Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer.

Current KRASG12C (OFF) inhibitors that target inactive GDP-bound KRASG12C cause responses in less than half of patients and these responses are not durable. A class of RASG12C (ON) inhibitors that targets active GTP-bound KRASG12C blocks ERK signaling more potently than the inactive-state inhibitors. Sensitivity to either class of agents is strongly correlated with inhibition of mTORC1 activity. We have previously shown that PI3K/mTOR and ERK-signaling pathways converge on key cellular processes and that inhibition of both pathways is required for inhibition of these processes and for significant antitumor activity. We find here that the combination of a KRASG12C inhibitor with a selective mTORC1 kinase inhibitor causes synergistic inhibition of Cyclin D1 expression and cap-dependent translation. Moreover, BIM upregulation by KRASG12C inhibition and inhibition of MCL-1 expression by the mTORC1 inhibitor are both required to induce significant cell death. In vivo, this combination causes deep, durable tumor regressions and is well tolerated. This study suggests that the ERK and PI3K/mTOR pathways each mitigate the effects of inhibition of the other and that combinatorial inhibition is a potential strategy for treating KRASG12C-dependent lung cancer.

Tenecteplase versus alteplase for thrombolysis in patients selected by use of perfusion imaging within 4·5 h of onset of ischaemic stroke (TASTE): a multicentre, randomised, controlled, phase 3 non-inferiority trial.

BACKGROUND: Intravenous tenecteplase increases reperfusion in patients with salvageable brain tissue on perfusion imaging and might have advantages over alteplase as a thrombolytic for ischaemic stroke. We aimed to assess the non-inferiority of tenecteplase versus alteplase on clinical outcomes in patients selected by use of perfusion imaging. METHODS: This international, multicentre, open-label, parallel-group, randomised, clinical non-inferiority trial enrolled patients from 35 hospitals in eight countries. Participants were aged 18 years or older, within 4·5 h of ischaemic stroke onset or last known well, were not being considered for endovascular thrombectomy, and met target mismatch criteria on brain perfusion imaging. Patients were randomly assigned (1:1) by use of a centralised web server with randomly permuted blocks to intravenous tenecteplase (0·25 mg/kg) or alteplase (0·90 mg/kg). The primary outcome was the proportion of patients without disability (modified Rankin Scale 0-1) at 3 months, assessed via masked review in both the intention-to-treat and per-protocol populations. We aimed to recruit 832 participants to yield 90% power (one-sided alpha=0·025) to detect a risk difference of 0·08, with an absolute non-inferiority margin of -0·03. The trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000243718, and the European Union Clinical Trials Register, EudraCT Number 2015-002657-36, and it is completed. FINDINGS: Recruitment ceased early following the announcement of other trial results showing non-inferiority of tenecteplase versus alteplase. Between March 21, 2014, and Oct 20, 2023, 680 patients were enrolled and randomly assigned to tenecteplase (n=339) and alteplase (n=341), all of whom were included in the intention-to-treat analysis (multiple imputation was used to account for missing primary outcome data for five patients). Protocol violations occurred in 74 participants, thus the per-protocol population comprised 601 people (295 in the tenecteplase group and 306 in the alteplase group). Participants had a median age of 74 years (IQR 63-82), baseline National Institutes of Health Stroke Scale score of 7 (4-11), and 260 (38%) were female. In the intention-to-treat analysis, the primary outcome occurred in 191 (57%) of 335 participants allocated to tenecteplase and 188 (55%) of 340 participants allocated to alteplase (standardised risk difference [SRD]=0·03 [95% CI -0·033 to 0·10], one-tailed pnon-inferiority=0·031). In the per-protocol analysis, the primary outcome occurred in 173 (59%) of 295 participants allocated to tenecteplase and 171 (56%) of 306 participants allocated to alteplase (SRD 0·05 [-0·02 to 0·12], one-tailed pnon-inferiority=0·01). Nine (3%) of 337 patients in the tenecteplase group and six (2%) of 340 in the alteplase group had symptomatic intracranial haemorrhage (unadjusted risk difference=0·01 [95% CI -0·01 to 0·03]) and 23 (7%) of 335 and 15 (4%) of 340 died within 90 days of starting treatment (SRD 0·02 [95% CI -0·02 to 0·05]). INTERPRETATION: The findings in our study provide further evidence to strengthen the assertion of the non-inferiority of tenecteplase to alteplase, specifically when perfusion imaging has been used to identify reperfusion-eligible stroke patients. Although non-inferiority was achieved in the per-protocol population, it was not reached in the intention-to-treat analysis, possibly due to sample size limtations. Nonetheless, large-scale implementation of perfusion CT to assist in patient selection for intravenous thrombolysis in the early time window was shown to be feasible. FUNDING: Australian National Health Medical Research Council; Boehringer Ingelheim.

Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial.

BACKGROUND: Individuals with minor ischaemic stroke and intracranial occlusion are at increased risk of poor outcomes. Intravenous thrombolysis with tenecteplase might improve outcomes in this population. We aimed to test the superiority of intravenous tenecteplase over non-thrombolytic standard of care in patients with minor ischaemic stroke and intracranial occlusion or focal perfusion abnormality. METHODS: In this multicentre, prospective, parallel group, open label with blinded outcome assessment, randomised controlled trial, adult patients (aged ≥18 years) were included at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the UK. Eligible patients with minor acute ischaemic stroke (National Institutes of Health Stroke Scale score 0-5) and intracranial occlusion or focal perfusion abnormality were enrolled within 12 h from stroke onset. Participants were randomly assigned (1:1), using a minimal sufficient balance algorithm to intravenous tenecteplase (0·25 mg/kg) or non-thrombolytic standard of care (control). Primary outcome was a return to baseline functioning on pre-morbid modified Rankin Scale score in the intention-to-treat (ITT) population (all patients randomly assigned to a treatment group and who did not withdraw consent to participate) assessed at 90 days. Safety outcomes were reported in the ITT population and included symptomatic intracranial haemorrhage and death. This trial is registered with ClinicalTrials.gov, NCT02398656, and is closed to accrual. FINDINGS: The trial was stopped early for futility. Between April 27, 2015, and Jan 19, 2024, 886 patients were enrolled; 369 (42%) were female and 517 (58%) were male. 454 (51%) were assigned to control and 432 (49%) to intravenous tenecteplase. The primary outcome occurred in 338 (75%) of 452 patients in the control group and 309 (72%) of 432 in the tenecteplase group (risk ratio [RR] 0·96, 95% CI 0·88-1·04, p=0·29). More patients died in the tenecteplase group (20 deaths [5%]) than in the control group (five deaths [1%]; adjusted hazard ratio 3·8; 95% CI 1·4-10·2, p=0·0085). There were eight (2%) symptomatic intracranial haemorrhages in the tenecteplase group versus two (<1%) in the control group (RR 4·2; 95% CI 0·9-19·7, p=0·059). INTERPRETATION: There was no benefit and possible harm from treatment with intravenous tenecteplase. Patients with minor stroke and intracranial occlusion should not be routinely treated with intravenous thrombolysis. FUNDING: Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, and the British Heart Foundation.

Long-term cognitive recovery following isolated bilateral infarction of the fornix presenting with amnesia.

Introduction: Isolated infarction of the fornix is a relatively rare stroke syndrome frequently associated with amnesia. The long-term cognitive outcome in cases of acute fornix infarction is poorly understood. This is largely due to the limited number of case studies that have documented cognitive outcomes beyond the acute recovery phase on quantifiable neuropsychological measures. We describe a patient who developed acute amnesia and was subsequently diagnosed on cerebral MRI with bilateral infarction in the anterior columns of the fornix. Method: Comprehensive neuropsychological review was undertaken prospectively at baseline, early and late phases of recovery. Results: At 9 months post-stroke, there was some reduction in the severity of memory dysfunction, but a significant anterograde amnesia persisted. Conclusion: This is one of the very few cases in the literature where neuropsychological function has been comprehensively and serially examined over the first year post-isolated bilateral fornix infarction. It is concluded that amnesia can persist well beyond 6 months in these cases, with associated functional impairment in daily life.

Tranexamic acid versus placebo in individuals with intracerebral haemorrhage treated within 2 h of symptom onset (STOP-MSU): an international, double-blind, randomised, phase 2 trial.

BACKGROUND: Tranexamic acid, an antifibrinolytic agent, might attenuate haematoma growth after an intracerebral haemorrhage. We aimed to determine whether treatment with intravenous tranexamic acid within 2 h of an intracerebral haemorrhage would reduce haematoma growth compared with placebo. METHODS: STOP-MSU was an investigator-led, double-blind, randomised, phase 2 trial conducted at 24 hospitals and one mobile stroke unit in Australia, Finland, New Zealand, Taiwan, and Viet Nam. Eligible participants had acute spontaneous intracerebral haemorrhage confirmed on non-contrast CT, were aged 18 years or older, and could be treated with the investigational product within 2 h of stroke onset. Using randomly permuted blocks (block size of 4) and a concealed pre-randomised assignment procedure, participants were randomly assigned (1:1) to receive intravenous tranexamic acid (1 g over 10 min followed by 1 g over 8 h) or placebo (saline; matched dosing regimen) commencing within 2 h of symptom onset. Participants, investigators, and treating teams were masked to group assignment. The primary outcome was haematoma growth, defined as either at least 33% relative growth or at least 6 mL absolute growth on CT at 24 h (target range 18-30 h) from the baseline CT. The analysis was conducted within the estimand framework with primary analyses adhering to the intention-to-treat principle. The primary endpoint and secondary safety endpoints (mortality at days 7 and 90 and major thromboembolic events at day 90) were assessed in all participants randomly assigned to treatment groups who did not withdraw consent to use any data. This study was registered with ClinicalTrials.gov, NCT03385928, and the trial is now complete. FINDINGS: Between March 19, 2018, and Feb 27, 2023, 202 participants were recruited, of whom one withdrew consent for any data use. The remaining 201 participants were randomly assigned to either placebo (n=98) or tranexamic acid (n=103; intention-to-treat population). Median age was 66 years (IQR 55-77), and 82 (41%) were female and 119 (59%) were male; no data on race or ethnicity were collected. CT scans at baseline or follow-up were missing or of inadequate quality in three participants (one in the placebo group and two in the tranexamic acid group), and were considered missing at random. Haematoma growth occurred in 37 (38%) of 97 assessable participants in the placebo group and 43 (43%) of 101 assessable participants in the tranexamic acid group (adjusted odds ratio [aOR] 1·31 [95% CI 0·72 to 2·40], p=0·37). Major thromboembolic events occurred in one (1%) of 98 participants in the placebo group and three (3%) of 103 in the tranexamic acid group (risk difference 0·02 [95% CI -0·02 to 0·06]). By 7 days, eight (8%) participants in the placebo group and eight (8%) in the tranexamic acid group had died (aOR 1·08 [95% CI 0·35 to 3·35]) and by 90 days, 15 (15%) participants in the placebo group and 19 (18%) in the tranexamic acid group had died (aOR 1·61 [95% CI 0·65 to 3·98]). INTERPRETATION: Intravenous tranexamic acid did not reduce haematoma growth when administered within 2 h of intracerebral haemorrhage symptom onset. There were no observed effects on other imaging endpoints, functional outcome, or safety. Based on our results, tranexamic acid should not be used routinely in primary intracerebral haemorrhage, although results of ongoing phase 3 trials will add further context to these findings. FUNDING: Australian Government Medical Research Future Fund.

A Randomized Controlled Trial of Tenecteplase Versus Standard of Care for Minor Ischemic Stroke with Proven Occlusion (TEMPO-2): Rational and design of a multicenter, randomized open-label clinical trial.

BACKGROUND: Almost half of acute ischemic stroke patients present with mild symptoms and there are large practice variations in their treatment globally. Individuals with an intracranial occlusion who present with minor stroke are at an increased risk of early neurological deterioration and poor outcomes. Individual patient data meta-analysis in the subgroup of patients with minor deficits showed benefit of alteplase in improving outcomes; however, this benefit has not been seen with intravenous alteplase in published randomized trials. DESIGN: TEMPO-2 (A Randomized Controlled Trial of Tenecteplase Versus Standard of Care for Minor Ischemic Stroke With Proven Occlusion) is a prospective, open label with blinded outcome assessment, randomized controlled trial, designed to test the superiority of intravenous tenecteplase (0.25 mg/kg) over nonthrombolytic standard of care, with an estimated sample size of 1274 patients. Adult patients presenting with acute ischemic stroke with the National Institutes of Health Stroke Scale (NIHSS) ⩽ 5 and visible arterial occlusion or perfusion deficit within 12 h of onset are randomized to receive either tenecteplase (0.25 mg/kg) or standard of care. The primary outcome is return to baseline neurological functioning, measured by the modified Rankin scale (mRS) at 90 days. Safety outcomes include death and symptomatic hemorrhage (intra or extra-cranial). Other secondary outcomes include mRS 0-1, mRS 0-2, ordinal shift analysis of the mRS, partial, and full recanalization on follow-up computed tomography angiogram. CONCLUSION: Results of this trial will aid in determining whether there is benefit of using tenecteplase (0.25 mg/kg) in treating patients presenting with minor stroke who are at high risk of developing poor outcomes due to presence of an intracranial occlusion. DATA ACCESS STATEMENT: Data will be available upon reasonable request.

Standardization of definition and management for bleeding disorder of unknown cause: communication from the SSC of the ISTH.

In many patients referred with significant bleeding phenotype, laboratory testing fails to define any hemostatic abnormalities. Clinical practice with respect to diagnosis and management of this patient cohort poses significant clinical challenges. We recommend that bleeding history in these patients should be objectively assessed using the International Society on Thrombosis and Haemostasis (ISTH) bleeding assessment tool. Patients with increased bleeding assessment tool scores should progress to hemostasis laboratory testing. To diagnose bleeding disorder of unknown cause (BDUC), normal complete blood count, prothrombin time, activated partial thromboplastin time, thrombin time, von Willebrand factor antigen, von Willebrand factor function, coagulation factors VIII, IX, and XI, and platelet light transmission aggregometry should be the minimum laboratory assessment. In some laboratories, additional specialized hemostasis testing may be performed to identify other rare causes of bleeding. We recommend that patients with a significant bleeding phenotype but normal laboratory investigations should be registered with a diagnosis of BDUC in preference to other terminology. Global hemostatic tests and markers of fibrinolysis demonstrate variable abnormalities, and their clinical significance remains uncertain. Targeted genomic sequencing examining candidate hemostatic genes has a low diagnostic yield. Underlying BDUC should be considered in patients with heavy menstrual bleeding since delays in diagnosis often extend to many years and negatively impact quality of life. Treatment options for BDUC patients include tranexamic acid, desmopressin, and platelet transfusions.

Algorithm for Rapid Exclusion of Clinically Relevant Plasma Levels of Direct Oral Anticoagulants in Patients Using the DOAC Dipstick: An Expert Consensus Paper.

BACKGROUND: With the widespread use of direct oral anticoagulants (DOACs), there is an urgent need for a rapid assay to exclude clinically relevant plasma levels. Accurate and rapid determination of DOAC levels would guide medical decision-making to (1) determine the potential contribution of the DOAC to spontaneous or trauma-induced hemorrhage; (2) identify appropriate candidates for reversal, or (3) optimize the timing of urgent surgery or intervention. METHODS AND RESULTS: The DOAC Dipstick test uses a disposable strip to identify factor Xa- or thrombin inhibitors in a urine sample. Based on the results of a systematic literature search followed by an analysis of a simple pooling of five retrieved clinical studies, the test strip has a high sensitivity and an acceptably high negative predictive value when compared with levels measured with liquid chromatography tandem mass spectrometry or calibrated chromogenic assays to reliably exclude plasma DOAC concentrations ≥30 ng/mL. CONCLUSION: Based on these data, a simple algorithm is proposed to enhance medical decision-making in acute care indications useful primarily in hospitals not having readily available quantitative tests and 24/7. This algorithm not only determines DOAC exposure but also differentiates between factor Xa and thrombin inhibitors to better guide clinical management.

Long-term treatment with rilzabrutinib in patients with immune thrombocytopenia.

ABSTRACT: Immune thrombocytopenia (ITP) is an autoimmune disease associated with autoantibody-mediated platelet destruction and impaired platelet production, resulting in thrombocytopenia and a predisposition to bleeding. The ongoing, global phase 1/2 study showed that rilzabrutinib, a Bruton tyrosine kinase inhibitor specifically developed to treat autoimmune disorders, could be an efficacious and well-tolerated treatment for ITP. Clinical activity, durability of response, and safety were evaluated in 16 responding patients who continued rilzabrutinib 400 mg twice daily in the long-term extension (LTE) study. At LTE entry, the median platelet count was 87 × 109/L in all patients, 68 × 109/L in those who had rilzabrutinib monotherapy (n = 5), and 156 × 109/L in patients who received concomitant ITP medication (thrombopoietin-receptor agonists and/or corticosteroids, n = 11). At a median duration of treatment of 478 days (range, 303-764), 11 of 16 patients (69%) continued to receive rilzabrutinib. A platelet count of ≥50 × 109/L was reported in 93% of patients for more than half of their monthly visits. The median percentage of LTE weeks with platelet counts ≥30 × 109/L and ≥50 × 109/L was 100% and 88%, respectively. Five patients discontinued concomitant ITP therapy and maintained median platelet counts of 106 × 109/L at 3 to 6 months after stopping concomitant ITP therapy. Adverse events related to treatment were grade 1 or 2 and transient, with no bleeding, thrombotic, or serious adverse events. With continued rilzabrutinib treatment in the LTE, platelet responses were durable and stable over time with no new safety signals. This trial is registered at www.clinicaltrials.gov as #NCT03395210 and www.clinicaltrialsregister.eu as EudraCT 2017-004012-19.

Results of an international survey of opinions on the definitions and treatments for heparin-induced thrombocytopenia: communication from the ISTH SSC Subcommittee on Platelet Immunology.

Heparin-induced thrombocytopenia (HIT) is rare, affecting fewer than 1 in 1500 hospital admissions. Despite the increasing adoption of new therapies in HIT, such as direct oral anticoagulants and pooled immunoglobulins, there is limited high-quality evidence to guide clinicians. Numerous uncommon presentations of HIT and HIT-like entities have recently been recognized, and a harmonized approach to their classification is required to study them better. We present the results of an international survey of opinions from experts and practitioners in the field of platelet immunology regarding the role of direct oral anticoagulants in HIT, novel definitions of subclassifications of HIT-like platelet factor 4 immune conditions (spontaneous autoimmune HIT, persistent autoimmune HIT, and treatment-refractory HIT), and the role for intravenous immunoglobulins in the treatment paradigm of HIT and these HIT-like conditions. From 102 survey responses, there was broad acceptance of rivaroxaban (74.5%) and apixaban (73.5%) even before platelet recovery, as well as for intravenous immunoglobulin in the management of spontaneous (85.6%), persistent (83.7%), and treatment-refractory HIT (87.4%). With this mandate for harmonizing terminologies and treatment approaches in special situations without robust clinical data owing to their rarity, we plan to conduct a robust survey, establish international consensus, and draft management guidelines for HIT and platelet factor 4 immune diseases in the near future.

Acquired Angioedema Associated with Lymphoproliferative Disorders.

Introduction: Acquired angioedema due to C1 esterase inhibitor deficiency (C1INH-AAE) is most associated with lymphoproliferative disorders (LPDs), particularly low-grade B-cell subtypes. The condition remains under-recognized with long diagnostic delays due to various challenges including a lack of awareness of the condition. Case Presentation: We discuss 4 cases of C1INH-AAE associated with low-grade B-cell LPDs, including various diagnostic and management challenges. As our cases illustrate, constitutional symptoms or overt manifestations of LPD at diagnosis are often absent. Hence, a comprehensive multimodal approach to screening for an underlying B-LPD is important when a diagnosis of acquired angioedema is made. Levels of complement C4, C1q, and C1INH are useful for diagnosing C1INH-AAE and for monitoring disease activity. Changes in these parameters may also indicate relapse of the underlying hematological malignancy. Treating the underlying disorder is important as this commonly leads to clinical improvement with decreased episodes of angioedema and normalization of complement studies. Conclusion: Awareness of C1INH-AAE can lead to an early diagnosis of hematological malignancies. The absence of constitutional symptoms emphasizes the need for a comprehensive multimodal approach to screening for LPD in C1INH-AAE. C4, C1INH level, and function are useful for monitoring disease activity.

Response to COVID-19 vaccination in patients on cancer therapy: Analysis in a SARS-CoV-2-naïve population.

BACKGROUND: Cancer patients have increased morbidity and mortality from COVID-19, but may respond poorly to vaccination. The Evaluation of COVID-19 Vaccination Efficacy and Rare Events in Solid Tumors (EVEREST) study, comparing seropositivity between cancer patients and healthy controls in a low SARS-CoV-2 community-transmission setting, allows determination of vaccine response with minimal interference from infection. METHODS: Solid tumor patients from The Canberra Hospital, Canberra, Australia, and healthy controls who received COVID-19 vaccination between March 2021 and January 2022 were included. Blood samples were collected at baseline, pre-second vaccine dose and at 1, 3 (primary endpoint), and 6 months post-second dose. SARS-CoV-2 anti-spike-RBD (S-RBD) and anti-nucleocapsid IgG antibodies were measured. RESULTS: Ninety-six solid tumor patients and 20 healthy controls were enrolled, with median age 62 years, and 60% were female. Participants received either AZD1222 (65%) or BNT162b2 (35%) COVID-19 vaccines. Seropositivity 3 months post vaccination was 87% (76/87) in patients and 100% (20/20) in controls (p = .12). Seropositivity was observed in 84% of patients on chemotherapy, 80% on immunotherapy, and 96% on targeted therapy (differences not satistically significant). Seropositivity in cancer patients increased from 40% (6/15) after first dose, to 95% (35/37) 1 month after second dose, then dropped to 87% (76/87) 3 months after second dose. CONCLUSION: Most patients and all controls became seropositive after two vaccine doses. Antibody concentrations and seropositivity showed a decrease between 1 and 3 months post vaccination, highlighting need for booster vaccinations. SARS-CoV-2 infection amplifies S-RBD antibody responses; however, cannot be adequately identified using nucleocapsid serology. This underlines the value of our COVID-naïve population in studying vaccine immunogenicity.

Platelets mediate the clearance of senescent red blood cells by forming prophagocytic platelet-cell complexes.

ABSTRACT: In humans, ∼0.1% to 0.3% of circulating red blood cells (RBCs) are present as platelet-RBC (P-RBC) complexes, and it is 1% to 2% in mice. Excessive P-RBC complexes are found in diseases that compromise RBC health (eg, sickle cell disease and malaria) and contribute to pathogenesis. However, the physiological role of P-RBC complexes in healthy blood is unknown. As a result of damage accumulated over their lifetime, RBCs nearing senescence exhibit physiological and molecular changes akin to those in platelet-binding RBCs in sickle cell disease and malaria. Therefore, we hypothesized that RBCs nearing senescence are targets for platelet binding and P-RBC formation. Confirming this hypothesis, pulse-chase labeling studies in mice revealed an approximately tenfold increase in P-RBC complexes in the most chronologically aged RBC population compared with younger cells. When reintroduced into mice, these complexes were selectively cleared from the bloodstream (in preference to platelet-free RBC) through the reticuloendothelial system and erythrophagocytes in the spleen. As a corollary, patients without a spleen had higher levels of complexes in their bloodstream. When the platelet supply was artificially reduced in mice, fewer RBC complexes were formed, fewer erythrophagocytes were generated, and more senescent RBCs remained in circulation. Similar imbalances in complex levels and senescent RBC burden were observed in humans with immune thrombocytopenia (ITP). These findings indicate that platelets are important for binding and clearing senescent RBCs, and disruptions in platelet count or complex formation and clearance may negatively affect RBC homeostasis and may contribute to the known risk of thrombosis in ITP and after splenectomy.

Management of Poststroke Hyperglycemia: Results of the TEXAIS Randomized Clinical Trial.

BACKGROUND: Hyperglycemia in acute ischemic stroke reduces the efficacy of stroke thrombolysis and thrombectomy, with worse clinical outcomes. Insulin-based therapies are difficult to implement and may cause hypoglycemia. We investigated whether exenatide, a GLP-1 (glucagon-like peptide-1) receptor agonist, would improve stroke outcomes, and control poststroke hyperglycemia with minimal hypoglycemia. METHODS: The TEXAIS trial (Treatment With Exenatide in Acute Ischemic Stroke) was an international, multicenter, phase 2 prospective randomized clinical trial (PROBE [Prospective Randomized Open Blinded End-Point] design) enrolling adult patients with acute ischemic stroke ≤9 hours of stroke onset to receive exenatide (5 µg BID subcutaneous injection) or standard care for 5 days, or until hospital discharge (whichever sooner). The primary outcome (intention to treat) was the proportion of patients with ≥8-point improvement in National Institutes of Health Stroke Scale score (or National Institutes of Health Stroke Scale scores 0-1) at 7 days poststroke. Safety outcomes included death, episodes of hyperglycemia, hypoglycemia, and adverse event. RESULTS: From April 2016 to June 2021, 350 patients were randomized (exenatide, n=177, standard care, n=173). Median age, 71 years (interquartile range, 62-79), median National Institutes of Health Stroke Scale score, 4 (interquartile range, 2-8). Planned recruitment (n=528) was stopped early due to COVID-19 disruptions and funding constraints. The primary outcome was achieved in 97 of 171 (56.7%) in the standard care group versus 104 of 170 (61.2%) in the exenatide group (adjusted odds ratio, 1.22 [95% CI, 0.79-1.88]; P=0.38). No differences in secondary outcomes were observed. The per-patient mean daily frequency of hyperglycemia was significantly less in the exenatide group across all quartiles. No episodes of hypoglycemia were recorded over the treatment period. Adverse events of mild nausea and vomiting occurred in 6 (3.5%) exenatide patients versus 0 (0%) standard care with no withdrawal. CONCLUSIONS: Treatment with exenatide did not reduce neurological impairment at 7 days in patients with acute ischemic stroke. Exenatide did significantly reduce the frequency of hyperglycemic events, without hypoglycemia, and was safe to use. Larger acute stroke trials using GLP-1 agonists such as exenatide should be considered. REGISTRATION: URL: www.australianclinicaltrials.gov.au; Unique identifier: ACTRN12617000409370. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03287076.

Frequency and outcomes of obinutuzumab-induced thrombocytopenia.

Obinutuzumab is a third-generation anti-CD20 monoclonal antibody widely used in the treatment of B-lymphoproliferative disorders but infrequently associated with severe thrombocytopenia, which can be life-threatening. The pathophysiology is unclear, but platelet clearance can be extremely rapid (usually within 24 h). In a retrospective case series, we have identified four cases among 149 recipients of obinutuzumab-containing chemotherapy regimens between 2015 and 2022 treated for haematological malignancies in Canberra, Australia (frequency 2.7%). We illustrate four cases of obinutuzumab-induced thrombocytopenia with a review of the literature. Research is required to identify the pathophysiology and improve early recognition and management of the condition in the context of multiagent chemotherapy.

The clinicopathological features of thrombosis with thrombocytopenia syndrome following ChAdOx1-S (AZD1222) vaccination and case outcomes in Australia: a population-based study.

Background: Thrombosis with thrombocytopenia syndrome (TTS) associated with viral vector COVID-19 vaccines, including ChAdOx1-S (AstraZeneca AZD1222) vaccine, can result in significant morbidity and mortality. We report the clinicopathological features of TTS following ChAdOx1-S vaccination and summarise the case outcomes in Australia. Methods: In this cohort study, patients diagnosed with TTS in Australia between 23 March and 31 December 2021 were identified according to predefined criteria. Cases were included if they met the Therapeutic Goods Administration (TGA) probable and confirmed case definitions and were reclassified using Centres for Disease Control and Prevention (CDC) definition for analysis. Data were collected on patient baseline characteristics, clinicopathological features, risk factors, treatment and outcomes. Findings: A total of 170 TTS cases were identified, with most occurring after the first dose (87%) of ChAdOx1-S. The median time to symptom onset after vaccination and symptom onset to admission was 11 and 2 days respectively. The median age of cases was 66 years (interquartile range 55-74). All except two patients received therapeutic anticoagulation and 66% received intravenous immunoglobulin. Overall, 85.3% of cases were discharged home after a median hospitalisation of 6 days, 9.4% required ongoing rehabilitation and 5.3% died. Eight deaths were related to TTS, with another dying from an unrelated condition while receiving treatment for TTS. Deaths occurred more commonly in those classified as Tier 1 according to the CDC definition and were associated with more severe thrombocytopenia and disease-related haemorrhage. Interpretation: TTS, while rare, can be severe and have catastrophic outcomes in some individuals. In Australia, the mortality rate was low compared to that reported in other high-income countries. Almost all received therapeutic anticoagulation with no bleeding complications and were successfully discharged. This emphasises the importance of community education and an established pathway for early recognition, diagnosis and treatment of TTS. Funding: Australian Commonwealth Department of Health and Aged Care. H.A Tran, N. Wood, J. Buttery, N.W. Crawford, S.D. Chunilal, V.M. Chen are supported by Medical Research Future Funds (MRFF) grant ID 2015305.

Will code one day run a code? Performance of language models on ACEM primary examinations and implications.

OBJECTIVE: Large language models (LLMs) have demonstrated mixed results in their ability to pass various specialist medical examination and their performance within the field of emergency medicine remains unknown. METHODS: We explored the performance of three prevalent LLMs (OpenAI's GPT series, Google's Bard, and Microsoft's Bing Chat) on a practice ACEM primary examination. RESULTS: All LLMs achieved a passing score, with scores with GPT 4.0 outperforming the average candidate. CONCLUSION: Large language models, by passing the ACEM primary examination, show potential as tools for medical education and practice. However, limitations exist and are discussed.

Lowering PCO2 With Noninvasive Ventilation Is Associated With Improved Survival in Chronic Hypercapnic Respiratory Failure.

BACKGROUND: Chronic hypercapnic respiratory failure is associated with high mortality. Although previous work has demonstrated a mortality improvement with high-intensity noninvasive ventilation in COPD, it is unclear whether a PCO2 reduction strategy is associated with improved outcomes in other populations of chronic hypercapnia. METHODS: The objective of this study was to investigate the association between PCO2 reduction (by using transcutaneous PCO2 as an estimate for PaCO2 and survival in a broad population of individuals treated with noninvasive ventilation for chronic hypercapnia. We hypothesized that reductions in PCO2 would be associated with improved survival. Therefore, we performed a cohort study of all the subjects evaluated from February 2012 to January 2021 for noninvasive ventilation initiation and/or optimization due to chronic hypercapnia at a home ventilation clinic in an academic center. We used multivariable Cox proportional hazard models with time-varying coefficients and PCO2 as a time-varying covariate to test the association between PCO2 and all-cause mortality and when adjusting for known cofounders. RESULTS: The mean ± SD age of 337 subjects was 57 ± 16 years, 37% women, and 85% white. In a univariate analysis, survival probability increased with reductions in PCO2 to < 50 mm Hg after 90 d, and these remained significant after adjusting for age, sex, race, body mass index, diagnosis, Charlson comorbidity index, and baseline PCO2 . In the multivariable analysis, the subjects who had a PaCO2 < 50 mm Hg had a reduced mortality risk of 94% between 90 and 179 d (hazard ratio [HR] 0.06, 95% CI 0.01-0.50), 69% between 180 and 364 d (HR 0.31, 95% CI 0.12-0.79), and 73% for 365-730 d (HR 0.27, 95% CI 0.13-0.56). CONCLUSIONS: Reduction in PCO2 from baseline for subjects with chronic hypercapnia treated with noninvasive ventilation was associated with improved survival. Management strategies should target the greatest attainable reductions in PCO2 .

Safety and Efficacy of Tenecteplase and Alteplase in Patients With Tandem Lesion Stroke: A Post Hoc Analysis of the EXTEND-IA TNK Trials.

BACKGROUND AND OBJECTIVES: The safety and efficacy of tenecteplase (TNK) in patients with tandem lesion (TL) stroke is unknown. We performed a comparative analysis of TNK and alteplase in patients with TLs. METHODS: We first compared the treatment effect of TNK and alteplase in patients with TLs using individual patient data from the EXTEND-IA TNK trials. We evaluated intracranial reperfusion at initial angiographic assessment and 90-day modified Rankin scale (mRS) with ordinal logistic and Firth regression models. Because 2 key outcomes, mortality and symptomatic intracranial hemorrhage (sICH), were few in number among those who received alteplase in the EXTEND-IA TNK trials, we generated pooled estimates for these outcomes by supplementing trial data with estimates of incidence obtained through a meta-analysis of studies identified in a systematic review. We then calculated unadjusted risk differences to compare the pooled estimates for those receiving alteplase with the incidence observed in the trial among those receiving TNK. RESULTS: Seventy-one of 483 patients (15%) in the EXTEND-IA TNK trials possessed a TL. In patients with TLs, intracranial reperfusion was observed in 11/56 (20%) of TNK-treated patients vs 1/15 (7%) alteplase-treated patients (adjusted odds ratio 2.19; 95% CI 0.28-17.29). No significant difference in 90-day mRS was observed (adjusted common odds ratio 1.48; 95% CI 0.44-5.00). A pooled study-level proportion of alteplase-associated mortality and sICH was 0.14 (95% CI 0.08-0.21) and 0.09 (95% CI 0.04-0.16), respectively. Compared with a mortality rate of 0.09 (95% CI 0.03-0.20) and an sICH rate of 0.07 (95% CI 0.02-0.17) in TNK-treated patients, no significant difference was observed. DISCUSSION: Functional outcomes, mortality, and sICH did not significantly differ between patients with TLs treated with TNK and those treated with alteplase. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that TNK is associated with similar rates of intracranial reperfusion, functional outcome, mortality, and sICH compared with alteplase in patients with acute stroke due to TLs. However, the CIs do not rule out clinically important differences. TRIAL REGISTRATION INFORMATION: clinicaltrials.gov/ct2/show/NCT02388061; clinicaltrials.gov/ct2/show/NCT03340493.