% CI) reduction in adjusted hospital LOS for dexamethasone-treated patients, compared to controls, was -2.8 (-3.7 to -1.9) days for all patients, -1.6 (-2.7 to -0.5) days for those with arthritis as the indication for THA, and -4.0 (-5.9 to -2.1) days for those with fracture as indication for THA (P \u3c 0.001 for all). Glycemic control measured by median capillary blood glucose was no different or slightly better in the dexamethasone group than the no dexamethasone group, except for postoperative day 1 among patients treated with insulin prior to surgery. Conclusions: Perioperative dexamethasone significantly reduces hospital LOS for patients with type 2 diabetes undergoing THA, with modest effects on hyperglycemia

Salivary stones and stenosis. A comprehensive classification

INTRODUCTION: Sialendoscopy and sialoMRI enables diagnosis of salivary gland obstructive pathologies, such as lithiasis, stenosis, and dilatations. Therefore, a classification of these pathologies is needed, allowing large series comparisons, for better diagnosis and treatment of salivary pathologies. MATERIAL AND METHODS: With help from people from the European Sialendoscopy Training Center (ESTC), the results of sialographies, sialoMRI and sialendoscopies, a comprehensive classification of obstructive salivary pathologies is described, based on the absence or presence of lithiasis (L), stenosis (S), and dilatation (D) ("LSD" classification). DISCUSSION: It appears that a classification of salivary gland obstructive pathologies should be described. We hope it will be widely used and of course criticized to be improved and to compare the results of salivary gland diagnostic methods, such as sialography and sialendoscopy, and also the results and indications for salivary gland therapeutic methods, such as lithotripsy, sialendoscopy, and/or open surgery

International Survey of Operative Practices for Otologists and Neurotologists during the COVID-19 Crisis

Objective:To investigate the influence of the COVID-19 pandemic on operative practices of otology and neurotology providers internationally.Study Design:Cross-sectional survey.Methods:A 78-question survey was distributed to otologists and neurotologists between May 12, 2020 and June 8, 2020 to assess the impact of the pandemic on surgical practices. Sections within the survey delineated time periods: prior to the crisis, onset of the crisis, during the crisis, postcrisis transition.Results:Of 396 survey respondents, 284 participants from 38 countries met inclusion criteria.Respondents were 16.9% female and 82.4% male, with a most common age range of 40 to 49 years (36.3%). 69.8% of participants had been in practice for over 10 years and most respondents worked in an academic medical center (79.2%). The average operative weekly caseload was 5.3 (SD 3.9) per surgeon prior to the crisis, 0.7 (SD 1.2) during the COVID-19 crisis, and 3.5 (SD 3.3) for those who had begun a postcrisis transition at the time of survey administration (p &lt; 0.001). 71.5% of providers did not perform an elective otologic or neurotologic operative procedure during the initial crisis period. 49.8% reported modifying their surgical technique due to the COVID-19 pandemic. Use of powered air-purifying respirators and filtering facepiece 2 or 3 (FFP2/FFP3) respirators were in minimal supply for 66.9% and 62.3% of respondents, respectively.Conclusion:The COVID-19 pandemic impacted the otology and neurotology community globally, resulting in significant changes in operative volume and case selection. Modification of surgical technique and shortages of personal protective equipment were frequently reported