Publications by authors named "Peter Bailey"

109 Publications

Mandatory dichotic integration of second-formant information: Contralateral sine bleats have predictable effects on consonant place judgments.

J Acoust Soc Am 2021 11;150(5):3693

Department of Psychology, University of York, Heslington, York YO10 5DD, United Kingdom.

Speech-on-speech informational masking arises because the interferer disrupts target processing (e.g., capacity limitations) or corrupts it (e.g., intrusions into the target percept); the latter should produce predictable errors. Listeners identified the consonant in monaural buzz-excited three-formant analogues of approximant-vowel syllables, forming a place of articulation series (/w/-/l/-/j/). There were two 11-member series; the vowel was either high-front or low-back. Series members shared formant-amplitude contours, fundamental frequency, and F1+F3 frequency contours; they were distinguished solely by the F2 frequency contour before the steady portion. Targets were always presented in the left ear. For each series, F2 frequency and amplitude contours were also used to generate interferers with altered source properties-sine-wave analogues of F2 (sine bleats) matched to their buzz-excited counterparts. Accompanying each series member with a fixed mismatched sine bleat in the contralateral ear produced systematic and predictable effects on category judgments; these effects were usually largest for bleats involving the fastest rate or greatest extent of frequency change. Judgments of isolated sine bleats using the three place labels were often unsystematic or arbitrary. These results indicate that informational masking by interferers involved corruption of target processing as a result of mandatory dichotic integration of F2 information, despite the grouping cues disfavoring this integration.
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http://dx.doi.org/10.1121/10.0007132DOI Listing
November 2021

Clinical Impact of Molecular Subtyping of Pancreatic Cancer.

Front Cell Dev Biol 2021 5;9:743908. Epub 2021 Nov 5.

Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.

Pancreatic ductal adenocarcinoma is a highly lethal malignancy, which has now become the seventh most common cause of cancer death in the world, with the highest mortality rates in Europe and North America. In the past 30 years, there has been some progress in 5-year survival (rates increasing from 2.5 to 10%), but this is still extremely poor compared to all other common cancer types. Targeted therapies for advanced pancreatic cancer based on actionable mutations have been disappointing, with only 3-5% showing even a short clinical benefit. There is, however, a molecular diversity beyond mutations in genes responsible for producing classical canonical signaling pathways. Pancreatic cancer is almost unique in promoting an excess production of other components of the stroma, resulting in a complex tumor microenvironment that contributes to tumor development, progression, and response to treatment. Various transcriptional subtypes have also been described. Most notably, there is a strong alignment between the Classical/Pancreatic progenitor and Quasi-mesenchymal/Basal-like/Squamous subtype signatures of Moffit, Collinson, Bailey, Puleo, and Chan-Seng-Yue, which have potential clinical impact. Sequencing of epithelial cell populations enriched by laser capture microscopy combined with single-cell RNA sequencing has revealed the potential genomic evolution of pancreatic cancer as being a consequence of a gene expression continuum from mixed Basal-like and Classical cell populations within the same tumor, linked to allelic imbalances in mutant KRAS, with metastatic tumors being more copy number-unstable compared to primary tumors. The Basal-like subtype appears more chemoresistant with reduced survival compared to the Classical subtype. Chemotherapy and/or chemoradiation will also enrich the Basal-like subtype. Squamous/Basal-like programs facilitate immune infiltration compared with the Classical-like programs. The immune infiltrates associated with Basal and Classical type cells are distinct, potentially opening the door to differential strategies. Single-cell and spatial transcriptomics will now allow single cell profiling of tumor and resident immune cell populations that may further advance subtyping. Multiple clinical trials have been launched based on transcriptomic response signatures and molecular subtyping including COMPASS, Precision Promise, ESPAC6/7, PREDICT-PACA, and PASS1. We review several approaches to explore the clinical relevance of molecular profiling to provide optimal bench-to-beside translation with clinical impact.
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http://dx.doi.org/10.3389/fcell.2021.743908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8603393PMC
November 2021

Perioperative immunotherapy for pancreatic cancer is on its way.

Hepatobiliary Surg Nutr 2021 Aug;10(4):534-537

Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany.

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http://dx.doi.org/10.21037/hbsn-21-238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350999PMC
August 2021

The HIF complex recruits the histone methyltransferase SET1B to activate specific hypoxia-inducible genes.

Nat Genet 2021 07 21;53(7):1022-1035. Epub 2021 Jun 21.

Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Department of Medicine, University of Cambridge, Cambridge, UK.

Hypoxia-inducible transcription factors (HIFs) are fundamental to cellular adaptation to low oxygen levels, but it is unclear how they interact with chromatin and activate their target genes. Here, we use genome-wide mutagenesis to identify genes involved in HIF transcriptional activity, and define a requirement for the histone H3 lysine 4 (H3K4) methyltransferase SET1B. SET1B loss leads to a selective reduction in transcriptional activation of HIF target genes, resulting in impaired cell growth, angiogenesis and tumor establishment in SET1B-deficient xenografts. Mechanistically, we show that SET1B accumulates on chromatin in hypoxia, and is recruited to HIF target genes by the HIF complex. The selective induction of H3K4 trimethylation at HIF target loci is both HIF- and SET1B-dependent and, when impaired, correlates with decreased promoter acetylation and gene expression. Together, these findings show SET1B as a determinant of site-specific histone methylation and provide insight into how HIF target genes are differentially regulated.
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http://dx.doi.org/10.1038/s41588-021-00887-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611696PMC
July 2021

Deep Learning Improves Pancreatic Cancer Diagnosis Using RNA-Based Variants.

Cancers (Basel) 2021 May 28;13(11). Epub 2021 May 28.

Biotechnology Center (BIOTEC), Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Tatzberg 47-49, 01307 Dresden, Germany.

For optimal pancreatic cancer treatment, early and accurate diagnosis is vital. Blood-derived biomarkers and genetic predispositions can contribute to early diagnosis, but they often have limited accuracy or applicability. Here, we seek to exploit the synergy between them by combining the biomarker CA19-9 with RNA-based variants. We use deep sequencing and deep learning to improve differentiating pancreatic cancer and chronic pancreatitis. We obtained samples of nucleated cells found in peripheral blood from 268 patients suffering from resectable, non-resectable pancreatic cancer, and chronic pancreatitis. We sequenced RNA with high coverage and obtained millions of variants. The high-quality variants served as input together with CA19-9 values to deep learning models. Our model achieved an area under the curve (AUC) of 96% in differentiating resectable cancer from pancreatitis using a test cohort. Moreover, we identified variants to estimate survival in resectable cancer. We show that the blood transcriptome harbours variants, which can substantially improve noninvasive clinical diagnosis.
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http://dx.doi.org/10.3390/cancers13112654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199344PMC
May 2021

DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association.

Commun Biol 2021 02 3;4(1):155. Epub 2021 Feb 3.

University of Sydney, Sydney, New South Wales, 2006, Australia.

Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs.
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http://dx.doi.org/10.1038/s42003-020-01469-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859232PMC
February 2021

Tenecteplase vs Alteplase Before Endovascular Therapy in Basilar Artery Occlusion.

Neurology 2021 03 6;96(9):e1272-e1277. Epub 2021 Jan 6.

From the Department of Medicine and Neurology (F. Alemseged, G.S., L.C., B.Y., M.W.P., S.M.D., P.J.M., N.Y. B.C.V.C.), University of Melbourne, and Department of Radiology (C.W., S.B., R.D.), Royal Melbourne Hospital, Parkville, Australia; Stroke Unit (F. Alemseged, A.R., F.S., M.D.) and Department of Biomedicine and Prevention (F.D.), University Hospital of Tor Vergata, Rome, Italy; Department of Neurology (F.C.N.), Austin Health, Melbourne, Australia; Department of Neurology (V.P.), Institute of Neuroradiology (D.K.), and Dresden Neurovascular Center (V.P., D.K.), University of Technology Dresden, Germany; Department of Interventional Neuroradiology (G.B.), Sainte-Anne-Hospital, Paris, France; Department of Neurology (T.J.K.), Royal Adelaide Hospital, Australia; Department of Neurology (T.Y.W.), Christchurch Hospital, New Zealand; Division of Medicine (D.S.), Princess Alexandra Hospital, Brisbane, Australia; NEUROFARBA Department (F. Arba), Careggi University Hospital, Florence; ASST Valcamonica (A.M.), Department of Neurology, Esine, Italy; Department of Neurosciences (H.M.D.), Eastern Health, Melbourne; Department of Neurology (P.B.), Gold Coast University Hospital, Queensland; Department of Neurology (B.O.), Gosford Hospital, New South Wales; and Population Health and Immunity Division (N.Y.), The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.

Objective: To investigate the efficacy of tenecteplase (TNK), a genetically modified variant of alteplase with greater fibrin specificity and longer half-life than alteplase, prior to endovascular thrombectomy (EVT) in patients with basilar artery occlusion (BAO).

Methods: To determine whether TNK is associated with better reperfusion rates than alteplase prior to EVT in BAO, clinical and procedural data of consecutive patients with BAO from the Basilar Artery Treatment and Management (BATMAN) registry and the Tenecteplase vs Alteplase before Endovascular Therapy for Ischemic Stroke (EXTEND-IA TNK) trial were retrospectively analyzed. Reperfusion >50% or absence of retrievable thrombus at the time of the initial angiogram was evaluated.

Results: We included 110 patients with BAO treated with IV thrombolysis prior to EVT (mean age 69 [SD 14] years; median NIH Stroke Scale score 16 [interquartile range (IQR) 7-32]). Nineteen patients were thrombolysed with TNK (0.25 mg/kg or 0.40 mg/kg) and 91 with alteplase (0.9 mg/kg). Reperfusion >50% occurred in 26% (n = 5/19) of patients thrombolysed with TNK vs 7% (n = 6/91) thrombolysed with alteplase (risk ratio 4.0, 95% confidence interval 1.3-12; = 0.02), despite shorter thrombolysis to arterial puncture time in the TNK-treated patients (48 [IQR 40-71] minutes) vs alteplase-treated patients (110 [IQR 51-185] minutes; = 0.004). No difference in symptomatic intracranial hemorrhage was observed (0/19 [0%] TNK, 1/91 [1%] alteplase; = 0.9).

Conclusions: TNK may be associated with an increased rate of reperfusion in comparison with alteplase before EVT in BAO. Randomized controlled trials to compare TNK with alteplase in patients with BAO are warranted.

Clinicaltrialsgov Identifiers: NCT02388061 and NCT03340493.

Classification Of Evidence: This study provides Class III evidence that TNK leads to higher reperfusion rates in comparison with alteplase prior to EVT in patients with BAO.
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http://dx.doi.org/10.1212/WNL.0000000000011520DOI Listing
March 2021

Poly(ADP-ribose) polymerase inhibition in pancreatic cancer.

Genes Chromosomes Cancer 2021 05 9;60(5):373-384. Epub 2021 Jan 9.

Department of Medical Oncology, Heidelberg University Hospital, National Center for Tumor Diseases, Heidelberg, Germany.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited treatment options. Recently, the poly(ADP-ribose) polymerase inhibitor (PARPi) olaparib has been approved for maintenance therapy after successful platinum-based chemotherapy in patients with germline mutations in BRCA1 and BRCA2. Approval was based on the POLO study that has shown a significant improvement in progression-free survival for patients with metastatic PDAC after at least 4 months of platinum-based chemotherapy. Hopefully, this first biomarker-directed targeted therapy for a relevant subgroup of pancreatic cancer patients is only the beginning of an era of personalized therapy for pancreatic cancer. The potential role for PARPi in improving survival in patients with pancreatic cancer containing somatic tumor mutations has yet to be established. Multiple studies investigating whether PARPi therapy might benefit a larger group of pancreatic cancer patients with homologous recombination repair deficiency and whether combinations with chemotherapy, immunotherapy, or small molecules can improve efficacy are currently underway. We here review the molecular basis for PARPi therapy in PDAC patients and recent developments in clinical studies.
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http://dx.doi.org/10.1002/gcc.22932DOI Listing
May 2021

Using Chromatin Accessibility to Delineate Therapeutic Subtypes in Pancreatic Cancer Patient-Derived Cell Lines.

STAR Protoc 2020 Sep 4;1(2):100079. Epub 2020 Aug 4.

Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1QH, UK.

Disrupted chromatin regulatory processes contribute to the development of cancer, in particular pancreatic ductal adenocarcinoma. The assay for transposase accessible chromatin with high-throughput sequencing (ATAC-seq) is typically used to study chromatin organization. Here, we present a revised ATAC-seq protocol to study chromatin accessibility in adherent patient-derived cell lines. We provide details on how to calculate the library molarity using Agilent's Bioanalyzer and an analysis pipeline for peak calling and transcription factor mapping. For complete details on the use and execution of this protocol, please refer to Brunton et al. (2020).
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http://dx.doi.org/10.1016/j.xpro.2020.100079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580199PMC
September 2020

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer.

Gastroenterology 2021 01 9;160(1):362-377.e13. Epub 2020 Oct 9.

Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.

Background & Aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress, and novel therapeutic response in PC to develop a biomarker-driven therapeutic strategy targeting DDR and replication stress in PC.

Methods: We interrogated the transcriptome, genome, proteome, and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient-derived xenografts and human PC organoids.

Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors, including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, cosegregates with response to platinum (P < .001) and PARP inhibitor therapy (P < .001) in vitro and in vivo. We generated a novel signature of replication stress that predicts response to ATR (P < .018) and WEE1 inhibitor (P < .029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < .001) but was not associated with DDR deficiency.

Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR-proficient PC and after platinum therapy.
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http://dx.doi.org/10.1053/j.gastro.2020.09.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167930PMC
January 2021

Inflammatory infiltration is associated with AR expression and poor prognosis in hormone naïve prostate cancer.

Prostate 2020 11 26;80(15):1353-1364. Epub 2020 Aug 26.

Unit of Gastrointestinal Cancer and Molecular Pathology, Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, UK.

Background: Tumor microenvironment inflammatory infiltration is proposed as a protumorigenic mechanism for prostate cancer with proinflammatory cytokines stimulating androgen receptor (AR) activity. However, association with patient prognosis remains unclear. This study derives an inflammatory gene signature associated with AR expression and investigates CD3+ and CD8+ T-lymphocyte infiltration association with AR and prognosis.

Methods: Gene profiling of inflammatory related genes was performed on 71 prostate biopsies. Immunohistochemistry on 243 hormone-naïve prostate cancers was performed for CD3, CD8, AR, and phosphorylated AR tumor expression.

Results: Multiple proinflammatory genes were differentially expressed in association with high AR expression compared with low AR expression including PI3KCA and MAKP8 (adjusted P < .05). High CD3+ and high CD8+ infiltration associated with reduced cancer-specific survival (P = .018 and P = .020, respectively). High CD3+ infiltration correlated with high tumor cytoplasmic AR expression and if assessed together, they associated with reduced cancer-specific and 5-year survival from 90% to 56% (P = .000179). High CD8+ cytotoxic infiltration associated with high androgen-independent tumor nuclear AR serine 213 phosphorylation (correlation coefficient = 0.227; P = .003) and when assessed together associated with poor clinico-pathological features including perineural invasion (P = .001). Multiple genes involved in proinflammatory signaling pathways are upregulated in high AR expressing prostate samples.

Conclusion: T-lymphocyte infiltration in hormone-naïve disease associates with androgen-independent driven disease and provides possible therapeutic targets to reduce transformation from hormone-naïve to castrate-resistant disease.
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http://dx.doi.org/10.1002/pros.24064DOI Listing
November 2020

ABHD11 maintains 2-oxoglutarate metabolism by preserving functional lipoylation of the 2-oxoglutarate dehydrogenase complex.

Nat Commun 2020 08 13;11(1):4046. Epub 2020 Aug 13.

Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge, CB2 0XY, UK.

2-oxoglutarate (2-OG or α-ketoglutarate) relates mitochondrial metabolism to cell function by modulating the activity of 2-OG dependent dioxygenases involved in the hypoxia response and DNA/histone modifications. However, metabolic pathways that regulate these oxygen and 2-OG sensitive enzymes remain poorly understood. Here, using CRISPR Cas9 genome-wide mutagenesis to screen for genetic determinants of 2-OG levels, we uncover a redox sensitive mitochondrial lipoylation pathway, dependent on the mitochondrial hydrolase ABHD11, that signals changes in mitochondrial 2-OG metabolism to 2-OG dependent dioxygenase function. ABHD11 loss or inhibition drives a rapid increase in 2-OG levels by impairing lipoylation of the 2-OG dehydrogenase complex (OGDHc)-the rate limiting step for mitochondrial 2-OG metabolism. Rather than facilitating lipoate conjugation, ABHD11 associates with the OGDHc and maintains catalytic activity of lipoyl domain by preventing the formation of lipoyl adducts, highlighting ABHD11 as a regulator of functional lipoylation and 2-OG metabolism.
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http://dx.doi.org/10.1038/s41467-020-17862-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426941PMC
August 2020

Precision Oncology in Surgery: Patient Selection for Operable Pancreatic Cancer.

Ann Surg 2020 08;272(2):366-376

Department of Surgery, Universitätsklinikum Erlangen, Erlangen, Germany.

Objective: We aimed to define preoperative clinical and molecular characteristics that would allow better patient selection for operative resection.

Background: Although we use molecular selection methods for systemic targeted therapies, these principles are not applied to surgical oncology. Improving patient selection is of vital importance for the operative treatment of pancreatic cancer (pancreatic ductal adenocarcinoma). Although surgery is the only chance of long-term survival, 80% still succumb to the disease and approximately 30% die within 1 year, often sooner than those that have unresected local disease.

Method: In 3 independent pancreatic ductal adenocarcinoma cohorts (total participants = 1184) the relationship between aberrant expression of prometastatic proteins S100A2 and S100A4 and survival was assessed. A preoperative nomogram based on clinical variables available before surgery and expression of these proteins was constructed and compared to traditional measures, and a postoperative nomogram.

Results: High expression of either S100A2 or S100A4 was independent poor prognostic factors in a training cohort of 518 participants. These results were validated in 2 independent patient cohorts (Glasgow, n = 198; Germany, n = 468). Aberrant biomarker expression stratified the cohorts into 3 distinct prognostic groups. A preoperative nomogram incorporating S100A2 and S100A4 expression predicted survival and nomograms derived using postoperative clinicopathological variables.

Conclusions: Of those patients with a poor preoperative nomogram score, approximately 50% of patients died within a year of resection. Nomograms have the potential to improve selection for surgery and neoadjuvant therapy, avoiding surgery in aggressive disease, and justifying more extensive resections in biologically favorable disease.
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http://dx.doi.org/10.1097/SLA.0000000000003143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373491PMC
August 2020

Altered RNA Splicing by Mutant p53 Activates Oncogenic RAS Signaling in Pancreatic Cancer.

Cancer Cell 2020 08 18;38(2):198-211.e8. Epub 2020 Jun 18.

The Kinghorn Cancer Centre, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia; Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, NSW, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, NSW, Australia.

Pancreatic ductal adenocarcinoma (PDAC) is driven by co-existing mutations in KRAS and TP53. However, how these mutations collaborate to promote this cancer is unknown. Here, we uncover sequence-specific changes in RNA splicing enforced by mutant p53 which enhance KRAS activity. Mutant p53 increases expression of splicing regulator hnRNPK to promote inclusion of cytosine-rich exons within GTPase-activating proteins (GAPs), negative regulators of RAS family members. Mutant p53-enforced GAP isoforms lose cell membrane association, leading to heightened KRAS activity. Preventing cytosine-rich exon inclusion in mutant KRAS/p53 PDACs decreases tumor growth. Moreover, mutant p53 PDACs are sensitized to inhibition of splicing via spliceosome inhibitors. These data provide insight into co-enrichment of KRAS and p53 mutations and therapeutics targeting this mechanism in PDAC.
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http://dx.doi.org/10.1016/j.ccell.2020.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028848PMC
August 2020

HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer.

Cell Rep 2020 05;31(6):107625

The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst and Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.

Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3β) a key regulator of glycolysis. Pharmacological inhibition of GSK3β results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3β inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC.
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http://dx.doi.org/10.1016/j.celrep.2020.107625DOI Listing
May 2020

Effect of Intravenous Tenecteplase Dose on Cerebral Reperfusion Before Thrombectomy in Patients With Large Vessel Occlusion Ischemic Stroke: The EXTEND-IA TNK Part 2 Randomized Clinical Trial.

JAMA 2020 04;323(13):1257-1265

Department of Medicine, Ballarat Base Hospital, Ballarat, Victoria, Australia.

Importance: Intravenous thrombolysis with tenecteplase improves reperfusion prior to endovascular thrombectomy for ischemic stroke compared with alteplase.

Objective: To determine whether 0.40 mg/kg of tenecteplase safely improves reperfusion before endovascular thrombectomy vs 0.25 mg/kg of tenecteplase in patients with large vessel occlusion ischemic stroke.

Design, Setting, And Participants: Randomized clinical trial at 27 hospitals in Australia and 1 in New Zealand using open-label treatment and blinded assessment of radiological and clinical outcomes. Patients were enrolled from December 2017 to July 2019 with follow-up until October 2019. Adult patients (N = 300) with ischemic stroke due to occlusion of the intracranial internal carotid, \basilar, or middle cerebral artery were included less than 4.5 hours after symptom onset using standard intravenous thrombolysis eligibility criteria.

Interventions: Open-label tenecteplase at 0.40 mg/kg (maximum, 40 mg; n = 150) or 0.25 mg/kg (maximum, 25 mg; n = 150) given as a bolus before endovascular thrombectomy.

Main Outcomes And Measures: The primary outcome was reperfusion of greater than 50% of the involved ischemic territory prior to thrombectomy, assessed by consensus of 2 blinded neuroradiologists. Prespecified secondary outcomes were level of disability at day 90 (modified Rankin Scale [mRS] score; range, 0-6); mRS score of 0 to 1 (freedom from disability) or no change from baseline at 90 days; mRS score of 0 to 2 (functional independence) or no change from baseline at 90 days; substantial neurological improvement at 3 days; symptomatic intracranial hemorrhage within 36 hours; and all-cause death.

Results: All 300 patients who were randomized (mean age, 72.7 years; 141 [47%] women) completed the trial. The number of participants with greater than 50% reperfusion of the previously occluded vascular territory was 29 of 150 (19.3%) in the 0.40 mg/kg group vs 29 of 150 (19.3%) in the 0.25 mg/kg group (unadjusted risk difference, 0.0% [95% CI, -8.9% to -8.9%]; adjusted risk ratio, 1.03 [95% CI, 0.66-1.61]; P = .89). Among the 6 secondary outcomes, there were no significant differences in any of the 4 functional outcomes between the 0.40 mg/kg and 0.25 mg/kg groups nor in all-cause deaths (26 [17%] vs 22 [15%]; unadjusted risk difference, 2.7% [95% CI, -5.6% to 11.0%]) or symptomatic intracranial hemorrhage (7 [4.7%] vs 2 [1.3%]; unadjusted risk difference, 3.3% [95% CI, -0.5% to 7.2%]).

Conclusions And Relevance: Among patients with large vessel occlusion ischemic stroke, a dose of 0.40 mg/kg, compared with 0.25 mg/kg, of tenecteplase did not significantly improve cerebral reperfusion prior to endovascular thrombectomy. The findings suggest that the 0.40-mg/kg dose of tenecteplase does not confer an advantage over the 0.25-mg/kg dose in patients with large vessel occlusion ischemic stroke in whom endovascular thrombectomy is planned.

Trial Registration: ClinicalTrials.gov Identifier: NCT03340493.
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http://dx.doi.org/10.1001/jama.2020.1511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139271PMC
April 2020

Genomic basis for RNA alterations in cancer.

Nature 2020 02 5;578(7793):129-136. Epub 2020 Feb 5.

BGI-Shenzhen, Shenzhen, China.

Transcript alterations often result from somatic changes in cancer genomes. Various forms of RNA alterations have been described in cancer, including overexpression, altered splicing and gene fusions; 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). 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.
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http://dx.doi.org/10.1038/s41586-020-1970-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054216PMC
February 2020

Mouse Ovarian Cancer Models Recapitulate the Human Tumor Microenvironment and Patient Response to Treatment.

Cell Rep 2020 01;30(2):525-540.e7

Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK. Electronic address:

Although there are many prospective targets in the tumor microenvironment (TME) of high-grade serous ovarian cancer (HGSOC), pre-clinical testing is challenging, especially as there is limited information on the murine TME. Here, we characterize the TME of six orthotopic, transplantable syngeneic murine HGSOC lines established from genetic models and compare these to patient biopsies. We identify significant correlations between the transcriptome, host cell infiltrates, matrisome, vasculature, and tissue modulus of mouse and human TMEs, with several stromal and malignant targets in common. However, each model shows distinct differences and potential vulnerabilities that enabled us to test predictions about response to chemotherapy and an anti-IL-6 antibody. Using machine learning, the transcriptional profiles of the mouse tumors that differed in chemotherapy response are able to classify chemotherapy-sensitive and -refractory patient tumors. These models provide useful pre-clinical tools and may help identify subgroups of HGSOC patients who are most likely to respond to specific therapies.
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http://dx.doi.org/10.1016/j.celrep.2019.12.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963791PMC
January 2020

Nontraumatic Myelopathy in Malawi: A Prospective Study in an Area with High HIV Prevalence.

Am J Trop Med Hyg 2020 02;102(2):451-457

Division of Infectious Diseases and Tropical Medicine, University Hospital, LMU Munich, Munich, Germany.

Nontraumatic myelopathy causes severe morbidity and is not uncommon in Africa. Clinically, patients often present with paraplegia, and extrinsic cord compression and transverse myelitis are most common causes. Data on exact pathogenesis are scanty because of limitations in diagnostic methods. In Queen Elizabeth Central Hospital, Blantyre, Malawi, we recorded consecutive patients presenting with nontraumatic paraplegia for maximally 6 months between January and July 2010 and from March to December 2011. The diagnostic workup included imaging and examining blood, stool, urine, sputum, and cerebrospinal fluid (CSF) samples for infection. After discharge, additional diagnostic tests, including screening for virus infections, borreliosis, syphilis, and schistosomiasis, were carried out in the Netherlands. The clinical diagnosis was, thus, revised in retrospect with a more accurate final differential diagnosis. Of 58 patients included, the mean age was 41 years (range, 12-83 years) and the median time between onset and presentation was 18 days (range, 0-121 days), and of 55 patients tested, 23 (42%) were HIV positive. Spinal tuberculosis ( = 24, 41%), tumors ( = 16, 28%), and transverse myelitis ( = 6, 10%) were most common; in six cases (10%), no diagnosis could be made. The additional tests yielded evidence for CSF infection with , , Epstein-Barr virus (EBV), HHV-6, HIV, as well as a novel cyclovirus. The diagnosis of the cause of paraplegia is complex and requires access to an magnetic resonance imaging (MRI) scan and other diagnostic (molecular) tools to demonstrate infection. The major challenge is to confirm the role of detected pathogens in the pathophysiology and to design an effective and affordable diagnostic approach.
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http://dx.doi.org/10.4269/ajtmh.19-0209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008330PMC
February 2020

CRISPR Cas9 in Pancreatic Cancer Research.

Front Cell Dev Biol 2019 18;7:239. Epub 2019 Oct 18.

Department for Surgical Research, Universitätsklinikum Erlangen, Erlangen, Germany.

Pancreatic cancer is now becoming a common cause of cancer death with no significant change in patient survival over the last 10 years. The main treatment options for pancreatic cancer patients are surgery, radiation therapy and chemotherapy, but there is now considerable effort to develop new and effective treatments. In recent years, CRISPR/Cas9 technology has emerged as a powerful gene editing tool with promise, not only as an important research methodology, but also as a new and effective method for targeted therapy. In this review, we summarize current advances in CRISPR/Cas9 technology and its application to pancreatic cancer research, and importantly as a means of selectively targeting key drivers of pancreatic cancer.
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http://dx.doi.org/10.3389/fcell.2019.00239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813368PMC
October 2019

Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis.

Cancer Cell 2019 09;36(3):319-336.e7

Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK. Electronic address:

The metastatic process of colorectal cancer (CRC) is not fully understood and effective therapies are lacking. We show that activation of NOTCH1 signaling in the murine intestinal epithelium leads to highly penetrant metastasis (100% metastasis; with >80% liver metastases) in Kras-driven serrated cancer. Transcriptional profiling reveals that epithelial NOTCH1 signaling creates a tumor microenvironment (TME) reminiscent of poorly prognostic human CRC subtypes (CMS4 and CRIS-B), and drives metastasis through transforming growth factor (TGF) β-dependent neutrophil recruitment. Importantly, inhibition of this recruitment with clinically relevant therapeutic agents blocks metastasis. We propose that NOTCH1 signaling is key to CRC progression and should be exploited clinically.
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http://dx.doi.org/10.1016/j.ccell.2019.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853173PMC
September 2019

Prolactin Promotes Fibrosis and Pancreatic Cancer Progression.

Cancer Res 2019 10 8;79(20):5316-5327. Epub 2019 Aug 8.

Department of Surgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.

Pancreatic ductal adenocarcinoma (PDAC) is associated with significant fibrosis. Recent findings have highlighted the profibrotic activity of tissue-resident macrophages in the pancreatic cancer microenvironment. Here, we show that neoplastic pancreatic epithelium, as well as a subset of tissue-resident macrophages, expresses the prolactin-receptor (PRLR). High mobility group box 1-induced prolactin expression in the pancreas maintained FAK1 and STAT3 phosphorylation within the epithelium and stroma. Gain-of-function and loss-of-function experiments demonstrated the essential role of prolactin in promoting collagen deposition and fibrosis. Finally, the signaling cascade downstream of prolactin/PRLR activated STAT3 rather than STAT5 in PDAC. These findings suggest that targeting prolactin together with IL6, a known major activator of STAT3, could represent a novel therapeutic strategy for treating pancreatic cancer. SIGNIFICANCE: Prolactin is a key factor in the cross-talk between the stroma and neoplastic epithelium, functioning to promote fibrosis and PDAC progression.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801092PMC
October 2019

The integrin αvβ6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy.

J Pathol 2019 11 30;249(3):332-342. Epub 2019 Jul 30.

Centre for Tumour Biology, Barts Cancer Institute, CRUK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, London, UK.

Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 4% and desperately needs novel effective therapeutics. Integrin αvβ6 has been linked with poor prognosis in cancer but its potential as a target in PDAC remains unclear. We report that transcriptional expression analysis revealed that high levels of β6 mRNA correlated strongly with significantly poorer survival (n = 491 cases, p = 3.17 × 10 ). In two separate cohorts, we showed that over 80% of PDACs expressed αvβ6 protein and that paired metastases retained αvβ6 expression. In vitro, integrin αvβ6 promoted PDAC cell growth, survival, migration, and invasion. Treatment of both αvβ6-positive human PDAC xenografts and transgenic mice bearing αvβ6-positive PDAC with the αvβ6 blocking antibody 264RAD, combined with gemcitabine, significantly reduced tumour growth (p < 0.0001) and increased survival (log-rank test, p < 0.05). Antibody therapy was associated with suppression of tumour cell activity (suppression of pErk growth signals, increased apoptosis seen as activated caspase-3) and suppression of the pro-tumourigenic microenvironment (suppression of TGFβ signalling, fewer αSMA-positive myofibroblasts, decreased blood vessel density). These data show that αvβ6 promotes PDAC growth through both tumour cell and tumour microenvironment mechanisms and represents a valuable target for PDAC therapy. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852434PMC
November 2019

Molecular subtypes of pancreatic cancer.

Nat Rev Gastroenterol Hepatol 2019 04;16(4):207-220

Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, Scotland, UK.

Cancers that appear morphologically similar often have dramatically different clinical features, respond variably to therapy and have a range of outcomes. Compelling evidence now demonstrates that differences in the molecular pathology of otherwise indistinguishable cancers substantially impact the clinical characteristics of the disease. Molecular subtypes now guide preclinical and clinical therapeutic development and treatment in many cancer types. The ability to predict optimal therapeutic strategies ahead of treatment improves overall patient outcomes, minimizing treatment-related morbidity and cost. Although clinical decision making based on histopathological criteria underpinned by robust data is well established in many cancer types, subtypes of pancreatic cancer do not currently inform treatment decisions. However, accumulating molecular data are defining subgroups in pancreatic cancer with distinct biology and potential subtype-specific therapeutic vulnerabilities, providing the opportunity to define a de novo clinically applicable molecular taxonomy. This Review summarizes current knowledge concerning the molecular subtyping of pancreatic cancer and explores future strategies for using a molecular taxonomy to guide therapeutic development and ultimately routine therapy with the overall goal of improving outcomes for this disease.
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http://dx.doi.org/10.1038/s41575-019-0109-yDOI Listing
April 2019

Mutant p53s generate pro-invasive niches by influencing exosome podocalyxin levels.

Nat Commun 2018 11 29;9(1):5069. Epub 2018 Nov 29.

Beatson Institute for Cancer Research, Glasgow, G61 1BD, Scotland, UK.

Mutant p53s (mutp53) increase cancer invasiveness by upregulating Rab-coupling protein (RCP) and diacylglycerol kinase-α (DGKα)-dependent endosomal recycling. Here we report that mutp53-expressing tumour cells produce exosomes that mediate intercellular transfer of mutp53's invasive/migratory gain-of-function by increasing RCP-dependent integrin recycling in other tumour cells. This process depends on mutp53's ability to control production of the sialomucin, podocalyxin, and activity of the Rab35 GTPase which interacts with podocalyxin to influence its sorting to exosomes. Exosomes from mutp53-expressing tumour cells also influence integrin trafficking in normal fibroblasts to promote deposition of a highly pro-invasive extracellular matrix (ECM), and quantitative second harmonic generation microscopy indicates that this ECM displays a characteristic orthogonal morphology. The lung ECM of mice possessing mutp53-driven pancreatic adenocarcinomas also displays increased orthogonal characteristics which precedes metastasis, indicating that mutp53 can influence the microenvironment in distant organs in a way that can support invasive growth.
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http://dx.doi.org/10.1038/s41467-018-07339-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265295PMC
November 2018

Different opinion on the reported role of Poldip2 and ACSM1 in a mammalian lipoic acid salvage pathway controlling HIF-1 activation.

Proc Natl Acad Sci U S A 2018 08 24;115(32):E7458-E7459. Epub 2018 Jul 24.

Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, CB2 0XY Cambridge, United Kingdom;

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http://dx.doi.org/10.1073/pnas.1804041115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6094132PMC
August 2018

Metabolic Regulation of Hypoxia-Inducible Transcription Factors: The Role of Small Molecule Metabolites and Iron.

Biomedicines 2018 May 17;6(2). Epub 2018 May 17.

Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge CB2 0XY, UK.

Hypoxia-inducible transcription factors (HIFs) facilitate cellular adaptations to low-oxygen environments. However, it is increasingly recognised that HIFs may be activated in response to metabolic stimuli, even when oxygen is present. Understanding the mechanisms for the crosstalk that exists between HIF signalling and metabolic pathways is therefore important. This review focuses on the metabolic regulation of HIFs by small molecule metabolites and iron, highlighting the latest studies that explore how tricarboxylic acid (TCA) cycle intermediates, 2-hydroxyglutarate (2-HG) and intracellular iron levels influence the HIF response through modulating the activity of prolyl hydroxylases (PHDs). We also discuss the relevance of these metabolic pathways in physiological and disease contexts. Lastly, as PHDs are members of a large family of 2-oxoglutarate (2-OG) dependent dioxygenases that can all respond to metabolic stimuli, we explore the broader role of TCA cycle metabolites and 2-HG in the regulation of 2-OG dependent dioxygenases, focusing on the enzymes involved in chromatin remodelling.
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http://dx.doi.org/10.3390/biomedicines6020060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027492PMC
May 2018

CSF1R Macrophages Sustain Pancreatic Tumor Growth through T Cell Suppression and Maintenance of Key Gene Programs that Define the Squamous Subtype.

Cell Rep 2018 05;23(5):1448-1460

Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. Electronic address:

Pancreatic ductal adenocarcinoma (PDAC) is resistant to most therapies including single-agent immunotherapy and has a dense desmoplastic stroma, and most patients present with advanced metastatic disease. We reveal that macrophages are the dominant leukocyte population both in human PDAC stroma and autochthonous models, with an important functional contribution to the squamous subtype of human PDAC. We targeted macrophages in a genetic PDAC model using AZD7507, a potent selective inhibitor of CSF1R. AZD7507 caused shrinkage of established tumors and increased mouse survival in this difficult-to-treat model. Malignant cell proliferation diminished, with increased cell death and an enhanced T cell immune response. Loss of macrophages rewired other features of the TME, with global changes in gene expression akin to switching PDAC subtypes. These changes were markedly different to those elicited when neutrophils were targeted via CXCR2. These results suggest targeting the myeloid cell axis may be particularly efficacious in PDAC, especially with CSF1R inhibitors.
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http://dx.doi.org/10.1016/j.celrep.2018.03.131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946718PMC
May 2018

Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke.

N Engl J Med 2018 04;378(17):1573-1582

From the Departments of Medicine and Neurology, Melbourne Brain Centre (B.C.V.C., N.Y., B.Y., T.Y.W., D.G.S., E.R., H.Z., P.S., G.S., M.W.P., S.M.D.), and the Department of Radiology (P.J.M., R.J.D., S.J.B., P.M.D.), Royal Melbourne Hospital, and the Florey Institute of Neuroscience and Mental Health (L.C., N.Y., V.T., H.A., H.M., C.F.B., G.A.D.), University of Melbourne, Parkville, VIC, the Departments of Neurology (T.J.K.) and Radiology (R.S.), Royal Adelaide Hospital, and the Department of Neurology, Lyell McEwin Hospital (D.F.), Adelaide, SA, the Department of Neurosciences, Eastern Health and Eastern Health Clinical School (H.M.D., C.F.B.), and the Departments of Neurology (H.M., T.G.P.) and Radiology (W. Chong, R.V.C., L.-A.S.), Monash Medical Centre, Monash University, Clayton, VIC, the Departments of Neurology (V.T., M.S.) and Radiology (M.B., H.A.), Austin Hospital, Austin Health, Heidelberg, VIC, School of Medicine, Faculty of Health, Deakin University, Melbourne, VIC (H.A.), and the Departments of Medicine and Neurology, Melbourne Medical School, University of Melbourne and Western Health, Sunshine Hospital, St. Albans, VIC (T.W.), the Departments of Neurology (D.G.S., H.B.) and Radiology (K.R., D.L.), Princess Alexandra Hospital, and the Departments of Neurology (A.A.W., C.M.) and Radiology (A.C., K. Mitchell, J.C., K. Mahady), Royal Brisbane and Women's Hospital and the University of Queensland, Brisbane, the Departments of Neurology (P.B.) and Radiology (H.R., L.V.), Gold Coast University Hospital, Southport, QLD, and the Department of Neurology, Priority Research Centre for Brain and Mental Health Research, John Hunter Hospital, University of Newcastle, Newcastle, NSW (T.A., F.M., C.R.L., C.G.-E., M.W.P.), the Department of Neurology, Royal North Shore Hospital and Kolling Institute, University of Sydney (M.K.), and the Department of Radiology, Royal North Shore Hospital (T.J.H., K.C.F., B.S.S.), St. Leonards, and the Department of Radiology, Westmead Hospital, Sydney (T.J.H., K.C.F., B.S.S.) - all in Australia; and the Departments of Neurology (T.Y.W., J.N.F.) and Radiology (W. Collecutt), Christchurch Hospital, Christchurch, New Zealand.

Background: Intravenous infusion of alteplase is used for thrombolysis before endovascular thrombectomy for ischemic stroke. Tenecteplase, which is more fibrin-specific and has longer activity than alteplase, is given as a bolus and may increase the incidence of vascular reperfusion.

Methods: We randomly assigned patients with ischemic stroke who had occlusion of the internal carotid, basilar, or middle cerebral artery and who were eligible to undergo thrombectomy to receive tenecteplase (at a dose of 0.25 mg per kilogram of body weight; maximum dose, 25 mg) or alteplase (at a dose of 0.9 mg per kilogram; maximum dose, 90 mg) within 4.5 hours after symptom onset. The primary outcome was reperfusion of greater than 50% of the involved ischemic territory or an absence of retrievable thrombus at the time of the initial angiographic assessment. Noninferiority of tenecteplase was tested, followed by superiority. Secondary outcomes included the modified Rankin scale score (on a scale from 0 [no neurologic deficit] to 6 [death]) at 90 days. Safety outcomes were death and symptomatic intracerebral hemorrhage.

Results: Of 202 patients enrolled, 101 were assigned to receive tenecteplase and 101 to receive alteplase. The primary outcome occurred in 22% of the patients treated with tenecteplase versus 10% of those treated with alteplase (incidence difference, 12 percentage points; 95% confidence interval [CI], 2 to 21; incidence ratio, 2.2; 95% CI, 1.1 to 4.4; P=0.002 for noninferiority; P=0.03 for superiority). Tenecteplase resulted in a better 90-day functional outcome than alteplase (median modified Rankin scale score, 2 vs. 3; common odds ratio, 1.7; 95% CI, 1.0 to 2.8; P=0.04). Symptomatic intracerebral hemorrhage occurred in 1% of the patients in each group.

Conclusions: Tenecteplase before thrombectomy was associated with a higher incidence of reperfusion and better functional outcome than alteplase among patients with ischemic stroke treated within 4.5 hours after symptom onset. (Funded by the National Health and Medical Research Council of Australia and others; EXTEND-IA TNK ClinicalTrials.gov number, NCT02388061 .).
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http://dx.doi.org/10.1056/NEJMoa1716405DOI Listing
April 2018
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