Showing papers by "Mayo Clinic published in 2020"
TL;DR: This year's edition of the Statistical Update includes data on the monitoring and benefits of cardiovascular health in the population, metrics to assess and monitor healthy diets, an enhanced focus on social determinants of health, a focus on the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors, implementation strategies, and implications of the American Heart Association’s 2020 Impact Goals.
Abstract: Background: The American Heart Association, in conjunction with the National Institutes of Health, annually reports on the most up-to-date statistics related to heart disease, stroke, and cardiovas...
5,078 citations
Turku University Hospital1, National University of Ireland, Galway2, University of Catania3, University of Naples Federico II4, University of Paris5, Bispebjerg Hospital6, University of Sheffield7, University of Cambridge8, Stavanger University Hospital9, Oslo University Hospital10, Hospital Clínico San Carlos11, Mayo Clinic12, University of Western Brittany13, Rabin Medical Center14, Slovak Medical University15, Saarland University16, University of Barcelona17, University of Brescia18, University of Bern19, University of Erlangen-Nuremberg20, Leiden University Medical Center21
TL;DR: In this article, the authors present guidelines for the management of patients with coronary artery disease (CAD), which is a pathological process characterized by atherosclerotic plaque accumulation in the epicardial arteries.
Abstract: Coronary artery disease (CAD) is a pathological process characterized by atherosclerotic plaque accumulation in the epicardial arteries, whether obstructive or non-obstructive. This process can be modified by lifestyle adjustments, pharmacological therapies, and invasive interventions designed to achieve disease stabilization or regression. The disease can have long, stable periods but can also become unstable at any time, typically due to an acute atherothrombotic event caused by plaque rupture or erosion. However, the disease is chronic, most often progressive, and hence serious, even in clinically apparently silent periods. The dynamic nature of the CAD process results in various clinical presentations, which can be conveniently categorized as either acute coronary syndromes (ACS) or chronic coronary syndromes (CCS). The Guidelines presented here refer to the management of patients with CCS. The natural history of CCS is illustrated in Figure 1.
3,448 citations
University of Washington1, National Institutes of Health2, Institute for Health Metrics and Evaluation3, Sapienza University of Rome4, Mayo Clinic5, FIU Herbert Wertheim College of Medicine6, Cincinnati Children's Hospital Medical Center7, Boston University8, Essentia Health9, University of Douala10, University of British Columbia11, Medical University of Graz12, Telethon Institute for Child Health Research13, University of Milan14, Cedars-Sinai Medical Center15, Johns Hopkins University16, University of California, San Diego17, University of Michigan18, University of Edinburgh19, University of Texas Southwestern Medical Center20, Queen Mary University of London21, University of Alabama at Birmingham22, Harvard University23, Tufts Medical Center24, All India Institute of Medical Sciences25, Northwestern University26, University of Kentucky27, Casa Sollievo della Sofferenza28, Columbia University29, Icahn School of Medicine at Mount Sinai30, University of Sydney31, University of Cape Town32, Federal University of Rio de Janeiro33, University of Ibadan34, Case Western Reserve University35, Stanford University36, Universidade Federal de Minas Gerais37, The George Institute for Global Health38, Uppsala University39, Dresden University of Technology40, King Fahd Medical City41, Tulane University42, Imperial College London43
TL;DR: CVD burden continues its decades-long rise for almost all countries outside high-income countries, and alarmingly, the age-standardized rate of CVD has begun to rise in some locations where it was previously declining in high- income countries.
3,315 citations
Christopher J L Murray1, Christopher J L Murray2, Christopher J L Murray3, Aleksandr Y. Aravkin2 +2269 more•Institutions (286)
TL;DR: The largest declines in risk exposure from 2010 to 2019 were among a set of risks that are strongly linked to social and economic development, including household air pollution; unsafe water, sanitation, and handwashing; and child growth failure.
3,059 citations
TL;DR: The extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 are reviewed to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.
Abstract: Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.
2,113 citations
TL;DR: The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.
Abstract: Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1,2,3. 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 promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10,11,12,13,14,15,16,17,18.
1,600 citations
TL;DR: The outcomes of a cohort of patients with cancer and COVID-19 are characterised and potential prognostic factors for mortality and severe illness are identified and race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality.
1,344 citations
Stanford University1, New York University2, Duke University3, Boston University4, Saint Louis University5, Imperial College London6, Northwick Park Hospital7, Hospital Universitario La Paz8, Durham University9, NewYork–Presbyterian Hospital10, Albany Medical College11, St. Michael's Hospital12, Montreal Heart Institute13, Auckland City Hospital14, All India Institute of Medical Sciences15, University of British Columbia16, Cedars-Sinai Medical Center17, Harvard University18, Brigham and Women's Hospital19, Saint Francis University20, Columbia University Medical Center21, University of Missouri–Kansas City22, Government Medical College, Thiruvananthapuram23, Sri Jayadeva Institute of Cardiovascular Sciences and Research24, University of São Paulo25, Emory University26, Veterans Health Administration27, Mayo Clinic28, Semmelweis University29, Flinders Medical Centre30, Université Paris-Saclay31, Uppsala University32, Uppsala University Hospital33, Keio University34, National Institutes of Health35, Vanderbilt University36, East Carolina University37, Icahn School of Medicine at Mount Sinai38
TL;DR: Evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years is not found.
Abstract: Background Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical ther...
1,324 citations
Université Paris-Saclay1, City of Hope National Medical Center2, Institute of Cancer Research3, Ohio State University4, Sheba Medical Center5, Kindai University6, Yonsei University7, University of Chicago8, McGill University9, University of Bordeaux10, University of Texas MD Anderson Cancer Center11, Mayo Clinic12, Foundation Medicine13, Merck & Co.14, New Generation University College15
TL;DR: The association of high tissue TMB (tTMB-high) with outcomes in ten tumour-type-specific cohorts from the phase 2 KEYNOTE-158 study, which assessed the anti-PD-1 monoclonal antibody pembrolizumab in patients with selected, previously treated, advanced solid tumours, was prospectively explored.
Abstract: Summary Background Tumour mutational burden (TMB) has been retrospectively correlated with response to immune checkpoint blockade. We prospectively explored the association of high tissue TMB (tTMB-high) with outcomes in ten tumour-type-specific cohorts from the phase 2 KEYNOTE-158 study, which assessed the anti-PD-1 monoclonal antibody pembrolizumab in patients with selected, previously treated, advanced solid tumours. Methods In the multi-cohort, open-label, non-randomised, phase 2 KEYNOTE-158 study, patients were enrolled from 81 academic facilities and community-based institutions across 21 countries in Africa, the Americas, Asia, and Europe. Eligible patients were aged 18 years or older, had a histologically or cytologically confirmed advanced (ie, unresectable or metastatic, or both) incurable solid tumour (eligible tumour types were anal, biliary, cervical, endometrial, mesothelioma, neuroendocrine, salivary, small-cell lung, thyroid, and vulvar), progression on or intolerance to one or more lines of standard therapy, had measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) assessed by independent central radiological review, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, adequate organ function, and a tumour sample for biomarker analysis. Participants were given pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. Tissue TMB (tTMB) was assessed in formalin-fixed paraffin-embedded tumour samples using the FoundationOne CDx assay (Foundation Medicine, Cambridge, MA, USA). The prespecified definition of tTMB-high status was at least 10 mutations per megabase. The primary endpoint was the proportion of patients with an objective response (complete or partial response) as per Response Evaluation Criteria in Solid Tumours (version 1.1) by independent central review. This prespecified analysis assessed the association between antitumour activity and tTMB in treated patients with evaluable tTMB data. Efficacy was assessed in all participants who received at least one dose of pembrolizumab, had evaluable tTMB data, and were enrolled at least 26 weeks before data cutoff (June 27, 2019), and safety was assessed in all participants who received at least one dose of pembrolizumab and had tTMB-high status. KEYNOTE-158 is registered at ClinicalTrials.gov, NCT02628067, and is ongoing. Findings Between Jan 15, 2016, and June 25, 2019, 1073 patients were enrolled. 1066 participants were treated as of data cutoff (June 27, 2019), of whom 805 (76%) were evaluable for TMB, and 105 (13%) of 805 had tTMB-high status and were assessed for safety. 1050 (98%) of 1066 patients enrolled by at least 26 weeks before data cutoff, of whom 790 (75%) were evaluable for TMB and included in efficacy analyses. 102 (13%) of these 790 patients had tTMB-high status (≥10 mutations per megabase), and 688 (87%) patients had non-tTMB-high status ( Interpretation tTMB-high status identifies a subgroup of patients who could have a robust tumour response to pembrolizumab monotherapy. tTMB could be a novel and useful predictive biomarker for response to pembrolizumab monotherapy in patients with previously treated recurrent or metastatic advanced solid tumours. Funding Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.
1,124 citations
Northwestern University1, Seattle Cancer Care Alliance2, Case Western Reserve University3, Washington University in St. Louis4, Ohio State University5, Stanford University6, University of California, San Diego7, Brigham and Women's Hospital8, Memorial Sloan Kettering Cancer Center9, University of Colorado Boulder10, University of Texas MD Anderson Cancer Center11, Mayo Clinic12, Fox Chase Cancer Center13, Harvard University14, Duke University15, University of Pennsylvania16, Vanderbilt University17, Yale University18, City of Hope National Medical Center19, University of Wisconsin-Madison20, University of Michigan21, University of California, San Francisco22, Johns Hopkins University23, University of South Florida24, University of Alabama at Birmingham25, University of Utah26, Roswell Park Cancer Institute27, National Comprehensive Cancer Network28
TL;DR: The NCCN Guidelines specific to the workup and treatment of patients with recurrent/stage IV breast cancer are discussed in this article.
Abstract: This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer focuses on the clinical presentation and workup of suspected bladder cancer, treatment of non-muscle-invasive urothelial bladder cancer, and treatment of metastatic urothelial bladder cancer because important updates have recently been made to these sections. Some important updates include recommendations for optimal treatment of non-muscle-invasive bladder cancer in the event of a bacillus Calmette-Guerin (BCG) shortage and details about biomarker testing for advanced or metastatic disease. The systemic therapy recommendations for second-line or subsequent therapies have also been revised. Treatment and management of muscle-invasive, nonmetastatic disease is covered in the complete version of the NCCN Guidelines for Bladder Cancer available at NCCN.org. Additional topics covered in the complete version include treatment of nonurothelial histologies and recommendations for nonbladder urinary tract cancers such as upper tract urothelial carcinoma, urothelial carcinoma of the prostate, and primary carcinoma of the urethra.
1,018 citations
Ikerbasque1, University of the Basque Country2, Carlos III Health Institute3, University of Salamanca4, University of Manchester5, National Health Service6, Imperial College London7, Mayo Clinic8, Sapienza University of Rome9, University of Copenhagen10, University of Glasgow11, University of Regensburg12, University of Padua13, Yale University14, University of Edinburgh15, University of Minnesota16, Marche Polytechnic University17, University of Rennes18, University of Paris19, University of Florence20, University of Milano-Bicocca21, University of Zurich22, Erasmus University Rotterdam23, University of Barcelona24
TL;DR: This expert Consensus Statement, endorsed by the ENS-CCA, summarizes the latest advances in CCA, including classification, genetics and treatment, and provides recommendations for CCA management and priorities across basic, translational and clinical research.
Abstract: Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly The current diagnosis of CCA by non-invasive approaches is not accurate enough, and histological confirmation is necessary Furthermore, the high heterogeneity of CCAs at the genomic, epigenetic and molecular levels severely compromises the efficacy of the available therapies In the past decade, increasing efforts have been made to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to improve patient outcomes In this expert Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we aim to summarize and critically discuss the latest advances in CCA, mostly focusing on classification, cells of origin, genetic and epigenetic abnormalities, molecular alterations, biomarker discovery and treatments Furthermore, the horizon of CCA for the next decade from 2020 onwards is highlighted
TL;DR: It is recommended that patients be recruited into ongoing trials, which would provide much needed evidence on the efficacy and safety of various therapies for COVID-19, given that the authors could not make a determination whether the benefits outweigh harms for most treatments.
Abstract: Background There are many pharmacologic therapies that are being used or considered for treatment of COVID-19. There is a need for frequently updated practice guidelines on their use, based on critical evaluation of rapidly emerging literature. Objective Develop evidence-based rapid guidelines intended to support patients, clinicians and other health-care professionals in their decisions about treatment and management of patients with COVID-19. Methods IDSA formed a multidisciplinary guideline panel of infectious disease clinicians, pharmacists, and methodologists with varied areas of expertise. Process followed a rapid recommendation checklist. The panel prioritized questions and outcomes. Then a systematic review of the peer-reviewed and grey literature was conducted. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of evidence and make recommendations. Results The IDSA guideline panel agreed on 7 treatment recommendations and provided narrative summaries of other treatments undergoing evaluations. Conclusions The panel expressed the overarching goal that patients be recruited into ongoing trials, which would provide much needed evidence on the efficacy and safety of various therapies for COVID-19, given that we could not make a determination whether the benefits outweigh harms for most treatments.
Joan B. Soriano1, Parkes J Kendrick2, Katherine R. Paulson2, Vinay Gupta2 +311 more•Institutions (178)
TL;DR: It is shown that chronic respiratory diseases remain a leading cause of death and disability worldwide, with growth in absolute numbers but sharp declines in several age-standardised estimators since 1990.
Memorial Sloan Kettering Cancer Center1, Cornell University2, University of Michigan3, Institut Gustave Roussy4, University of Verona5, University of Kansas6, Baylor University Medical Center7, Mayo Clinic8, Memorial Hospital of South Bend9, Johns Hopkins University School of Medicine10, Seoul National University Hospital11, Fox Chase Cancer Center12, University of Chicago13, Katholieke Universiteit Leuven14, Incyte15, Hannover Medical School16
TL;DR: These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements.
Abstract: Summary Background Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements. Methods In this multicentre, open-label, single-arm, multicohort, phase 2 study (FIGHT-202), patients aged 18 years or older with disease progression following at least one previous treatment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 recruited from 146 academic or community-based sites in the USA, Europe, the Middle East, and Asia were assigned to one of three cohorts: patients with FGFR2 fusions or rearrangements, patients with other FGF/FGFR alterations, or patients with no FGF/FGFR alterations. All enrolled patients received a starting dose of 13·5 mg oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision. The primary endpoint was the proportion of patients who achieved an objective response among those with FGFR2 fusions or rearrangements, assessed centrally in all patients who received at least one dose of pemigatinib. This study is registered with ClinicalTrials.gov , NCT02924376 , and enrolment is completed. Findings Between Jan 17, 2017, and March 22, 2019, 146 patients were enrolled: 107 with FGFR2 fusions or rearrangements, 20 with other FGF/FGFR alterations, 18 with no FGF/FGFR alterations, and one with an undetermined FGF/FGFR alteration. The median follow-up was 17·8 months (IQR 11·6–21·3). 38 (35·5% [95% CI 26·5–45·4]) patients with FGFR2 fusions or rearrangements achieved an objective response (three complete responses and 35 partial responses). Overall, hyperphosphataemia was the most common all-grade adverse event irrespective of cause (88 [60%] of 146 patients). 93 (64%) patients had a grade 3 or worse adverse event (irrespective of cause); the most frequent were hypophosphataemia (18 [12%]), arthralgia (nine [6%]), stomatitis (eight [5%]), hyponatraemia (eight [5%]), abdominal pain (seven [5%]), and fatigue (seven [5%]). 65 (45%) patients had serious adverse events; the most frequent were abdominal pain (seven [5%]), pyrexia (seven [5%]), cholangitis (five [3%]), and pleural effusion (five [3%]). Overall, 71 (49%) patients died during the study, most frequently because of disease progression (61 [42%]); no deaths were deemed to be treatment related. Interpretation These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements. Funding Incyte Corporation.
Columbia University1, Mayo Clinic2, University of Barcelona3, Université de Montréal4, University of Caen Lower Normandy5, Ludwig Maximilian University of Munich6, German Center for Neurodegenerative Diseases7, University of California, San Diego8, University of Wisconsin-Madison9, National and Kapodistrian University of Athens10, Johns Hopkins University School of Medicine11, Imperial College London12, University of Sydney13, University of Helsinki14
TL;DR: The reserve, resilience, and protective factors professional interest area established a whitepaper workgroup to develop consensus definitions for cognitive reserve, brain reserve, and brain maintenance and evaluated measures that have been used to implement these concepts in research settings and developed guidelines for research that explores or utilizes these concepts.
Abstract: Several concepts, which in the aggregate get might be used to account for "resilience" against age- and disease-related changes, have been the subject of much research. These include brain reserve, cognitive reserve, and brain maintenance. However, different investigators have use these terms in different ways, and there has never been an attempt to arrive at consensus on the definition of these concepts. Furthermore, there has been confusion regarding the measurement of these constructs and the appropriate ways to apply them to research. Therefore the reserve, resilience, and protective factors professional interest area, established under the auspices of the Alzheimer's Association, established a whitepaper workgroup to develop consensus definitions for cognitive reserve, brain reserve, and brain maintenance. The workgroup also evaluated measures that have been used to implement these concepts in research settings and developed guidelines for research that explores or utilizes these concepts. The workgroup hopes that this whitepaper will form a reference point for researchers in this area and facilitate research by supplying a common language.
TL;DR: An overview of convalescent plasma is provided, from evidence of benefit, regulatory considerations, logistical work flow and proposed clinical trials, as scale up is brought underway to mobilize this critical resource.
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has spurred a global health crisis. To date, there are no proven options for prophylaxis for those who have been exposed to SARS-CoV-2, nor therapy for those who develop COVID-19. Immune (i.e., "convalescent") plasma refers to plasma that is collected from individuals following resolution of infection and development of antibodies. Passive antibody administration through transfusion of convalescent plasma may offer the only short-term strategy for conferring immediate immunity to susceptible individuals. There are numerous examples in which convalescent plasma has been used successfully as postexposure prophylaxis and/or treatment of infectious diseases, including other outbreaks of coronaviruses (e.g., SARS-1, Middle East respiratory syndrome [MERS]). Convalescent plasma has also been used in the COVID-19 pandemic; limited data from China suggest clinical benefit, including radiological resolution, reduction in viral loads, and improved survival. Globally, blood centers have robust infrastructure for undertaking collections and constructing inventories of convalescent plasma to meet the growing demand. Nonetheless, there are nuanced challenges, both regulatory and logistical, spanning donor eligibility, donor recruitment, collections, and transfusion itself. Data from rigorously controlled clinical trials of convalescent plasma are also few, underscoring the need to evaluate its use objectively for a range of indications (e.g., prevention vs. treatment) and patient populations (e.g., age, comorbid disease). We provide an overview of convalescent plasma, including evidence of benefit, regulatory considerations, logistical work flow, and proposed clinical trials, as scale-up is brought underway to mobilize this critical resource.
TL;DR: A quantitative, evidence-based scoring framework is introduced; the implementation of the five-tier classification system widely used in sequence variant classification is encouraged; and “uncoupling” the evidence- based classification of a variant from its potential implications for a particular individual is recommended.
TL;DR: Considering the potential value of early detection in deadly malignancies, further evaluation of this test is justified in prospective population-level studies.
TL;DR: The findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer’s disease pathology, and might be a therapeutic target inAPOE4 carriers.
Abstract: Vascular contributions to dementia and Alzheimer's disease are increasingly recognized1-6. Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is an early biomarker of human cognitive dysfunction7, including the early clinical stages of Alzheimer's disease5,8-10. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer's disease11-14, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes15-19, which maintain BBB integrity20-22. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the e3/e4 or e4/e4 alleles) are distinguished from those without APOE4 (e3/e3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-β or tau pathology measured in cerebrospinal fluid or by positron emission tomography23. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRβ7,8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-β and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway19 in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer's disease pathology, and might be a therapeutic target in APOE4 carriers.
McMaster University1, Lanzhou University2, Cochrane Collaboration3, Chosun University4, Chongqing Medical University5, University of Toronto6, University of Oslo7, Norwegian Institute of Public Health8, Toronto General Hospital9, University of Western Ontario10, Hull York Medical School11, University of British Columbia12, University of Kansas13, Pontifical Catholic University of Chile14, Mayo Clinic15, Monash University16, University Health Network17, Utrecht University18
TL;DR: Glucocorticoids probably reduce mortality and mechanical ventilation in patients with covid-19 compared with standard care and the effectiveness of most interventions is uncertain because most of the randomised controlled trials so far have been small and have important study limitations.
Abstract: Objective To compare the effects of treatments for coronavirus disease 2019 (covid-19). Design Living systematic review and network meta-analysis. Data sources WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, up to 1 March 2021 and six additional Chinese databases up to 20 February 2021. Studies identified as of 12 February 2021 were included in the analysis. Study selection Randomised clinical trials in which people with suspected, probable, or confirmed covid-19 were randomised to drug treatment or to standard care or placebo. Pairs of reviewers independently screened potentially eligible articles. Methods After duplicate data abstraction, a bayesian network meta-analysis was conducted. Risk of bias of the included studies was assessed using a modification of the Cochrane risk of bias 2.0 tool, and the certainty of the evidence using the grading of recommendations assessment, development, and evaluation (GRADE) approach. For each outcome, interventions were classified in groups from the most to the least beneficial or harmful following GRADE guidance. Results 196 trials enrolling 76 767 patients were included; 111 (56.6%) trials and 35 098 (45.72%) patients are new from the previous iteration; 113 (57.7%) trials evaluating treatments with at least 100 patients or 20 events met the threshold for inclusion in the analyses. Compared with standard care, corticosteroids probably reduce death (risk difference 20 fewer per 1000 patients, 95% credible interval 36 fewer to 3 fewer, moderate certainty), mechanical ventilation (25 fewer per 1000, 44 fewer to 1 fewer, moderate certainty), and increase the number of days free from mechanical ventilation (2.6 more, 0.3 more to 5.0 more, moderate certainty). Interleukin-6 inhibitors probably reduce mechanical ventilation (30 fewer per 1000, 46 fewer to 10 fewer, moderate certainty) and may reduce length of hospital stay (4.3 days fewer, 8.1 fewer to 0.5 fewer, low certainty), but whether or not they reduce mortality is uncertain (15 fewer per 1000, 30 fewer to 6 more, low certainty). Janus kinase inhibitors may reduce mortality (50 fewer per 1000, 84 fewer to no difference, low certainty), mechanical ventilation (46 fewer per 1000, 74 fewer to 5 fewer, low certainty), and duration of mechanical ventilation (3.8 days fewer, 7.5 fewer to 0.1 fewer, moderate certainty). The impact of remdesivir on mortality and most other outcomes is uncertain. The effects of ivermectin were rated as very low certainty for all critical outcomes, including mortality. In patients with non-severe disease, colchicine may reduce mortality (78 fewer per 1000, 110 fewer to 9 fewer, low certainty) and mechanical ventilation (57 fewer per 1000, 90 fewer to 3 more, low certainty). Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to reduce risk of death or have an effect on any other patient-important outcome. The certainty in effects for all other interventions was low or very low. Conclusion Corticosteroids and interleukin-6 inhibitors probably confer important benefits in patients with severe covid-19. Janus kinase inhibitors appear to have promising benefits, but certainty is low. Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to have any important benefits. Whether or not remdesivir, ivermectin, and other drugs confer any patient-important benefit remains uncertain. Systematic review registration This review was not registered. The protocol is publicly available in the supplementary material. Readers’ note This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication. This is the fourth version of the original article published on 30 July 2020 (BMJ 2020;370:m2980), and previous versions can be found as data supplements. When citing this paper please consider adding the version number and date of access for clarity.
Memorial Sloan Kettering Cancer Center1, University Hospitals of Cleveland2, Washington University in St. Louis3, University of Utah4, Duke University5, University of Wisconsin-Madison6, Harvard University7, Moffitt Cancer Center8, Vanderbilt University9, Stanford University10, Johns Hopkins University11, University of Tennessee Health Science Center12, Mayo Clinic13, Fox Chase Cancer Center14, University of Texas MD Anderson Cancer Center15, Brigham and Women's Hospital16, Roswell Park Cancer Institute17, University of Colorado Boulder18, City of Hope National Medical Center19, University of California, San Diego20, Northwestern University21, Ohio State University22, Fred Hutchinson Cancer Research Center23, University of Pennsylvania24, University of Michigan25, University of California, San Francisco26, National Comprehensive Cancer Network27
TL;DR: The NCCN Guidelines for Head and Neck Cancers as mentioned in this paper describe supportive care recommendations for patients with H&N cancers and the rationale supporting a new section on imaging recommendations for head and neck cancers.
Abstract: Treatment is complex for patients with head and neck (H&N) cancers with specific site of disease, stage, and pathologic findings guiding treatment decision-making. Treatment planning for H&N cancers involves a multidisciplinary team of experts. This article describes supportive care recommendations in the NCCN Guidelines for Head and Neck Cancers, as well as the rationale supporting a new section on imaging recommendations for patients with H&N cancers. This article also describes updates to treatment recommendations for patients with very advanced H&N cancers and salivary gland tumors, specifically systemic therapy recommendations.
TL;DR: It is found that a chimeric adenoviral vector overcame the inherent resistance of primary human macrophages to genetic manipulation and imparted a sustained pro-inflammatory (M1) phenotype in humanized mice.
Abstract: Chimeric antigen receptor (CAR) T cell therapy has shown promise in hematologic malignancies, but its application to solid tumors has been challenging1–4. Given the unique effector functions of macrophages and their capacity to penetrate tumors5, we genetically engineered human macrophages with CARs to direct their phagocytic activity against tumors. We found that a chimeric adenoviral vector overcame the inherent resistance of primary human macrophages to genetic manipulation and imparted a sustained pro-inflammatory (M1) phenotype. CAR macrophages (CAR-Ms) demonstrated antigen-specific phagocytosis and tumor clearance in vitro. In two solid tumor xenograft mouse models, a single infusion of human CAR-Ms decreased tumor burden and prolonged overall survival. Characterization of CAR-M activity showed that CAR-Ms expressed pro-inflammatory cytokines and chemokines, converted bystander M2 macrophages to M1, upregulated antigen presentation machinery, recruited and presented antigen to T cells and resisted the effects of immunosuppressive cytokines. In humanized mouse models, CAR-Ms were further shown to induce a pro-inflammatory tumor microenvironment and boost anti-tumor T cell activity. Primary macrophages engineered to express chimeric antigen receptors have anti-tumor activity in humanized mice.
TL;DR: Clinicians should be vigilant to provide prompt monitoring and treatments of COVID-19 patients and an endomyocardial biopsy may help identify active cardiac infection through viral genome amplification and possibly refine the treatment risks of systemic immunosuppression.
Cornell University1, Memorial Sloan Kettering Cancer Center2, Hebron University3, University of Texas MD Anderson Cancer Center4, University of California, San Francisco5, University of Wisconsin-Madison6, Harvard University7, University of Chicago8, Mayo Clinic9, University of Washington10, Johns Hopkins University11, Seoul National University Hospital12, Trinity College, Dublin13, University of Arizona14, University of Southern California15, Agios Pharmaceuticals16, University of Manchester17, Fudan University18
TL;DR: Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivOSidenib was well tolerated, and this study shows the clinical benefit of targeting IDH1 mutations in advanced,IDH1-mutant cholangiocarcinoma.
Abstract: Summary Background Isocitrate dehydrogenase 1 (IDH1) mutations occur in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome. The aim of this international phase 3 study was to assess the efficacy and safety of ivosidenib (AG-120)—a small-molecule targeted inhibitor of mutated IDH1—in patients with previously treated IDH1-mutant cholangiocarcinoma. Methods This multicentre, randomised, double-blind, placebo-controlled, phase 3 study included patients from 49 hospitals in six countries aged at least 18 years with histologically confirmed, advanced, IDH1-mutant cholangiocarcinoma who had progressed on previous therapy, and had up to two previous treatment regimens for advanced disease, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (2:1) with a block size of 6 and stratified by number of previous systemic treatment regimens for advanced disease to oral ivosidenib 500 mg or matched placebo once daily in continuous 28-day cycles, by means of an interactive web-based response system. Placebo to ivosidenib crossover was permitted on radiological progression per investigator assessment. The primary endpoint was progression-free survival by independent central review. The intention-to-treat population was used for the primary efficacy analyses. Safety was assessed in all patients who had received at least one dose of ivosidenib or placebo. Enrolment is complete; this study is registered with ClinicalTrials.gov , NCT02989857 . Findings Between Feb 20, 2017, and Jan 31, 2019, 230 patients were assessed for eligibility, and as of the Jan 31, 2019 data cutoff date, 185 patients were randomly assigned to ivosidenib (n=124) or placebo (n=61). Median follow-up for progression-free survival was 6·9 months (IQR 2·8–10·9). Progression-free survival was significantly improved with ivosidenib compared with placebo (median 2·7 months [95% CI 1·6–4·2] vs 1·4 months [1·4–1·6]; hazard ratio 0·37; 95% CI 0·25–0·54; one-sided p Interpretation Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivosidenib was well tolerated. This study shows the clinical benefit of targeting IDH1 mutations in advanced, IDH1-mutant cholangiocarcinoma. Funding Agios Pharmaceuticals.
TL;DR: This Review discusses what is currently known about human humoral and cellular immune responses to severe acute respiratory syndrome coronavirus 2 and relates this knowledge to the COVID-19 vaccines currently in phase 3 clinical trials.
University of Milan1, University of Washington2, University of South Florida3, Georgetown University4, University of Minnesota5, Mayo Clinic6, University of Kansas7, University of Liège8, University of Chicago9, Vanderbilt University10, Stanford University11, Université libre de Bruxelles12, Washington University in St. Louis13, Tel Aviv University14, University of Pennsylvania15, City of Hope National Medical Center16, Duke University17, Heidelberg University18
TL;DR: Common CV toxicities related to cancer therapy are defined, along with suggested strategies for prevention, detection and treatment, and guidance regarding prevention, screening, monitoring and treatment of CV toxicity is provided.
Emory University1, Johns Hopkins University2, National Institutes of Health3, Stanford University4, University of Pennsylvania5, Arizona State University6, Veterans Health Administration7, Icahn School of Medicine at Mount Sinai8, Mayo Clinic9, University of Florida10, Pacific Northwest National Laboratory11, NewYork–Presbyterian Hospital12, Rush University Medical Center13, Baylor College of Medicine14
TL;DR: Large-scale, comprehensive proteomic profiling of Alzheimer’s disease brain and cerebrospinal fluid reveals disease-associated protein coexpression modules and highlights the importance of glia and energy metabolism in disease pathogenesis.
Abstract: Our understanding of Alzheimer's disease (AD) pathophysiology remains incomplete. Here we used quantitative mass spectrometry and coexpression network analysis to conduct the largest proteomic study thus far on AD. A protein network module linked to sugar metabolism emerged as one of the modules most significantly associated with AD pathology and cognitive impairment. This module was enriched in AD genetic risk factors and in microglia and astrocyte protein markers associated with an anti-inflammatory state, suggesting that the biological functions it represents serve a protective role in AD. Proteins from this module were elevated in cerebrospinal fluid in early stages of the disease. In this study of >2,000 brains and nearly 400 cerebrospinal fluid samples by quantitative proteomics, we identify proteins and biological processes in AD brains that may serve as therapeutic targets and fluid biomarkers for the disease.
TL;DR: A surveillance, diagnostic, and management strategy is proposed that balances potential patient risks and healthcare staff exposure with improvement in meaningful clinical outcomes of acute COVID-19 cardiovascular syndrome.
Abstract: Coronavirus disease 2019 (COVID-19) is a rapidly expanding global pandemic caused by severe acute respiratory syndrome coronavirus 2, resulting in significant morbidity and mortality. A substantial minority of patients hospitalized develop an acute COVID-19 cardiovascular syndrome, which can manifest with a variety of clinical presentations but often presents as an acute cardiac injury with cardiomyopathy, ventricular arrhythmias, and hemodynamic instability in the absence of obstructive coronary artery disease. The cause of this injury is uncertain but is suspected to be related to myocarditis, microvascular injury, systemic cytokine-mediated injury, or stress-related cardiomyopathy. Although histologically unproven, severe acute respiratory syndrome coronavirus 2 has the potential to directly replicate within cardiomyocytes and pericytes, leading to viral myocarditis. Systemically elevated cytokines are also known to be cardiotoxic and have the potential to result in profound myocardial injury. Prior experience with severe acute respiratory syndrome coronavirus 1 has helped expedite the evaluation of several promising therapies, including antiviral agents, interleukin-6 inhibitors, and convalescent serum. Management of acute COVID-19 cardiovascular syndrome should involve a multidisciplinary team including intensive care specialists, infectious disease specialists, and cardiologists. Priorities for managing acute COVID-19 cardiovascular syndrome include balancing the goals of minimizing healthcare staff exposure for testing that will not change clinical management with early recognition of the syndrome at a time point at which intervention may be most effective. This article aims to review the best available data on acute COVID-19 cardiovascular syndrome epidemiology, pathogenesis, diagnosis, and treatment. From these data, we propose a surveillance, diagnostic, and management strategy that balances potential patient risks and healthcare staff exposure with improvement in meaningful clinical outcomes.
TL;DR: Multiple myeloma accounts for approximately 10% of hematologic malignancies in the United States and is the second most common cancer in women.
Abstract: Disease overview Multiple myeloma accounts for approximately 10% of hematologic malignancies. Diagnosis The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy proven plasmacytoma plus evidence of one or more multiple myeloma defining events (MDE) namely CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) features felt related to the plasma cell disorder, bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain (FLC) ratio ≥100 (provided involved FLC is ≥100 mg/L), or >1 focal lesion on magnetic resonance imaging (MRI). Risk stratification The presence of del(17p), t(4;14), t(14;16), t(14;20), gain 1q, or p53 mutation is considered high-risk multiple myeloma. Presence of any two high risk factors is considered double-hit myeloma; three or more high risk factors is triple-hit myeloma. Risk-adapted initial therapy In transplant eligible patients, induction therapy consists of bortezomib, lenalidomide, dexamethasone (VRd) given for approximately 3-4 cycles followed by autologous stem cell transplantation (ASCT). In high-risk patients, daratumumab, bortezomib, lenalidomide, dexamethasone (Dara-VRd) is an alternative to VRd. Selected standard risk patients can get additional cycles of induction, and delay transplant until first relapse. Patients not candidates for transplant are typically treated with VRd for approximately 8-12 cycles followed by lenalidomide; alternatively these patients can be treated with daratumumab, lenalidomide, dexamethasone (DRd). Maintenance therapy After ASCT, standard risk patients need lenalidomide maintenance, while bortezomib-based maintenance is needed for patients with high-risk myeloma. Management of refractory disease Most patients require a triplet regimen at relapse, with the choice of regimen varying with each successive relapse.
Cedars-Sinai Medical Center1, Emory University2, Medical City Dallas Hospital3, Columbia University Medical Center4, Cleveland Clinic5, Laval University6, University of Pennsylvania7, MedStar Washington Hospital Center8, University of Missouri–Kansas City9, Washington University in St. Louis10, Mayo Clinic11, Intermountain Medical Center12, Providence St. Vincent Medical Center13, Rutgers University14, New York University15, Primary Children's Hospital16, Scott & White Hospital17, Stanford University18, Columbia University19, Edwards Lifesciences Corporation20
TL;DR: There was no significant difference in the incidence of death or disabling stroke at 5 years after TAVR as compared with surgical aortic-valve replacement among patients with severe, symptomaticAortic stenosis who were at intermediate surgical risk.
Abstract: Background There are scant data on long-term clinical outcomes and bioprosthetic-valve function after transcatheter aortic-valve replacement (TAVR) as compared with surgical aortic-valve r...