ObjectivesTo evaluate the ability of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase (UCH-L1) to detect concussion in children and adult trauma patients with a normal mental status and assess biomarker concentrations over time as gradients of injury in concussive and non-concussive head and body trauma.DesignLarge prospective cohort study.SettingThree level I trauma centres in the USA.ParticipantsPaediatric and adult trauma patients of all ages, with and without head trauma, presenting with a normal mental status (Glasgow Coma Scale score of 15) within 4 hours of injury. Rigorous screening for concussive symptoms was conducted. Of 3462 trauma patients screened, 751 were enrolled and 712 had biomarker data. Repeated blood sampling was conducted at 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 and 180 hours postinjury in adults.Main outcomesDetection of concussion and gradients of injury in children versus adults by comparing three groups of patients: (1) those with concussion; (2) those with head trauma without overt signs of concussion (non-concussive head trauma controls) and (3) those with peripheral (body) trauma without head trauma or concussion (non-concussive body trauma controls).ResultsA total of 1904 samples from 712 trauma patients were analysed. Within 4 hours of injury, there were incremental increases in levels of both GFAP and UCH-L1 from non-concussive body trauma (lowest), to mild elevations in non-concussive head trauma, to highest levels in patients with concussion. In concussion patients, GFAP concentrations were significantly higher compared with body trauma controls (p<0.001) and with head trauma controls (p<0.001) in both children and adults, after controlling for multiple comparisons. However, for UCH-L1, there were no significant differences between concussion patients and head trauma controls (p=0.894) and between body trauma and head trauma controls in children. The AUC for initial GFAP levels to detect concussion was 0.80 (0.73–0.87) in children and 0.76 (0.71–0.80) in adults. This differed significantly from UCH-L1 with AUCs of 0.62 (0.53–0.72) in children and 0.69 (0.64–0.74) in adults.ConclusionsIn a cohort of trauma patients with normal mental status, GFAP outperformed UCH-L1 in detecting concussion in both children and adults. Blood levels of GFAP and UCH-L1 showed incremental elevations across three injury groups: from non-concussive body trauma, to non-concussive head trauma, to concussion. However, UCH-L1 was expressed at much higher levels than GFAP in those with non-concussive trauma, particularly in children. Elevations in both biomarkers in patients with non-concussive head trauma may be reflective of a subconcussive brain injury. This will require further study.
In adults, glial fibrillary acidic protein (GFAP) has been shown to out-perform S100b in detecting intracranial lesions on computed tomography (CT) in mild traumatic brain injury (TBI). This study examined the ability of GFAP and S100b to detect intracranial lesions on CT in children and youth involved in trauma. This prospective cohort study enrolled a convenience sample of children and youth at two pediatric and one adult Level 1 trauma centers following trauma, including both those with and without head trauma. Serum samples were obtained within 6 h of injury. The primary outcome was the presence of traumatic intracranial lesions on CT scan. There were 155 pediatric trauma patients enrolled, 114 (74%) had head trauma and 41 (26%) had no head trauma. Out of the 92 patients who had a head CT, eight (9%) had intracranial lesions. The area under the receiver operating characteristic curve (AUC) for distinguishing head trauma from no head trauma for GFAP was 0.84 (0.77-0.91) and for S100b was 0.64 (0.55-0.74; p < 0.001). Similarly, the AUC for predicting intracranial lesions on CT for GFAP was 0.85 (0.72-0.98) versus 0.67 (0.50-0.85) for S100b ( p = 0.013). Additionally, we assessed the performance of GFAP and S100b in predicting intracranial lesions in children ages 10 years or younger and found the AUC for GFAP was 0.96 (95% confidence interval [CI] 0.86-1.00) and for S100b was 0.72 (0.36-1.00). In children younger than 5 years old, the AUC for GFAP was 1.00 (95% CI 0.99-1.00) and for S100b 0.62 (0.15-1.00). In this population with mild TBI, GFAP out-performed S100b in detecting head trauma and predicting intracranial lesions on head CT. This study is among the first published to date to prospectively compare these two biomarkers in children and youth with mild TBI.
Objectives This study examined the performance of serum glial fibrillary acidic protein (GFAP) in detecting traumatic intracranial lesions on computed tomography (CT) scan in children and youth with mild and moderate traumatic brain injury (TBI), and assessed its performance in trauma control patients without head trauma. Methods This prospective cohort study enrolled children and youth presenting to three Level I trauma centers following blunt head trauma with Glasgow Coma Scale (GCS) scores of 9 to 15, as well as trauma control patients with GCS scores of 15 who did not have blunt head trauma. The primary outcome measure was the presence of intracranial lesions on initial CT scan. Blood samples were obtained in all patients within six hours of injury and measured by ELISA for GFAP (ng/ml). Results A total of 257 children and youth were enrolled in the study and had serum samples drawn within 6 hours of injury for analysis: 197 had blunt head trauma and 60 were trauma controls. CT scan of the head was performed in 152 patients and traumatic intracranial lesions on CT scan were evident in 18 (11%), all of whom had GCS scores of 13 to 15. When serum levels of GFAP were compared in children and youth with traumatic intracranial lesions on CT scan to those without CT lesions, median GFAP levels were significantly higher in those with intracranial lesions (1.01, IQR 0.59 to 1.48) than those without lesions (0.18, IQR 0.06 to 0.47). The area under the receiver operating characteristic (ROC) curve (AUC) for GFAP in detecting children and youth with traumatic intracranial lesions on CT was 0.82 (95% CI = 0.71 to 0.93). In those presenting with GCS scores of 15, the AUC for detecting lesions was 0.80 (95% CI = 0.68 to 0.92). Similarly, in children under five years old the AUC was 0.83 (95% CI = 0.56 to 1.00). Performance for detecting intracranial lesions at a GFAP cutoff level of 0.15 ng/ml yielded a sensitivity of 94%, a specificity of 47%, and a negative predictive value of 98%. Conclusions In children and youth of all ages, GFAP measured within 6 hours of injury was associated with traumatic intracranial lesions on CT and with severity of TBI. Further study is required to validate these findings before clinical application.
This study examined the performance of serum ubiquitin C-terminal hydrolase (UCH-L1) in detecting traumatic intracranial lesions on computed tomography (CT) scan (+CT) in children and youth with mild and moderate TBI (mmTBI) and assessed its performance in trauma control patients without head trauma. This prospective cohort study enrolled children and youth presenting to three level 1 trauma centers after blunt head trauma and a Glasgow Coma Scale (GCS) score of 9-15 as well as trauma control patients with GCS 15 that did not have blunt head trauma. The primary outcome measure was the presence of intracranial lesions on initial CT scan. Blood samples were obtained in all patients within 6 h of injury and measured by enzyme-linked immunosorbent assay ELISA for UCH-L1 (ng/mL). A total of 256 children and youth were enrolled in the study and had serum samples drawn within 6 h of injury for analysis; 196 had blunt head trauma and 60 were trauma controls. CT scan of the head was performed in 151 patients and traumatic intracranial lesions on CT scan were evident in 17 (11%), all of whom had a GCS of 13-15. The area under the receiver operating characteristic curve (AUC) for UCH-L1 in detecting children and youth with traumatic intracranial lesions on CT was 0.83 (95% confidence interval [CI], 0.73-0.93). In those presenting with a GCS of 15, the AUC for detecting lesions was 0.83 (95% CI, 0.72-0.94). Similarly, in children under 5 years of age, the AUC was 0.79 (95% CI, 0.59-1.00). Performance for detecting intracranial lesions at a UCH-L1 cut-off level of 0.18 ng/mL yielded a sensitivity of 100%, a specificity of 47%, and a negative predictive value of 100%. UCH-L1 showed good performance in infants and toddlers younger than 5 years and performed well in children and youth with a GCS score of 15. Before clinical application, further study in larger cohort of children and youth with mild TBI is warranted.
Introduction The Gleason score is a strong prognostic factor for treatment failure in pathologically organ-confined prostate cancer (pT2) treated by radical prostatectomy (RP). However, within each Gleason score, there is clinical heterogeneity with respect to treatment outcome, even in patients with the same pathological stage and prostate-specific antigen (PSA) at diagnosis. This may be due to minimal residual disease (MRD) remaining after surgery. We hypothesise that the sub-type of MRD determines the risk of and timing of treatment failure, is a biological classification, and may explain in part clinical heterogeneity. We present a study of pT2 patients treated with RP, the subtypes of MRD for each Gleason score and clinical outcomes. Patients and methods Patients with Gleason ≤6 (G6) or Gleason 7 (G7) pT2 cancer participated in the study. One month after surgery, blood was taken for circulating prostate cell (CPCs); mononuclear cells were obtained by differential gel centrifugation and identified using immunocytochemistry with anti-PSA. The detection of one CPC/sample was defined as a positive test. Touch-preparations from bone-marrow biopsies were used to detect micro-metastasis using immunocytochemistry with anti-PSA. Biochemical failure was defined as a PSA >0.2 ng/mL. Patients were classified as: Group A MRD negative (CPC and micro-metastasis negative), Group B (only micro-metastasis positive) and Group C (CPC positive). Biochemical failure-free survival (BFFS) using Kaplan–Meier and time to failure using Restricted Mean Survival Time (RMST) after 10 years of follow-up were calculated for each group based on the Gleason score. Results Of a cohort of 253 men, four were excluded for having Gleason 8 or 9 prostate cancer, leaving a study group of 249 men of whom 52 had G7 prostate cancer. G7 patients had a higher frequency of MRD (69% versus 36%) and worse prognosis. G6 and G7 patients negative for MRD had similar BBFS rates, 98% at 10 years, time to failure 9.9 years. Group C, G6 patients had a higher BFFS and longer time to failure compared to G7 patients (19% versus 5% and 7 versus 3 years). Group B showed similar results up to 5 years, thereafter G6 had a lower BFFS 63% versus 90%. Conclusions G7 and G6 pT2 patients have different patterns of MRD and relapse. Risk stratification using MRD sub-types may help to define the need for adjuvant therapy. This needs confirmation with large randomised long-term trials.
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