Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial

Background Tranexamic acid reduces surgical bleeding and decreases mortality in patients with traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury (TBI) and can cause brain herniation and death. We aimed to assess the effects of tranexamic acid in patients with TBI. Methods This randomised, placebo-controlled trial was done in 175 hospitals in 29 countries. Adults with TBI who were within 3 h of injury, had a Glasgow Coma Scale (GCS) score of 12 or lower or any intracranial bleeding on CT scan, and no major extracranial bleeding were eligible. The time window for eligibility was originally 8 h but in 2016 the protocol was changed to limit recruitment to patients within 3 h of injury. This change was made blind to the trial data, in response to external evidence suggesting that delayed treatment is unlikely to be effective. We randomly assigned (1:1) patients to receive tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 h) or matching placebo. Patients were assigned by selecting a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was head injury-related death in hospital within 28 days of injury in patients treated within 3 h of injury. We prespecified a sensitivity analysis that excluded patients with a GCS score of 3 and those with bilateral unreactive pupils at baseline. All analyses were done by intention to treat. This trial was registered with ISRCTN (ISRCTN15088122), ClinicalTrials.gov (NCT01402882), EudraCT (2011-003669-14), and the Pan African Clinical Trial Registry (PACTR20121000441277). Results Between July 20, 2012, and Jan 31, 2019, we randomly allocated 12 737 patients with TBI to receive tranexamic acid (6406 [50·3%] or placebo [6331 [49·7%], of whom 9202 (72·2%) patients were treated within 3 h of injury. Among patients treated within 3 h of injury, the risk of head injury-related death was 18·5% in the tranexamic acid group versus 19·8% in the placebo group (855 vs 892 events; risk ratio [RR] 0·94 [95% CI 0·86-1·02]). In the prespecified sensitivity analysis that excluded patients with a GCS score of 3 or bilateral unreactive pupils at baseline, the risk of head injury-related death was 12·5% in the tranexamic acid group versus 14·0% in the placebo group (485 vs 525 events; RR 0·89 [95% CI 0·80-1·00]). The risk of head injury-related death reduced with tranexamic acid in patients with mild-to-moderate head injury (RR 0·78 [95% CI 0·64-0·95]) but not in patients with severe head injury (0·99 [95% CI 0·91-1·07]; p value for heterogeneity 0·030). Early treatment was more effective than was later treatment in patients with mild and moderate head injury (p=0·005) but time to treatment had no obvious effect in patients with severe head injury (p=0·73). The risk of vascular occlusive events was similar in the tranexamic acid and placebo groups (RR 0·98 (0·74-1·28). The risk of seizures was also similar between groups (1·09 [95% CI 0·90-1·33]). Interpretation Our results show that tranexamic acid is safe in patients with TBI and that treatment within 3 h of injury reduces head injury-related death. Patients should be treated as soon as possible after injury. Funding National Institute for Health Research Health Technology Assessment, JP Moulton Charitable Trust, Department of Health and Social Care, Department for International Development, Global Challenges Research Fund, Medical Research Council, and Wellcome Trust (Joint Global Health Trials scheme)

Abstract P6-01-40: Integrative transcriptomic analysis and cohort validation identify key genes in chemotherapy treatment response in Latino breast cancer patients

Abstract Purpose: Breast cancer (BC) is one of the most frequent invasive cancers and one of the main causes of cancer mortality in women. Effective treatment interventions for BC are urgently required to improve survival rate and quality of life. Chemotherapy has been widely applied in BC treatment; however, therapeutic resistance remains an unresolved issue. Currently, only a minority of patients benefit from chemotherapy, emphasizing the need to identify more effective hub genes associated with therapy response. The overarching goal of this study is to assess hub genes correlated with BC chemotherapy treatment response via multiple databases and validate the workflow in an independent cohort of Hispanic/Latino (Colombian) women diagnosed with invasive Luminal B BC candidates for neoadjuvant chemotherapy. Design: Screening and multistep filtering of common genes correlated with chemotherapeutic response was performed by integrating differentially expressed genes between responders and non-responders in publicly available datasets. For each database, the differentially expressed genes (DEGs) between non-responders and responders were identified using GEO2R and LIMMA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted for the identified common genes using Metascape and DAVID. Functional enrichment analysis and protein-protein interaction (PPI) network for DEGs were constructed using (STRING) database. Hub genes were identified from PPI network by Cytoscape software analysis. The mRNA expression of hub genes in BC and normal tissues was subsequently explored by UALCAN. Evaluation of the effect of hub genes on survival was performed using Kaplan-Meier plotter. Hub genes were imported into the DGIdb to obtain the potential for BC chemotherapy-associated treatment drugs. The previous workflow was then applied/validated to an Illumina high-throughput RNA sequencing of 50 Luminal B cases (HER2+ and HER2-) of Hispanic/Latino patients. Results: 490 DEGs were obtained from the intersection of five public databases. Pathway enrichment analysis revealed DEGs were associated with cell cycle, estrogen response, adaptive immune response, and regulation of kinase activity, among others. Thirty-two hub genes were identified from PPI network analysis with high degree nodes and betweennesscentrality. Significant differential expression of hub genes between BC tissue and normal tissues was observed in UALCAN. These genes were significantly associated with survival probability. Fifteen potential targeted therapeutic drugs were identified through DGIdb database. Validation workflow in independent Luminal B cohort showed 238 DEGs, 90 hub genes with high degree and enrichment in the regulation of hormone levels, cellular response to EGFR, signaling by ERBB2 and MAPK. GATA3 was the hub gene found in both databases and the validation set. Both databases and validation set show hub genes, enriched pathways, and drugs that indicate their close association with tumorigenesis and would contribute to acting an important role in therapy response prediction. Conclusions: This workflow was created using public databases and applied to a patient’s cohort of different ancestries. This methodology can successfully provide potential biomarkers that correlate with therapy response. Genes were selected from PPI network. Most of them were independent biomarkers of BC treatment response, including that in underrepresented patients. Moreover, these genes may exert critical function in non-response and progression. Citation Format: Hedda Michelle Guevara-Nieto, Rafael Parra-Medina, Juan C. Mejia-Henao, Patricia López-Correa, Sandra Diaz, Jone Garai, Jovanny Zabaleta, Liliana López-Kleine, Alba L. Combita. Integrative transcriptomic analysis and cohort validation identify key genes in chemotherapy treatment response in Latino breast cancer patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-40.</jats:p

Missense and loss-of-function variants at GWAS loci in familial Alzheimer's disease

Few rare variants have been identified in genetic loci from genome-wide association studies (GWAS) of Alzheimer's disease (AD), limiting understanding of mechanisms, risk assessment, and genetic counseling.BACKGROUNDFew rare variants have been identified in genetic loci from genome-wide association studies (GWAS) of Alzheimer's disease (AD), limiting understanding of mechanisms, risk assessment, and genetic counseling.Using genome sequencing data from 197 families in the National Institute on Aging Alzheimer's Disease Family Based Study and 214 Caribbean Hispanic families, we searched for rare coding variants within known GWAS loci from the largest published study.METHODSUsing genome sequencing data from 197 families in the National Institute on Aging Alzheimer's Disease Family Based Study and 214 Caribbean Hispanic families, we searched for rare coding variants within known GWAS loci from the largest published study.Eighty-six rare missense or loss-of-function (LoF) variants completely segregated in 17.5% of families, but in 91 (22.1%) families Apolipoprotein E (APOE)- 4 was the only variant segregating. However, in 60.3% of families, APOE 4, missense, and LoF variants were not found within the GWAS loci.RESULTSEighty-six rare missense or loss-of-function (LoF) variants completely segregated in 17.5% of families, but in 91 (22.1%) families Apolipoprotein E (APOE)- 4 was the only variant segregating. However, in 60.3% of families, APOE 4, missense, and LoF variants were not found within the GWAS loci.Although APOE 4and several rare variants were found to segregate in both family datasets, many families had no variant accounting for their disease. This suggests that familial AD may be the result of unidentified rare variants.DISCUSSIONAlthough APOE 4and several rare variants were found to segregate in both family datasets, many families had no variant accounting for their disease. This suggests that familial AD may be the result of unidentified rare variants.Rare coding variants from GWAS loci segregate in familial Alzheimer's disease. Missense or loss of function variants were found segregating in nearly 7% of families. APOE- 4 was the only segregating variant in 29.7% in familial Alzheimer's disease. In Hispanic and non-Hispanic families, different variants were found in segregating genes. No coding variants were found segregating in many Hispanic and non-Hispanic families.HIGHLIGHTSRare coding variants from GWAS loci segregate in familial Alzheimer's disease. Missense or loss of function variants were found segregating in nearly 7% of families. APOE- 4 was the only segregating variant in 29.7% in familial Alzheimer's disease. In Hispanic and non-Hispanic families, different variants were found in segregating genes. No coding variants were found segregating in many Hispanic and non-Hispanic families

Understanding the neuroprotective effect of tranexamic acid: an exploratory analysis of the CRASH-3 randomised trial

Background: The CRASH-3 trial hypothesised that timely tranexamic acid (TXA) treatment might reduce deaths from intracranial bleeding after traumatic brain injury (TBI). To explore the mechanism of action of TXA in TBI, we examined the timing of its effect on death. Methods: The CRASH-3 trial randomised 9202 patients within 3 h of injury with a GCS score ≤ 12 or intracranial bleeding on CT scan and no significant extracranial bleeding to receive TXA or placebo. We conducted an exploratory analysis of the effects of TXA on all-cause mortality within 24 h of injury and within 28 days, excluding patients with a GCS score of 3 or bilateral unreactive pupils, stratified by severity and country income. We pool data from the CRASH-2 and CRASH-3 trials in a one-step fixed effects individual patient data meta-analysis. Results: There were 7637 patients for analysis after excluding patients with a GCS score of 3 or bilateral unreactive pupils. Of 1112 deaths, 23.3% were within 24 h of injury (early deaths). The risk of early death was reduced with TXA (112 (2.9%) TXA group vs 147 (3.9%) placebo group; risk ratio [RR] RR 0.74, 95% CI 0.58–0.94). There was no evidence of heterogeneity by severity (p = 0.64) or country income (p = 0.68). The risk of death beyond 24 h of injury was similar in the TXA and placebo groups (432 (11.5%) TXA group vs 421 (11.7%) placebo group; RR 0.98, 95% CI 0.69–1.12). The risk of death at 28 days was 14.0% in the TXA group versus 15.1% in the placebo group (544 vs 568 events; RR 0.93, 95% CI 0.83–1.03). When the CRASH-2 and CRASH-3 trial data were pooled, TXA reduced early death (RR 0.78, 95% CI 0.70–0.87) and death within 28 days (RR 0.88, 95% CI 0.82–0.94). Conclusions: Tranexamic acid reduces early deaths in non-moribund TBI patients regardless of TBI severity or country income. The effect of tranexamic acid in patients with isolated TBI is similar to that in polytrauma. Treatment is safe and even severely injured patients appear to benefit when treated soon after injury. Trial registration: ISRCTN15088122, registered on 19 July 2011; NCT01402882, registered on 26 July 2011