Recurrent Thrombectomy in Patients with Prior Mechanical Endovascular Revascularization: A Single Center Experience

Background: Mechanical endovascular reperfusion therapy (MER) has become the standard of care for treatment of large vessel occlusion (LVO) acute ischemic strokes (AIS) with expansion of treatment window to 24 hours from LNW. Nearly 25% of all stroke patients have a recurrent event within 5 years. Intravenous alteplase use in AIS patients with recent ischemic stroke history is often restricted due to the risk of intracranial hemorrhage, however this may not apply for MER. Bouslama et al found no statistically significant differences in the reperfusion rates, hemorrhagic complications, clinical outcomes, and mortality between patients who underwent repeated thrombectomy (RT) and those who had a single thrombectomy. Methods:This was a retrospective case series study of the endovascular database for patients who underwent RT in our institution from March 2016 till March 2018. Demographic data, clinical presentation, imaging, procedural data and clinical outcomes were evaluated. Results:Of the total 145 patients with AIS that received MER, 8 (5.5%) RT occurred in 5 patients. Mean age was 67 ± 21 years. Four of the five patients were females. All five patients achieved successful reperfusion (TICI 2b-3). Three patients underwent one RT, one had two RT, and one had three RT. The average time between consecutive MER (8 total periods) was 106 days. The time between the first to last MER for each patient ranged from 3 days to 2 years. All patients were optimized on their medical therapy after the first stroke. Four of the five patients (80%) had RT in the same vascular territory. One patient had post-procedure focal high-grade stenosis after the 3rd intervention in the same artery that was treated later with elective angioplasty. One RT was complicated with fatal intracranial hemorrhage due to late presentation despite presence of large area of penumbra. 3 months MRS was 2. Conclusion: In patients presented with recurrent LVO, RT appears to be effective and relatively safe. Based on the available literature, prior MER should not discourage aggressive treatment that may potentially lead to a good clinical outcome. It is unclear if prior MER therapies cause endothelial injury leading to a predilection for local in-situ thrombus or denovo stenosis formation predisposing to re-occlusions. The risk of reperfusion injury in a recently infarcted territory should be weighted carefully when considering as hemorrhagic complications remain possible.https://scholarlycommons.henryford.com/merf2019clinres/1031/thumbnail.jp

Genomic basis for RNA alterations in cancer.

Transcript alterations often result from somatic changes in cancer genomes1. Various forms of RNA alterations have been described in cancer, including overexpression2, altered splicing3 and gene fusions4; however, it is difficult to attribute these to underlying genomic changes owing to heterogeneity among patients and tumour types, and the relatively small cohorts of patients for whom samples have been analysed by both transcriptome and whole-genome sequencing. Here we present, to our knowledge, the most comprehensive catalogue of cancer-associated gene alterations to date, obtained by characterizing tumour transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA)5. Using matched whole-genome sequencing data, we associated several categories of RNA alterations with germline and somatic DNA alterations, and identified probable genetic mechanisms. Somatic copy-number alterations were the major drivers of variations in total gene and allele-specific expression. We identified 649 associations of somatic single-nucleotide variants with gene expression in cis, of which 68.4% involved associations with flanking non-coding regions of the gene. We found 1,900 splicing alterations associated with somatic mutations, including the formation of exons within introns in proximity to Alu elements. In addition, 82% of gene fusions were associated with structural variants, including 75 of a new class, termed 'bridged' fusions, in which a third genomic location bridges two genes. We observed transcriptomic alteration signatures that differ between cancer types and have associations with variations in DNA mutational signatures. This compendium of RNA alterations in the genomic context provides a rich resource for identifying genes and mechanisms that are functionally implicated in cancer

High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations.

The impact of somatic structural variants (SVs) on gene expression in cancer is largely unknown. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data and RNA sequencing from a common set of 1220 cancer cases, we report hundreds of genes for which the presence within 100 kb of an SV breakpoint associates with altered expression. For the majority of these genes, expression increases rather than decreases with corresponding breakpoint events. Up-regulated cancer-associated genes impacted by this phenomenon include TERT, MDM2, CDK4, ERBB2, CD274, PDCD1LG2, and IGF2. TERT-associated breakpoints involve ~3% of cases, most frequently in liver biliary, melanoma, sarcoma, stomach, and kidney cancers. SVs associated with up-regulation of PD1 and PDL1 genes involve ~1% of non-amplified cases. For many genes, SVs are significantly associated with increased numbers or greater proximity of enhancer regulatory elements near the gene. DNA methylation near the promoter is often increased with nearby SV breakpoint, which may involve inactivation of repressor elements

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

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

Trends in Cerebral Large Vessel Occlusions: The Clustering of Strokes at Henry Ford Health System

Introduction: Several studies have examined trends of ischemic stroke and its association with medical, environmental, meteorological, social and economic factors in micropopulations. We investigated these factors and their association with large vessel occlusions (LVOs) that underwent mechanical thrombectomy at a certified comprehensive stroke center. Methods: A retrospective analysis was conducted of LVOs which underwent mechanical thrombectomy for reperfusion during a four-year period (2015-2018) to determine if a clustering phenomenon was present and if an association with several meteorological and social factors pertinent to the field of stroke neurology was present. Barometric pressure, temperature, dew point, humidity, and planetary A-Index were all analyzed using simple logistic regression to determine if an association was present with LVOs requiring mechanical thrombectomy for the years 2015-2018, and with all years combined. Results: 301 mechanical thrombectomies were performed during the study time period. For the year 2017, a clustering phenomenon was present with 89 (85%) of endovascular cases accusing within 48 hours of another endovascular case, as well as in 2018 with 114 (88%) of cases occurring within 48 hours of another case. No statistically significant association was observed in relation to LVOs requiring endovascular intervention and barometric pressure change, temperature, humidity, dew point, or planetary A-Index. While a slightly larger change in atmospheric pressure was observed in the 48-hour window prior to an LVO requiring endovascular intervention, these results were not statistically significant. Similarly, LVOs requiring endovascular intervention occurred more frequently during a 48-hour window of elevated planetary A-Index but these results were not consistent over the study time period. There was a significant increase in the number of mechanical thrombectomies performed after the early results of both the DAWN trial and DEFUSE-3 trial were published. Conclusions: Over a four-year span, no statistically significant association between meteorological, environmental, or social factors and LVOs requiring endovascular intervention was observed. While a clustering pattern of stroke occurrence observed at our institution may be generated by an external influence, no identifiable cause/mechanism of action was discovered.https://scholarlycommons.henryford.com/merf2019clinres/1034/thumbnail.jp

Anterior Cerebral Artery: Variant Anatomy and Pathology

The anterior cerebral artery (ACA) contains anatomical variants that are closely related to its embryology and development. In this study, the authors reviewed the most commonly encountered variants of the ACA and anterior communicating artery. They also reviewed the embryological origins of these variants as well as a variety of associated pathologies. Several variants are described and highlighted with illustrations including: (1) the aberrant origin of the ACA from the internal carotid artery and its developmental association with the ophthalmic artery; (2) the persistent olfactory artery; (3) the azygous ACA; (4) the triplicated ACA; and (5) multiple anterior communicating arteries. The formation of aneurysms is associated with such variants, thus their knowledge and the embryology behind their development are crucial to prevent injury to the patient